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2014

1st September 2014, maytansine


First isolated in 1972 from the African plant Maytenus ovatus, later named Maytenus serrata, by Professor S. Morris Kupchan and co-workers at the University of Virginia using bioassay-guided methods, the 19-membered macrolactam maytansine (CHEBI:6701) was found to combine broad spectrum antitumour activity with extraordinarily high potency [1]. However, it took a further five years before a more efficient isolation procedure was developed using M. buchananii and sufficient quantities of maytansine became available to enable clinical trials to proceed. In the meantime, with funding particularly from the US National Cancer Institute, a number of closely related compounds known as 'maytansinoids' were isolated from members of the bittersweet (Celastraceae), buckthorn (Rhamnaceae), and spurge (Euphorbiaceae) plant families. Unfortunately, early hopes that maytansine or maytansinoids could be readily developed into a clinically useful anticancer drug were dashed by disappointing Phase II clinical trials, probably a result of the dose-limiting cytotoxicity of the maytansinoids in humans.

What was required was a means to selectively deliver the cytotoxic maytansinoid to the tumour cells, leaving healthy cells alone. This is the idea behind antibody-drug conjugates: a cytotoxic drug is joined to an antibody that specifically targets a certain marker in the tumour – such as a protein which, ideally, is only found in tumour cells. The antibodies bind to the tumour cells and in so doing trigger the tumour cell to absorb the antibody and its attached cytotoxin. Once inside the tumour cell, the cytotoxin is released, causing the death of the cell. Since healthy cells are largely spared the effects of the toxin, the side effects commonly associated with traditional chemotherapy such as hair loss, nausea, and fatigue should also be reduced.

In one approach to finding a suitable maytansinoid-antibody conjugate, Genentech, a subsidiary of Roche since 2009, chose the monoclonal antibody trastuzumab (brand names Herclon and Herceptin), which binds to the HER2/neu receptor, an important biomarker for around 20-30% of breast cancer patients [2]. To complete the conjugate, Genentech attached the maytansinoid mertansine to the antibody. The resulting conjugate, trastuzumab emtansine (also known as ado-trastuzumab emtansine; brand name Kadcyla) attacks breast cancer in two ways. The trastuzumab stops the cancer cells from overexpressing the HER2 protein, stopping them from growing and spreading, while the attached cytotoxic mertansine fragment kills the cancerous cells. Trials found that, although trastuzumab emtansine was not a cure, it could help control the disease: the median overall survival time of women with HER2-positive breast cancer who were already resistant to trastuzumab alone was almost 6 months longer using trastuzumab emtansine than the previous best treatment [3] and the US Food and Drug Administration approved trastuzumab emtansine for the treatment of HER2-positive advanced breast cancer (i.e. cancer that has spread to other parts of the body, cannot be surgically removed and has stopped responding to initial treatment) in February 2013 [4].

The improved outcome for HER2-positive breast cancer patients comes at a price, however. Excluding VAT and administration costs, a course of treatment of trastuzumab emtansine for an average period of 14.5 months for a typical patient (70.1 kg; weekly dose 3.6 mg/kg) would cost over £90,000 - many times that of current treatments [5]. In the UK, an estimated 8,300 women and 60 men are diagnosed with HER2-positive breast cancer each year [5], so the cost to the National Health Service of the trastuzumab emtansine treatment would be substantial. The question is, could these costs be justified by the benefits of the improved outcomes? The National Institute for Health and Care Excellence (NICE) is charged with the task of determining whether new treatments, procedures, diagnostic agents, etc., represent value for money. In general, NICE will not recommend a treatment as cost-effective unless it costs less than £30,000 per quality-adjusted life year (QALY). The QALY value of trastuzumab emtansine was estimated to be around £166,000. Even though Roche proposed a discount to the full list price of the drug, it was not sufficient to affect the outcome. Last month, the NICE Appraisal Committee submitted their final determination to the Institute, recommending rejection of the drug [6]. It follows a similar decision from Ireland's equivalent pricing body, the National Centre for Pharmacoeconomics (NCPE Ireland), in June [7]. While Roche have complained about the way in which cancer drugs are appraised, pointing out that NICE have rejected the last eight breast cancer drugs in a row, it seems unlikely that the funding formula is going to be overhauled anytime soon.

The background image is a detail from a Creative Commons licensed depiction of an antibody, such as trastuzumab, blocking a receptor, such as the HER2/neu receptor, on the surface of a cancer cell, so preventing cell signalling.

Reference(s)

    1. Kupchan, S.M., Komoda, Y., Court, W.A., Thomas, G.J., Smith, R.M., Karim, A., Glimore, C.J., Hartiwanger, R.C.,and Bryan, R.F. (1972) Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J. Am. Chem. Soc., 94(4), 1354–1356.
    2. Mitri, Z., Constantine, T. and O’Regan, R. (2012) The HER2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy. Chemother. Res. Pract., 743193.
    3. Verma, S., Miles, D., Gianni, L., Krop, I.E., Welslau, M., Baselga, J., Pegram, M., Oh, D.-Y., Diéras, V., Guardino, E., Fang, L., Lu, M.W., Olsen, S. and Blackwell, K. (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. New Engl. J. Med., 367(19), 1783–1791.
    4. FDA approves new treatment for late-stage breast cancer (FDA press release), February 22, 2013.
    5. Kadcyla: NICE disappointed by manufacturer’s decision (NICE press release), August 7, 2014.
    6. Final appraisal determination - trastuzumab emtansine for treating HER2-positive, unresectable locally advanced or metastatic breast cancer after treatment with trastuzumab and a taxane. National Institute for Health and Care Excellence, August 2014.
    7. Trastuzumab emtansine summary National Centre for Pharmacoeconomics, June 30, 2014.

4th August 2014, psilocybin


Psilocybin (CHEBI:8614) is the active ingredient in more than 200 species of mushrooms, collectively known as psilocybin mushrooms, psychedelic mushrooms or magic mushrooms, that have long been widely used for their hallucinogenic properties. A prodrug, it is rapidly converted by the body to the active metabolite psilocin which has mind-altering effects that are similar (in some aspects) to those observed with other hallucinogenics such as lysergic acid diethylamide (LSD) and mescaline. Although these compounds are non-addictive, prolonged usage and overdose can lead to brain damage and reactions such as anxiety, paranoia and delusions. However, scientists have been unsure as to exactly what happens to the brain when under the influence of psychedelic drugs.

Now, a team of researchers led by Enzo Tagliazucchi at Goethe University Frankfurt have found that psilocybin induces changes in the brain that are similar to those that occur during dreams [1]. The researchers injected 15 volunteers with liquid psilocybin while they were lying in a functional magnetic resonance imaging (fMRI) scanner and compared the scans with images taken when the same people were given a placebo. This revealed that while under influence of the drug, there was increased activity in the hippocampus and anterior cingulate cortex. These areas of the brain are involved in emotions and the formation of memories, and were among the first to evolve. The team also observed decreased activity in the more recently evolved regions of the brain associated with self-control and higher thinking, such as the thalamus, posterior cingulate and medial prefrontal cortex. This activation pattern is similar to that observed when someone is dreaming. The researchers now intend to utilise their findings to explore the potential use of hallucinogens for treatment of depression.

The background image is a Creative Commons licensed picture of Psilocybe weilii.

Reference(s)

    1. Tagliazucchi, E., Carhart-Harris, R., Leech, R., Nutt, D. and Chialvo, D.R. (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Hum. Brain Mapp., DOI: 10.1002/hbm.22562, published online 2 July 2014.

7th July 2014, Tetrodotoxin


Tetrodotoxin (CHEBI:9506), commonly abbreviated to TTX, is a low molecular weight neurotoxin characteristically distributed in both terrestrial and marine animal kingdoms [1]. It derives its name from Tetraodontiformes (tetras-four and odontos-tooth), an order that includes pufferfish, porcupinefish, ocean sunfish and several other such species in which the toxin is found. TTX is generally present in the gonads, liver, intestines and skin of these species, the amount fluctuating according to the species, region and seasonal variations [2]. Although TTX is found in these fish and other animals (e.g. gastropods, newts, blue-ringed octopuses etc.), studies have revealed that it is actually synthesised by endo-symbiotic bacteria (e.g. Pseudoalteromonas tetraodonis, certain species of Pseudomonas and Vibrio, etc.) that naturally inhabit the gut of the animal. It has been proposed that the animal initially acquires the TTX-producing bacteria via the food web [3].

Tetrodotoxin poisoning has been primarily attributed to the consumption of puffer fish, a culinary delicacy in Japan and other regions along the coast of Asia that is locally known as fugu [4]. The toxin is thermally stable and cannot be destroyed by cooking or storage under freezing temperatures. On ingestion, it blocks the voltage-gated sodium channel, thus inhibiting the production and propagation of action potentials, mainly in skeletal muscles, neurons and nerve fibres [5]. Clinical manifestations of tetrodotoxication (puffer fish poisoning) include shortness of breath, numbness, tingling, light-headedness, paralysis, irregular heartbeat and eventual death. TTX is several times more potent than cyanide: the lethal dose in humans is just 2-3 mg. When taken in near-lethal doses, it leaves the person in a state of impending death; it is colloquially known as "zombie powder", particularly in the voodoo and Haitian cultures. British explorer, Captain James Cook was the first person to record TTX poisoning in 1774 after an incident of ingestion of puffer fish liver near Polynesian islands. Amusingly, Ian Fleming, best known for his James Bond series of spy novels, also appeared to have a special attraction for TTX as it features in two of his novels – From Russia, with Love and Dr. No – as a chemical used for an assassination attempt on the MI6 agent [6].

In the 1890s, D. Takahashi, the first professor of pharmacology at the University of Tokyo, worked towards the pharmacological characterisation and identification of the toxic principle from puffer fish. However, it was not until 1909 that the Japanese scientist Dr. Yoshizumi Tahara isolated the purified toxin from the ovaries of the pufferfish and coined the name “tetrodotoxin” [7]. The chemical structure of TTX wasn't finally solved until 1964, when three independent studies led by the great American synthetic organic chemist Robert Burns Woodward [8] at Harvard, Prof. Toshio Goto of the Chemical Institute of Nagoya University [9] and Prof. Kyosuke Tsuda of the Institute of Applied Microbiology (now the Institute of Molecular and Cellular Biosciences) at the University of Tokyo [10] each published the correct structure.

Recently, a research group led by Amber Stokes from California State University, Bakersfield, California, has established the occurrence of the neurotoxin TTX for the first time in terrestrial invertebrates. The group found that two terrestrial flatworm species, Bipalium adventitium and Bipalium kewense, use TTX in predation to immobilise their prey [11]. However, little knowledge is currently available regarding the production or acquisition of the toxin in the tissues of the organisms.

The background image is a Creative Commons licensed picture of a puffer fish, Arothron hispidus, at the Big Island of Hawaii.

Reference(s)

    1. Yasumoto, T., Nagai, H., Yasumura, D., Michishita, T., Endo, A., Yotsu, M. and Kotaki, Y. (1986) Interspecies distribution and possible origin of tetrodotoxin. Ann. N. Y. Acad. Sci., 479, 44–51.
    2. Deeds, J. (2012) Tetrodotoxin, in Bad Bug Book. Foodborne Pathogenic Microorganisms and Natural Toxins. Second Edition., 211–217. Food and Drug Administration
    3. Bane, V., Lehane, M., Dikshit, M., O’Riordan, A. and Furey, A. (2014) Tetrodotoxin: chemistry, toxicity, source, distribution and detection. Toxin, 6(2), 693–755.
    4. Kheifets, J., Rozhavsky, B., Girsh Solomonovich, Z., Marianna, R. and Soroksky, A. (2012) Severe tetrodotoxin poisoning after consumption of Lagocephalus sceleratus (Pufferfish, Fugu) fished in Mediterranean sea, treated with cholinesterase Inhibitor. Case Rep. Crit. Care, 2012, 782507.
    5. Moczydlowski, E.G. (2013) The molecular mystique of tetrodotoxin. Toxicon, 63, 165–183.
    6. Moore, J.W. and Narahashi, T. (1967) Tetrodotoxin's highly selective blockage of an ionic channel. Fed. Proc., 26(6), 1655–1663.
    7. Suehiro, M. (1994) Historical review on chemical and medical studies of globefish toxin before World War II. Yakushigaku Zasshi, 29(3), 428–434.
    8. Woodward, R.B. (1964) The structure of tetrodotoxin. Pure Appl. Chem., 9(1), 49–74.
    9. Goto, T., Kishi, Y., Takahashi, S. and Hirata, Y. (1965) Tetrodotoxin. Tetrahedron, 21(8), 2059–2088.
    10. Tsuda, K., Ikuma, S., Kawamura, M., Tachikawa, R. and Sakai, K. (1964) Tetrodotoxin. VII. On the structure of tetrodotoxin and its derivatives. Chem. Pharm. Bull., 12(11), 1357–1374.
    11. Stokes A.N., Ducey, P.K., Neuman-Lee, L., Hanifin, C.T., French, S.S., Pfrender, M.E., Brodie, E.D.3rd and Brodie, E.D.Jr. (2014) Confirmation and distribution of tetrodotoxin for the first time in terrestrial invertebrates: two terrestrial flatworm species (Bipalium adventitium and Bipalium kewense). PLoS One, 9(6), e100718.

2nd June 2014, Vitamin E


At the University of California, Berkeley in 1922, the pioneering histologist and medical researcher Katharine Scott Bishop (1889–1975) and the anatomist and endocrinologist Herbert McLean Evans (1882–1971) found that rats did not reproduce if they were fed a semi-synthetic purified diet in which lard was the sole source of fat, but that this fertility defect was corrected by a 'substance X' present in lipid extracts of various grains [1]. The essential dietary component required to prevent such fertility defects is known today as vitamin E (CHEBI:33234), a term which covers four tocopherols (named from the Greek tokos, birth, and pherein, to bear or carry, so meaning 'to carry a pregnancy') and four tocotrienols. Both groups are based on a chroman-6-ol skeleton which is substituted by a hydrocarbon chain at position 2, and are designated as α-, β-, γ-, and δ- depending on the number and position of methyl groups attached to the aromatic ring. The most active compound is (+)-α-tocopherol. First isolated in a pure form in 1935 by Gladys Anderson Emerson (1903–1984), its structure was elucidated by Erhard Fernholz (1909–1940) at Princeton in 1938 [2]; the first synthesis was published later that year by the Swiss organic chemist and Nobel Prize winner Paul Karrer (1889–1971) and his team [3,4].

Found particularly in olive and sunflower oils, α-tocopherol is the main source of vitamin E in the European diet and in dietary supplements. However, a higher intake of rapeseed (canola), soya bean (soybean) and maize (corn) oils means that in the American diet, the most common form is γ-tocopherol. The two forms differ by only one methyl group, but that is sufficient to confer distinct biological properties on each form. Thus while both forms correct the birth defect studied by Bishop and Evans, and both have a relatively similar capacity to scavenge reactive oxygen species [5,6], γ-tocopherol also reacts with reactive nitrogen species, whereas α-tocopherol does not [7].

At the Division of Allergy and Immunology of the Feinberg School of Medicine at Northwestern University in Chicago, a group led by Associate Professor Joan Cook-Mills has previously shown that, in mice, α-tocopherol supplementation reduces the symptoms of eosinophilic lung inflammation and airway hyperresponsiveness, whereas γ-tocopherol supplementation worsens the symptoms [8,9]. The group later found a mechanism to explain the difference – while both α- and γ-tocopherol bind to protein kinase Cα, α-tocopherol inhibits its action whereas γ-tocopherol increases its action [10].

Following a major study involving over 4,500 participants, Cook-Mills and her team have recently found that the different properties of α- and γ- tocopherol also influence human health. While consumption of α-tocopherol was associated with improved lung function, the study found that consumption of γ-tocopherol was associated with an increased incidence of lung inflammation and, possibly, asthma [11]. It is perhaps no coincidence that the rise in rates of asthma in the US over the last 40 years coincides with a switch in US diets from lard and butter to soya bean, rapeseed and maize oils (which had been thought to be healthier for the heart). The average blood plasma level of γ-tocopherol in the US is more than four times that in southern European and Scandinavian countries where sunflower and olive oils are consumed, and where asthma rates are significantly lower.

The image is a Creative Commons licensed picture of Katharine Scott Bishop, who co-discovered vitamin E with Herbert Evans.

Reference(s)

    1. Evans, H.M. and Bishop, K.S. (1922) On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science (Washington, DC, U. S.), 56(1458), 650–651.
    2. Fernholz, E. (1938) On the constitution of α-tocopherol. J. Am. Chem. Soc., 60(3), 700–705.
    3. Karrer, P., Fritzsche, H., Ringier, B.H. and Salomon, H. (1938) α-Tocopherol. Helv. Chim. Acta, 21(1), 520–525.
    4. Karrer, P., Fritzsche, H., Ringier, B.H. and Salomon, H. (1938) Synthese des α-Tocopherols. Helv. Chim. Acta, 21(1), 820–825.
    5. Yoshida, Y., Saito, Y., Jones, L.S. and Shigeri, Y. (2007) Chemical reactivities and physical effects in comparison between tocopherols and tocotrienols: physiological significance and prospects as antioxidants. J. Biosci. Bioeng., 104(6), 439–445.
    6. Nishio, K., Horie, M., Akazawa, Y., Sichiri, M., Iwahashi, H., Hagihara, Y., Yoshida, Y. and Niki, E. (2013) Attenuation of lipopolysaccharide (LPS)-induced cytotoxicity by tocopherols and tocotrienols. Redox Biol., 1(1), 97–103.
    7. Patel, A., Liebner, F., Netscher, T., Mereiter, K. and Rosenau, T. (2007) Vitamin E chemistry. Nitration of non-α-tocopherols: products and mechanistic considerations. J. Org. Chem., 72(17), 6504–6512.
    8. Berdnikovs, S., Abdala-Valencia, H., McCary, C., Somand, M., Cole, R., Garcia, A., Bryce, P. and Cook-Mills, J.M. (2009) Isoforms of vitamin E have opposing immunoregulatory functions during inflammation by regulating leukocyte recruitment. J. Immunol., 182(7), 4395–4405.
    9. Cook-Mills, J.M. and McCary, C.A. (2010) Isoforms of vitamin E differentially regulate inflammation. Endocr., Metab. Immune Disord.: Drug Targets, 10(4), 348–366.
    10. McCary, C.A., Yoon, Y., Panagabko, C., Cho, W., Atkinson, J. and Cook-Mills, J.M. (2012) Vitamin E isoforms directly bind PKCα and differentially regulate activation of PKCα. Biochem. J., 441(1), 189–198.
    11. Marchese, M.E., Kumar, R., Colangelo, L.A., Avila, P.C., Jacobs, D.R.Jr., Gross, M., Sood, A., Liu, K. and Cook-Mills, J.M. (2014) The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study. Respir. Res., 15, 31.

6th May 2014, 5α-androst-16-en-3-one


The role of serendipity has been a common occurrence throughout the history of scientific innovation and discovery. Examples include Alexander Fleming's accidental discovery of penicillin in 1928 and the invention of the microwave oven by Percy Spencer in 1945. Recently, John McGlone of Texas Tech University in Lubbock, who studies animal behaviour, has discovered that the pig pheromone 5α-androst-16-en-3-one (commonly known as androstenone, CHEBI:37894) can be employed to control the behaviour of unruly or over-exuberant dogs. The discovery was made when McGlone sprayed his own pet dog, which was barking excessively, with the pheromone and was intrigued when the barking suddenly stopped.

The findings were studied further by the research team [1]. Dogs were sprayed using an aerosol containing androstenone, while simultaneously exposing them to a loud noise that would normally frighten or excite them. Compared to a spray of alcohol and noise alone, the androstenone was found to be much more effective at calming the dogs. In a second study, the dogs' heart rates were monitored and were found to be unaltered by treatment with androstenone, indicating that they were not scared or stressed. McGlone has subsequently worked with pet care company Sergeant's to develop the androstenone spray, which is now commercially available as a training tool.

Androstenone is found in boar saliva and helps induce sows to mate. In dogs, it works through the olfactory system, acting as an interomone; that is, a substance that is produced by one species but has an effect on the behaviour of a different species. As yet, it is unclear whether the effect on dogs is actually anything to do with androstenone being a pig pheromone.

The background image is a Creative Commons licensed picture showing Buster, a two-year old Lhasa Apso.

Reference(s)

    1. McGlone, J.J., Thompson, W.G. and Guay, K.A. (2014) Case Study: The pig pheromone androstenone, acting as an interomone, stops dogs from barking. Prof. Anim. Sci., 30,105–108.

7th April 2014, Dimethyl sulfide


Plant defence against herbivory defines a cascade of morphological, biochemical, and molecular alterations in plants to improve their survival and reproduction by reducing herbivore preference and performance [1]. Plant resistance against herbivores can be either constitutive (expressed irrespective of the external stimuli) or induced in response to an attack by the predator. Inducible plant defence is a paradigm of phenotypic plasticity that elicits physiological or behavioural changes in the invader [2]. In turn, the impact of plant resistance on the herbivores can be either direct or indirect. The resistance factors for direct plant defence include morphological features such as thorns, spines, and prickles, trichomes [3], wax-coated cell walls, as well as secretions like gummosis or sap that trap insect predators [4]. Plants also produce toxic chemicals such as insect repellents or feeding deterrents that can adversely affect the growth and development of herbivores [5]. Indirect methods of defence include tritrophic interactions, whereby plants protect themselves by attracting natural enemies of the herbivores such as parasitoids and predators. This is mediated via a release of volatile cues, commonly known as herbivore-induced plant volatiles (HIPVs), by the plants when attacked [6].

HIPVs primarily comprise of terpenoids, fatty acid derivatives and phenylpropanoids and can be emitted either from injured plant tissues, or systematically from uninjured tissues. Also known as infochemicals, the HIPVs communicate between the infested plant and the natural carnivorous enemies of the attacking herbivores as well as neighbouring plants and different parts of the damaged plants (inter- and intra-plant signalling respectively) [7].

According to a recent paper published on the study of mutualistic interactions in the Southern Ocean by Matthew Savoca and Gabrielle A. Nevitt from Department of Neurobiology, Physiology, and Behavior at University of California, Davis, dimethyl sulfide (DMS, CHEBI:17437), widely studied in the context of regulation of the global climate (the ‘CLAW’ hypothesis – the acronym is made up from the first letter of the surnames of its proponents), mediates tritrophic interactions between phytoplankton (a group of photosynthesising microorganisms including diatoms, dinoflagellates, cyanobacteria and algae; the primary producers) and procellariiformes (an order of seabirds which include albatrosses, petrels and shearwaters; top predators) [8]. DMS, produced mainly from the algal metabolite dimethylsulfoniopropionate (DMSP) during lysis of the algal cell triggered by grazing crustaceans such as krill (primary consumers), is known to attract some species of procellariiform seabirds. These carnivorous species in turn selectively forage on krill. Additionally, the defecation by marine top predators serves as a potential source of recycled iron for the phytoplankton. The challenge now is to understand the response of such marine ecosystems to the possible extinction of marine top predators – of the 21 albatross species on the International Union for Conservation of Nature IUCN Red List, 19 are threatened and the other two are "near threatened" – and the subsequent loss of their contribution to the trace-nutrient recycling [9].

The background image is a Creative Commons licensed picture showing a Northern krill (Meganyctiphanes norvegica).

Reference(s)

    1. Cory, J.S. and Hoover, K. (2006) Plant-mediated effects in insect-pathogen interactions. Trends Ecol. Evol., 21(5), 278–286.
    2. War, A.R., Paulraj, M.G., Ahmad, T., Buhroo, A.A., Hussain, B., Ignacimuthu, S. and Sharma, H.C. (2012) Mechanisms of plant defense against insect herbivores. Plant Signaling Behav., 7(10), 1306–1320.
    3. Riddick, E.W. and Simmons, A.M. (2014) Do plant trichomes cause more harm than good to predatory insects? Pest Manage. Sci., doi: 10.1002/ps.3772, published online 1 March 2014.
    4. Skrzypek, E., Miyamoto, K., Saniewski, M. and Ueda, J. (2005) Identification of jasmonic acid and its methyl ester as gum-inducing factors in tulips. J. Plant Res., 118(1), 27–30.
    5. Ibanez, S., Gallet, C. and Després, L. (2012) Plant insecticidal toxins in ecological networks. Toxins, 4(4), 228–243.
    6. War, A.R., Sharma, H.C., Paulraj, M.G., War, M.Y. and Ignacimuthu, S. (2011) Herbivore induced plant volatiles: their role in plant defense for pest management. Plant Signaling Behav., 6(12), 1973–1978.
    7. Arimura, G., Matsui, K. and Takabayashi, J. (2009) Chemical and molecular ecology of herbivore-induced plant volatiles: proximate factors and their ultimate functions. Plant Cell Physiol., 50(5), 911–923.
    8. Savoca, M.S. and Nevitt, G.A. (2014) Evidence that dimethyl sulfide facilitates a tritrophic mutualism between marine primary producers and top predators. Proc. Natl. Acad. Sci. U. S. A., doi: 10.1073/pnas.1317120111, published online 18 March 2014.
    9. Fitzgerald, K.T. (2013) Longline fishing (how what you don't know can hurt you). Top. Companion Anim. Med., 28(4), 151–162.

3rd March 2014, 5-Hydroxymethylfurfural


5-Hydroxymethylfurfural (CHEBI:412516), commonly abbreviated to 5-HMF, was one of the compounds that was studied by Louis-Camille Maillard (1878–1936) during his investigations into the browning reaction that now bears his name [1] (although the first coherent scheme to explain the various products did not appear for another 40 years [2]). The Maillard reaction occurs during the heating of substances containing reducing_sugars, such as D-glucopyranose, and free amino groups (of amino acids or, in proteins, mainly the ε-amino group of L-lysine, but also the α-amino groups of terminal amino acids). It is of particular importance in the food industry, as its products play an important part in the aroma, taste and colour of foods prepared by baking, roasting or toasting.

Although 5-HMF is virtually absent from fresh food, it is naturally generated as a Maillard reaction product during the drying or cooking of sugar-containing food via acid-catalysed thermal dehydration of D-fructofuranose, sucrose, and, to a lesser degree, D-glucopyranose. It is estimated that in a Western diet, intakes of 5-HMF generally range between 4 and 30 mg per person per day, although individual levels can vary widely – an intake of up to 350 mg can result from beverages made from dried plums [3]. However, it is the presence of 5-HMF in sparkling wines, rather than foods, together with the potential benefits of this to the wine producers, that has recently made news.

Sparkling wines are produced by treating a blend of base wines with sugar and yeasts and allowing the resulting mixture to ferment, thereby introducing enough carbon dioxide into the wine to make it effervescent. The fermentation can be carried out either within sealed bottles (the traditional or Champenoise method, used for Champagne, Cava, Crémant and Spumante), or in steel tanks, with the product being bottled under pressure in a continuous process (the Charmat method, used for Asti, Prosecco and Sekt). Whichever method is used, and however good the resulting product, the producers cannot easily determine how long its shelf life will be. It is known that environmental factors such as temperature are very important, but measuring the degree to which a bottle of wine has aged is problematic. Wineries currently use the 'browning' of their wine as the basis of their tests. Wine browning during its ageing and storage is a result of a non-enzymatic process of oxidation and polymerisation of the phenolic compounds present in the wine: determining the wine's absorbance of light at a wavelength of 420 nm therefore provides a simple and rapid method for measuring the amount of browning that has occurred in a sample of wine. While the technique is successful with white wines, however, the grapes used in the production of many sparkling wines tend to give pale- or straw-yellow products, with the consequence that the absorbance test is not very sensitive [4].

Now a group led by Montserrat Riu-Aumatell of the Institute for Research on Nutrition and Food Safety (INSA-UB) at the University of Barcelona has found a solution to the problem. They analysed samples of six sparkling wines kept at refrigerator (4 °C), cellar (16 °C) and room (20 °C) temperature for absorbance at 420 nm, phenolic components, and 5-HMF at regular intervals over a period of two years. They found that the amount of 5-HMF gave the clearest indication as to the freshness of the wines, showing a linear increase over time at each temperature for all of the wines tested. They also noted that refrigerating sparkling wines almost entirely prevents browning. To make their results of more practical use to the wineries, the group also developed a mathematical model that allows producers to predict the shelf life of sparkling wines as a function of storage time and temperature [5].

The background image is a Creative Commons licensed picture of 1915 English magazine illustration of a lady riding a champagne cork.

Reference(s)

    1. Maillard, L.-C. (1912) Action des acides aminés sur les sucres. Formation des melanoidins par voie methodique. Compt. Rend., 154, 66–68
    2. Hodge, J.E. (1953) Dehydrated foods. Chemistry of browning reactions in model systems. J. Agric. Food Chem., 1(15), 928–943.
    3. Abraham, K., Gûrtler, R., Berg, K., Heinemeyer, G., Lampen, A. and Appel, K.E. (2011), Toxicology and risk assessment of 5-hydroxymethylfurfural in food. Mol. Nutr. Food Res., 55(5), 667–678.
    4. Serra-Cayuela, A., Aguilera-Curiel, M.A., Riu-Aumatell, M., Buxaderas, S. and López-Tamames, E. (2013) Browning during biological aging and commercial storage of Cava sparkling wine and the use of 5-HMF as a quality marker.Food Res. Int., 53(1), 226–231.
    5. Serra-Cayuela, A., Jourdes, M., Riu-Aumatell, M., Buxaderas, S., Teissedre, P.-L. and López-Tamames, E. (2014) Kinetics of browning, phenolics, and 5-hydroxymethylfurfural in commercial sparkling wines. J. Agric. Food Chem., 62(5), 1159–1166.

3rd February 2014, ω–3 fatty acid


The flesh of oily fish such as mackerel and salmon, plus the livers of white fish such as cod, are the main sources of ω–3 fatty acids (CHEBI:25681), which are known to be essential components of the human diet. The most important ones are icosapentaenoic acid (also known as eicosapentaenoic acid and most commonly abbreviated to EPA) and docosahexaenoic acid (DHA), which are thought to provide a range of benefits to human health, including lowering of cholesterol levels and reducing the risk of coronary heart disease, cancer, depression and attention-deficit hyperactivity disorder. Fish do not actually produce ω–3 fatty acids themselves. In the ocean, they accumulate them by eating smaller fish that have in turn eaten algae, the only marine organisms that produce significant quantities of EPA and DHA. Farmed fish, that have no access to these algae, are instead fed fishmeal enriched with fish oil containing EPA/DHA. However overfishing, climate change and ocean acidification have diminished global fish stocks, resulting in supplies of high quality fish oil becoming limited. Hence alternative and sustainable sources of ω–3 fatty acids are needed to relieve some of the pressure on the oceans.

One potential source has been unearthed by Professor Johnathan Napier and colleagues at Rothamsted Research in Harpenden, UK, The team have genetically modified a biofuel plant called Camelina sativa, the seeds of which are known to be rich in α-linolenic acid, a key intermediate in the biosynthesis of EPA and DHA [1]. They took seven genes from the algae that produce these fatty acids and inserted them into the genome of C. sativa. The seeds of the modified plant yielded oil that, when purified, contained around 12% EPA and 14% DHA, the same proportions as in fish oil [1]. The team anticipate that the plant oil could be available commercially within 10 years. It could then help replace the fish oil used in capsules or fed to farmed fish.

In a separate study, Rolf Müller and colleagues at Saarland University have found that certain species of myxobacteria (also known as slime bacteria after the slime they produce to aid their movement) possess the genes necessary to synthesise certain ω–3 fatty acids by employing multi-enzyme systems known as polyunsaturated fatty acid (PUFA) synthases [2]. Müller’s team has so far discovered two distinct species: Sorangium cellulosum can make linoleic acid (a key precursor for EPA and DHA) while the recently discovered genus Aetherobacter has been found to produce prolific amounts of EPA and DHA. Although both strains grow slowly and are difficult to handle, the team report that the genes can be transferred to and expressed by Myxococcus xanthus, a fast growing model strain of myxobacteria [2]. The next challenge will be to exploit or engineer this natural biosynthetic pathway to develop an economically feasible process for production of EPA and DHA.

This month's image is a Creative Commons licensed picture showing a migrating school of mackerel.

Reference(s)

    1. Ruiz-Lopez, N. Haslam, R.P., Napier, J.A. and Sayanova, O. (2014) Successful high-level accumulation of fish oil omega-3 long-chain polyunsaturated fatty acids in a transgenic oilseed crop. Plant. J., 77,198–208.
    2. Gemperlein, K., Rachid, S., Ronald O. Garcia, R.O., Wenzel, S.C. and Müller, R. (2014) Polyunsaturated fatty acid biosynthesis in myxobacteria: Different PUFA synthases and their product diversity.DOI:10.1039/C3SC53163E, published online 2 January 2014.

4th January 2014, Tannin


Tannins (CHEBI:26848) are the polyphenolic compounds of relatively high molecular weight that have the ability to form complexes with proteins and various other organic compounds [1]. Generally associated with the ripening of fruits [2] and organoleptic properties of drinks such as wine [3] and tea, tannins are the ubiquitous plant-based substances responsible for the astringent taste found in many foods and beverages.

The term "tannin" originates from the ancient practice of using extracts from trees to convert animal hide to leather, a process commonly known as tanning. This technique exploits the inherent property of the tannins to bind with various macromolecules. When applied to animal skin, tannins bind to the collagen proteins making the hide imputrescible (resistant to decay) and flexible for end use.

Tannins are the most abundant secondary metabolites found principally in the bark, leaves and immature fruits of species throughout the plant kingdom, where they play a role defending the plant against herbivores by deterrence or toxicity. Structurally, they can be classified as hydrolysable tannins (HTs) and condensed tannins (CTs, also known as proanthocyanidins). The HTs generally consist of a carbohydrate core partially or totally esterified with phenolic groups such as in gallic acid (in gallotannins) or ellagic acid (in ellagitannins). CTs, however, are polymers of flavonoid units joined together by non-hydrolysable carbon-carbon bonds.

Research on tannin-herbivore interactions has played a significant role in the field of ecology due to the possible influence of tannins on the feeding behaviour of many invertebrate and vertebrate herbivores [4]. In fact, high levels of tannins in tree leaves are commonly believed to increase the resistance of trees to insects. This has been attributed to the interference of the tannins with the digestion in the insect herbivore by inhibition of enzymes, metabolic activities of symbiotic microorganisms (rumen microbes) that contribute to digestion, or by reducing the digestibility of ingested nutrients. According to a recent theory, tannins oxidise in insects at high gut pH to form semiquinone radicals and quinones as well as other reactive oxygen species capable of causing toxicity or oxidative stress in the gut tissues [5]. In herbivorous animals, tannins are believed to decrease protein utilisation, palatability and feed intake or interfere with the various enzyme activities.

Acorns, the fruit of oak trees (genus Quercus), are particularly rich in tannins and are commonly known to be an energy source for birds such as pigeons and woodpeckers, and many rodents including mice and squirrels. In horses, cattle and sheep, the ingestion of these tannin-rich nuts can cause severe loss of appetite, tremors and eventual death due to internal bleeding resulting from kidney or stomach damage. Pigs, however, seem to flourish on an acorn-rich diet. In fact, the ancient right of pannage, whereby local people can release their domestic pigs into forests for a certain period of time each year, is intended to remove the acorn crop so protecting foraging cattle and horses. This year in the New Forest, in southern England, the wet spring followed by the hot summer produced a bumper crop of acorns, resulting in the deaths of unusually high numbers of animals: forty-seven ponies and sixteen cattle had died by late November, compared with four to six animals in a normal year. As a result, the end of this year's pannage season, as decided by the Forestry Commission following consultation with the Court of Verderers, was extended twice – initially from the first week of November to mid-December and then further to the end of December [6, 7].

The image is a Creative Commons licensed picture shows a detail of a miniature, "Harvesting acorn to feed swine", from the Queen Mary Psalter (ca. 1310–1320).

Reference(s)

    1. Huang, X.D., Liang, J.B., Tan, H.Y., Yahya, R., Long, R. and Ho, Y.W. (2011) Protein-binding affinity of Leucaena condensed tannins of differing molecular weights. J. Agric. Food Chem., 59(19), 10677–10682.
    2. Geny, L., Saucier, C., Bracco, S., Daviaud, F. and Glories, Y. (2003) Composition and cellular localization of tannins in grape seeds during maturation. J. Agric. Food Chem., 51(27), 8051–8054.
    3. Lorrain, B., Ky, I., Pechamat, L. and Teissedre, P.L. (2013) Evolution of analysis of polyphenols from grapes, wines, and extracts. Molecules, 18(1), 1076–1100.
    4. Barbehenn, R.V. and Peter Constabel, C. (2011) Tannins in plant-herbivore interactions. Phytochemistry, 72(13), 1551–1565.
    5. Barbehenn, R.V., Jaros, A., Lee, G., Mozola, C., Weir, Q. and Salminen, J.P. (2009) Hydrolyzable tannins as "quantitative defenses": limited impact against Lymantria dispar caterpillars on hybrid poplar. J. Insect Physiol., 55(4), 297–304.
    6. Acorn glut kills New Forest ponies. news.bbc.co.uk. 11 November 2013.
    7. Pannage dates - further extension. Verderers of the New Forest.



2013

2nd December 2013, Dinitrogen oxide


The history of dinitrogen oxide (CHEBI:17045) involves some of the great names of 18thand 19th Century British science. First synthesised in 1772 by Joseph Priestley, who heated iron filings with a little nitric acid and isolated the resulting gas ('phlogisticated nitrous air'), it is better known today as 'laughing gas', nitrous oxide, or simply by its formula, N2O.

In the 1790s, the English physician Thomas Beddoes, a proponent of 'pneumatic medicine', was administering various 'airs' to his patients, including oxygen, hydrogen, fixed air (carbon dioxide), and hydrocarbonate (a mixture of carbon monoxide and hydrogen). On the advice of Erasmus Darwin, the Scottish engineer James Watt called Beddoes in to treat his daughter, Jessie, who was suffering from consumption (now known as pulmonary tuberculosis) [1]. Although the treatment was unsuccessful (Jessie died, aged 15, in June 1794), Watt worked with Beddoes to publish the book 'Considerations on the Medicinal Use and on the Production of Factitious Airs' (1794), which included details of a new machine invented by Watt to produce the 'Factitious Airs' (i.e. nitrous oxide) as well as a novel 'breathing apparatus' for inhaling the gas. Watt also manufactured equipment to generate, clean and store gases for use in Beddoes' Pneumatic Institution at Hotwells in Bristol, to which Humphry Davy was appointed laboratory superintendent in 1798, aged just 19 [1].

It was due to Davy that nitrous oxide became the gas that was principally used at the Institution. He described the results of his experiments in his book 'Researches, chemical and philosophical, chiefly concerning nitrous oxide, or dephlogisticated nitrous air, and its respiration' (1800). Although he included notes on the analgesic effects of the gas (page 465) and suggested its use during surgical operations (page 556), over 40 years elapsed before attempts were made to use nitrous oxide for anaesthesia, for it was the bizarre, uncontrolled behaviour of the subjects who breathed the 'laughing gas' that attracted attention. 'Laughing gas parties' flourished among the British upper class, while Beddoes' hospital was rendered ridiculous. It was converted into a conventional hospital during a typhus outbreak in 1800 and closed in 1802; Davy left in 1801 to join Sir Joseph Banks at the newly-formed Royal Institution [1,2].

Although records of itinerant lecturers giving exhibitions of the effects of 'laughing gas' in the US date back to the 1830s, when Samuel Colt presented a show aimed at funding the patent for his revolver, it was not until 1844 that the anaesthetic properties of the gas were used for medical purposes. That it happened at all is due in no small part to the remarkable Gardner Quincy Colton (1814-1898). Born in Georgia, Vermont, the son of a weaver, he was apprenticed to a chairmaker for five years and subsequently moved to New York, making chairs there for several years. He enrolled in the Crosby Street College of Physicians and Surgeons (now Columbia University) in 1842, but left after 2 years, subsequently giving lectures on chemistry and natural philosophy. In the spring of 1844, he put on an exhibition of the properties of nitrous oxide in the Broadway Tabernacle, charging 25 cents each for tickets. Thousands of people attended – his total receipts came to $535, encouraging him to repeat his show throughout New England [3].

At a show in Hartford, Connecticut on December 10th 1844, Colton administered the gas to Samuel A. Cooley, a druggist's assistant. As Cooley subsequently danced and jumped about, he injured himself on some wooden benches on the stage. As the effect of the gas subsided, he took his seat next to a local dentist, Dr. Horace Wells, who observed that, despite having bleeding shins, Cooley did not notice any pain until the effects of the 'laughing gas' had worn off. At the end of the show, Wells discussed the matter with Colton and the following day, at Wells' office, Colton administered nitrous oxide to Wells while Dr. John B. Riggs, a neighbouring dentist, extracted one of Wells' teeth [4]. It was the first tooth ever drawn without pain. Wells subsequently used nitrous oxide anaesthesia for both dentistry and surgery, but after his death in 1848, use of nitrous oxide ceased. Its reintroduction in 1863 was due to Colton – he resumed his laughing gas exhibitions [5], through which he met and joined forces with another dentist, Joseph H. Smith of New Haven, Connecticut. By the time of Colton's death in 1898, it is estimated that he had extracted nearly a million teeth [6].

Over 200 years after Davy's experiments, nitrous oxide remains the most widely used inhalation anaesthetic in dentistry [7]. But while N2O exists naturally in the atmosphere in trace amounts (it is produced by bacteria in soils and oceans), the additional emissions resulting from human activity are now starting to cause problems. A new report by the United Nations Environment Programme (UNEP) warns that, following the adoption of the Montreal Protocol to phase out the production of CFCs and other ozone depleting substances, nitrous oxide is now the most important contributor to the loss of the ozone layer [8]. Furthermore, its ability to absorb energy combined with an average lifetime in the atmosphere of around 110 years means that it is a greenhouse gas with huge global warming potential – for a 100 year time horizon on a weight for weight basis, it is over 300 times more potent than carbon dioxide. Anthropogenic sources of nitrous oxide emissions are now the third largest climate-forcing agent, coming behind only carbon dioxide and methane. The report points out that concerted action to reduce emissions could therefore have a major impact on both the ozone layer and the rate of climate change. By far the largest single source of these emissions is agriculture, where the report recommends the more efficient use of fertilisers, minimising the loss of nitrogen to the environment during crop cultivation, and reducing food waste.

The background image is a Creative Commons licensed picture of a satirical cartoon of 1830 showing a Royal Institution lecture on pneumatics with Humphry Davy administering laughing gas while Count Rumford (who established the Royal Institution with Sir Joseph Banks) looks on.

Reference(s)

    1. Stansfield, D.A. and Stansfield, R.G. (1986) Dr. Thomas Beddoes and James Watt: preparatory work 1794-1796 for the Bristol Pneumatic Institute. Med. Hist., 30(3), 276–302.
    2. Wright, A.J. (1995) Davy comes to America: Woodhouse, Barton, and the nitrous oxide crossing. J. Clin. Anesth., 7(4), 348–355.
    3. Smith, G.B. (1991) Gardner Quincy Colton: pioneer of nitrous oxide anesthesia. Anesth. Analg., 72(6), 382–391.
    4. Haridas, R.P. (2013) Horace Wells' demonstration of nitrous oxide in Boston. Anesthesiology, 119(5), 1014–1022.
    5. Bause, G.S. (2009) Colton's laughing gas broadside. Anesthesiology, 110(3), 555.
    6. Gardner Q. Colton dead. New York Times, August 12th, 1898.
    7. Becker, D.E. and Rosenberg, M. (2008) Nitrous oxide and the inhalation anesthetics. Anesth. Prog., 55(4), 124–131.
    8. Drawing down N2O to protect climate and the ozone layer. United Nations Environment Programme, November 2013.

4th November 2013, N-[5-(1-naphthylmethyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide


Systemic fungal infections or systemic mycoses have become a major concern over the past two decades owing to an increase in the proportion of immunodeficient people such as patients suffering from AIDS or neoplastic disease, recipients of hematopoietic stem cell and organ transplants, and premature infants often resulting in high morbidity and mortality rates [1]. In contrast to these opportunistic pathogens that cause diseases only in unhealthy hosts, the dimorphic fungi, which include Candida albicans [2], Coccidioides immitis [3] and Histoplasma capsulatum [4], are capable of infecting even immunocompetent individuals.

Host cell toxicity has, however, impeded the development of antifungal agents to combat systemic mycoses. This is broadly related to the common eukaryotic nature of both the fungal pathogen and the mammalian host cell and the consequent difficulty in finding factors in the pathogen that are sufficiently distinctive from their host to be exploited as drug targets. The more commonly used clinical classes for the management of invasive mycoses include polyenes, azoles and echinocandins. The polyene amphotericin B, a bacterial metabolite, binds with the sterol components of the fungal membrane causing impairment of the membrane functions and subsequent cell death [5]. The azole antifungals such as fluconazole [6] inhibit the enzyme lanosterol 14α-demethylase involved in the synthesis of sterols, while the echinocandins, popularly known as the "penicillin of antifungals", inhibit the production of fungal cell wall glucan. Although the echinocandins are generally more effective antifungals than the polyenes and the azoles, they are ineffective against the Cryptococcus species and H. capsulatum [7].

The lung disease histoplasmosis is caused by inhaling spores of H. capsulatum. It is endemic to the Ohio and Mississippi river valleys, so giving rise to one of its alternative names Ohio valley disease. It is also known as Darling's disease after the name of its discoverer, Samuel Taylor Darling. The fungal pathogen grows as a saprobic filamentous mould in an environment associated with large amounts of bird or bat droppings. Contact with such soil can lead to a variety of clinical disorders varying from pulmonary infections that mimic symptoms of mild pneumonia to severe cases of respiratory distress syndrome in hosts exposed to large inocula of H. capsulatum [8].

In a recent phenotypic screening of a library of 3600 commercially available chemicals by Chad A. Rappleye and co-workers at The Ohio State University, a set of compounds was identified that exhibited antifungal activity against Histoplasma but which showed only low toxicity towards the host cells [9]. These compounds were based on purine analogue scaffolds and were simultaneously tested for inhibition of yeast growth and mammalian macrophage toxicity. The study identified an aminothiazole, N-[5-(1-naphthylmethyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide (CHEBI:76002), better known as 41F5, that is highly toxic to the pathogen both in vitro and within macrophages but with reduced toxicity compared with other antifungals. Currently, the target of 41F5 is unidentified; however, its origin from a purinome-focused library (i.e. a library of proteins associated with purines) [10] suggests inhibitory activity against a purine-binding or purine-utilising factor in yeast cells. Although 41F5 bears structural resemblance to the recently licensed broad-spectrum antifungal abafungin [11], the former is distinct in being fungistatic (i.e. it inhibits the growth of fungi) thus suggesting a different antifungal cellular target.

The background image is a Creative Commons licensed picture showing two tuberculate macroconida (asexual, non-motile spores) of a Jamaican isolate of Histoplasma capsulatum.

Reference(s)

    1. Low, C.Y. and Rotstein, C. (2011) Emerging fungal infections in immunocompromised patients. F1000 Med. Rep., 3(14).
    2. Cascio, A., Pantaleo, D., Corona, G., Barberi, G., Delfino, D., Romeo, O., Iaria, C. and Barberi, I . (2013) Neonatal liver abscesses associated with candidemia. Three cases and review of literature. J. Matern.-Fetal Neonat. Med., doi: 10.3109/14767058.2013.837878, published online 2 Oct 2013.
    3. Brown, J., Benedict, K., Park, B.J. and Thompson G.R. III. (2013) Coccidioidomycosis: epidemiology. Clin. Epidemiol., 5(1), 185–197.
    4. Holbrook, E.D., Edwards, J.A., Youseff, B.H. and Rappleye, C.A. (2011) Definition of the extracellular proteome of pathogenic-phase Histoplasma capsulatum. J. Proteome Res., 10(4), 1929–1943.
    5. Charbonneau, C., Fournier, I., Dufresne, S., Barwicz, J. and Tancréde, P. (2001) The interactions of amphotericin B with various sterols in relation to its possible use in anticancer therapy. Biophys. Chem., 91(2), 125–133.
    6. Ouellet, D., Bramson, C., Roman, D., Remmers, A.E., Randinitis, E., Milton, A. and Gardner, M. (2007) Effects of three cytochrome P450 inhibitors, ketoconazole, fluconazole, and paroxetine, on the pharmacokinetics of lasofoxifene. Br. J. Clin. Pharmacol., 63(1), 59–66.
    7. Maligie, M.A and Selitrennikoff, C.P. (2005) Cryptococcus neoformans resistance to echinocandins: (1,3)β-glucan synthase activity is sensitive to echinocandins. Antimicrob. Agents Chemother., 49(7), 2851–2856.
    8. Kataria, Y.P., Campbell, P.B. and Burlingham, B.T. (1981) Acute pulmonary histoplasmosis presenting as adult respiratory distress syndrome: effect of therapy on clinical and laboratory features. South. Med. J., 74(5), 534–537, 542.
    9. Edwards, J.A., Kemski, M.M. and Rappleye, C.A. (2013) Identification of an aminothiazole with antifungal activity against intracellular Histoplasma capsulatum. Antimicrob. Agents Chemother., 57(9), 4349–4359.
    10. Fadden, P., Huang, K.H., Veal, J.M., Steed, P.M., Barabasz, A.F., Foley, B., Hu, M., Partridge, J.M., Rice, J., Scott, A., et al. (2010) Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90. Chem. Biol., 17(7), 686–694.
    11. Tomillero, A. and Moral, M.A. (2010) Gateways to clinical trials. Methods Find. Exp. Clin. Pharmacol., 32(1), 47–86.

7th October 2013, Tramadol


The synthetic opioid analgesic tramadol (CHEBI:9648) was first marketed in 1977 by Grünenthal GmbH and has been used worldwide for the treatment of moderate to severe pain without any significant side-effects [1]. The drug has a wide range of additional applications, including treatment of rheumatoid arthritis, restless legs syndrome, motor neurone disease and fibromyalgia. In a recent research programme aimed at discovering natural products for use as pain relievers, a team led by Michel De Waard, a neuroscientist at the Université Joseph Fourier in Grenoble, has discovered the root bark of the African plant Nauclea latifolia to be a natural source of tramadol [2]. Although there are other previous examples of synthetic drugs that have later been found in nature, this is the first instance where the discovery has involved clinically relevant concentrations.

Commonly known as the 'African peach' or 'pin cushion tree', N. latifolia is a flowering, sub-Saharan evergreen that grows widely across Central and West Africa and has a long tradition of use by local populations to treat a wide variety of ailments including epilepsy, malaria, general pain and many infectious diseases. To uncover the source of the plant's reported pain killing effect, the researchers fractioned methanolic extracts of the plant by high performance liquid chromatography (HPLC). After testing the resulting fractions in a biological assay using live mice, the team were able to determine the structure of the active compound in the fractions with the highest analgesic potency and confirm it to be identical with tramadol [2]. Further spectroscopic and isotope ratio analyses confirmed that the compound extracted was indeed natural in origin, and not a by-product of cross-contamination. The team have developed a simplified and inexpensive process for extracting the drug and are hopeful this might be of benefit to local communities. Although synthetic tramadol is not a costly drug in most developing countries, it is still considered expensive for many African citizens.

Both synthetic and the newly discovered natural tramadol are racemic mixtures composed of equal amounts of (1R,2R)-(+)- and (1S,2S)-(–)-enantiomers. Both enantiomers are pharmacologically active with (1R,2R)-(+)-tramadol(depicted in the image) exhibiting 10-fold higher analgesic activity compared with (1S,2S)-(–)-tramadol. In addition, the racemate seems to be superior to either enantiomer alone [3]. Relatively few natural products occur as racemic mixtures (less than 1% of the metabolome of the biosphere) [2]. The research team plan to investigate the biosynthetic pathway for the formation of the racemic mixture as well as the potential to extract tramadol from the other ten species of Nauclea that are known to exist in Africa.

The background image is a Creative Commons licensed picture showing the fruit and flower of Nauclea latifolia.

Reference(s)

    1. Leppert W. (2009). Tramadol as an analgesic for mild to moderate cancer pain. Pharmacol. Rep., 61, 978–992.
    2. Boumendjel, A., Taïwe, G.S., Bum, E.N., Chabrol, T., Beney, C., Sinniger, V., Haudecoeur, R., Marcourt, L., Challal, S., Queiroz, E.F., Souard, F., Le Borgne, M., Lomberget, T., Depaulis, A., Lavaud, C., Robins, R., Wolfender, J.-L., Bonaz, B. and De Waard., M. (2013). Occurrence of the synthetic analgesic tramadol in an African medicinal plant. Angew. Chem. Int. Ed., doi:10.1002/anie.201305697, published online 6 September 2013.
    3. Grond, S., Meuser, T., Zech, D., Hennig, U. and Lehmann, K.A. (1995). Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia. Pain, 62, 313–320.

2nd September 2013, Ivermectin


The avermectin antiparasitics were discovered as a result of a collaborative agreement between Merck & Co Inc, in the US and the Kitasato Institute (now part of Kitasato University) in Japan. From a batch of 54 microbial isolates sent from the Institute to Merck in March 1974, one proved to have particularly potent anthelminthic activity – crude extracts containing unknown amounts of the unknown active principle were active when incorporated into the diet of mice at a concentration of just 3 ppm. The active components were the avermectins, while the microorganism producing them was a new species of Streptomyces which was named S. avermitilis [1]. It is extremely rare – in the following five years, Merck screened 250,000 microbial cultures for activity against either Heligmosomoides bakeri or the model roundworm C. elegans; S. avermitilis was not found in any of the samples [2].

As part of a chemical derivatisation programme, Merck found that the selective hydrogenation of the 22-23 double bond of a mixture of avermectin B1a and B1b gave a product with improved efficacy and safety characteristics. Now known as the broad-spectrum antiparasitic drug ivermectin (CHEBI:6078), it was found to be active against various nematodes occupying various segments of the intestinal tract in various species, against some extraintestinal parasites including blood-dwelling filarial microfilariae (the minute first-stage larvae), and against some internal parasites when applied externally [2]. Thanks to the development of ivermectin, there is now a real possibility that the parasitic disease onchocerciasis, the second most common infectious cause of blindness in the world, can be defeated.

Onchocerciasis affects large areas of sub-Saharan Africa as well as more isolated areas of Central and South America, and is one of only seventeen conditions now classed by the World Health Organisation (WHO) as a neglected tropical disease. In 2001, the WHO estimated that 18 million people were infected with the parasite [3]. The vectors for the disease are certain species of black fly of the genus Simulium [4], which are unusual in that they develop and breed in flowing water. Consequently, the disease is particularly prevalent in areas close to rivers, so giving rise to its alternative name, river blindness. Over 85 million people live in affected areas; in highly endemic areas, around 50% of men over the age of 40 are blind. As a consequence, large numbers of children miss out on education as they have to stay at home to act as full-time carers for parents who have become blind, while economic productivity in infected areas is greatly reduced, with vast tracts of arable land (usually the most fertile, being close to rivers) being abandoned, leaving only 'ghost villages' behind.

River blindness is caused by the bacterium Wolbachia pipientis, an endosymbiont of the parasitic roundworm Onchocerca volvulus which is transmitted to its ultimate human hosts via the bite of a female black fly that is infected by the roundworm. A black fly initially ingests microfilariae of the roundworm when it takes a blood meal from an infected human host. The microfilariae enter the gut and flight muscles of the fly and over the following week develop through the first, second, and third larval stages, whereupon they move to the fly's proboscis and into its saliva. When the black fly takes another blood meal, the larvae pass into the blood of the next human host. They then migrate to the subcutaneous tissue and undergo two more moults, forming nodules under the skin as they mature into adult worms over the next 6-12 months, whereupon they mate, after which the females will produce around 1,000 microfilariae each day. These can be found throughout the body of the human host, but preferentially reside in the skin (where they may be ingested when another black fly takes a blood meal from the human host, so continuing the cycle of infection) and the eye. When microfilariae die, surface proteins from the Wolbachia endosymbionts are released, inducing intense inflammatory immune responses and causing severe itching, depigmentation, swelling, and a loss of elasticity in the skin, together with inflammation of the cornea of the eye (keratitis). The resulting scarring slowly causes the entire cornea to become opaque, eventually leading to blindness.

Ivermectin is the drug of choice for onchocerciasis eradication programmes - it requires no refrigeration, and only needs to be administered once or twice a year. It rapidly kills the microfilariae and although it does not kill the adult worms, it does prevent the adult females from releasing microfilariae. Since the adult worms can live in their human hosts for many years, the treatment needs to be continued for the lifetime of the adult worms (up to ten years) to rid the human population of the worms and so break the cycle of infection.

Just such an eradication policy has been followed by Colombia, where the disease was restricted to the isolated riverside community of Naicioná. The Onchocerciasis Elimination Program of the Americas (OEPA), run by The Carter Center, organised the administration of ivermectin, donated by Merck, to the entire community every six months for 12 years. In 2007, it was found that the disease had stopped spreading. The drug treatment was stopped and the community was monitored for a further three years. In 2012, an international mission visited to verify that onchocerciasis was no longer present. On July 29th 2013, the WHO and the Colombian President Juan Manuel Santos officially announced that Colombia had become the first country ever to eliminate onchocerciasis. Ecuador has also completed the ivermectin treatment programme and has requested a visit from the WHO verification team, while Mexico and Guatemala (once the most affected areas of the American continent) have interrupted the cycle of the disease and suspended ivermectin treatment [5].

Although the problem of onchocerciasis in Africa is on a much greater scale to that on the American continent – 99% of those suffering from the disease live in Africa – it is thought that the methods used in Colombia will provide a useful model for combating the disease throughout the African continent.

The background image is a Creative Commons licensed picture showing an adult black fly (Simulium yahense) magnified approximately 100 times. In this remarkable image, obtained by conventional scanning electron microscopy, the parasitic roundworm Onchocerca volvulus can be seen emerging from the insect's antenna.

Reference(s)

    1. Kim, S.B. and Goodfellow, M. (2002) Streptomyces avermitilis sp. nov., nom. rev., a taxonomic home for the avermectin-producing streptomycetes. Int. J. Syst. Evol. Microbiol., 52(6), 2011–2014.
    2. Campbell, W.C. (2012) History of avermectin and ivermectin, with notes on the history of other macrocyclic lactone antiparasitic agents. Curr. Pharmaceut. Biotechnol., 13(6), 853–865.
    3. World Health Organisation (2001) http://www.who.int/water_sanitation_health/diseases/oncho/en/.
    4. Saint André, A.v., Blackwell, N.M., Hall, L.R., Hoerauf, A., Brattig, N.W., Volkmann, L., Taylor, M.J., Ford, L., Hise, A.G., Lass, J.H., Diaconu, E. and Pearlman, E. (2002) The role of endosymbiotic Wolbachia bacteria in the pathogenesis of river blindness. Science (New York, N.Y.), 295(5561), 1892–1895.
    5. Wyss, J. (2013) Colombia eradicates "river blindness," paving way for hemisphere and Africa. Miami Herald, http://www.who.int/water_sanitation_health/diseases/oncho/en/.

5th August 2013, Curcumin


Curcuma longa is a rhizomatous, herbaceous perennial member of the Zingiberaceae (ginger) family which is native to tropical South Asia. Its dried rhizome is the source of the spice turmeric, a dark yellow powder that has long been used as a flavouring and colouring agent in Indian and Middle Eastern cuisine as well as a therapeutic agent in Ayurvedic medicine for the treatment of both common ailments such as coughs, cold, cuts and burns and more serious diseases including cancer and Alzheimer's disease [1]. Among the several pharmacologically active metabolites [2] produced by the plant is curcumin (CHEBI:3962) [3], a hydrophobic polyphenol isolated from the rhizome, which has been shown to exhibit antioxidant [4], anti-inflammatory [5], antimicrobial [6], hepatoprotective [7] and anticancer [8,9] activities.

Myeloma, also known as multiple myeloma (MM), is a type of bone marrow cancer in which abnormal white blood cells accumulate in the bone marrow and so interfere in the production of normal blood cells. Recently, in an effort to develop an effective cure for human MM, a team of Chinese researchers have adopted a 'hybrid molecule' strategy which aims to achieve a synergistic effect by combining drugs with similar pharmacological roles [10]. They synthesised a series of hybrid molecules based on the structures of curcumin [11] and thalidomide, a sedative, that was used as a sleeping pill and for the treatment of morning sickness during pregnancy but later withdrawn as it inadvertently became the most notable teratogen in history [12]. However, thalidomide has recently been identified as a potential anticancer agent [13].

Subsequent biological studies conducted against a series of MM cells established that the hybrids 5-[2-(feruloyl)ethen-1-yl]thalidomide (CHEBI:74774) and 5-(2,2-diferuloylethen-1-yl)thalidomide (CHEBI:74775) exhibited considerably enhanced lethal effects against the target human MM cells as compared to the individual molecules alone. The increased activity was attributed to the production of reactive oxygen species that trigger induction of apoptosis in cancer cells causing cell death. Furthermore, the researchers found that the hybrids also displayed NF-κB inhibitory activity against human lung cancer cells. These findings suggest that the hybrid strategy in drug design can yield novel multifunctional leads with improved activity as potential candidates for treatment of human MM.

Our background image is a Creative Commons licensed picture showing different parts of the plant Curcuma longa, published in Köhler's Medicinal Plants.

Reference(s)

    1. Singh, S. (2007) From exotic spice to modern drug? Cell, 130(5), 765–768.
    2. Dr. Duke's Phytochemical and Ethnobotanical Databases.
    3. Lechtenberg, M., Quandt, B. and Nahrstedt, A. (2004) Quantitative determination of curcuminoids in Curcuma rhizomes and rapid differentiation of Curcuma domestica Val. and Curcuma xanthorrhiza Roxb. by capillary electrophoresis. Phytochem. Anal., 15(3), 152–158.
    4. Kou, M.C., Chiou, S.Y., Weng, C.Y., Wang, L., Ho, C.T. and Wu, M.J. (2013) Curcuminoids distinctly exhibit antioxidant activities and regulate expression of scavenger receptors and heme oxygenase-1. Mol. Nutr. Food Res., doi: 10.1002/mnfr.201200227, published online 5 Feb 2013.
    5. Basnet, P. and Skalko-Basnet, N. (2011) Curcumin: an anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules, 16(6), 4567–4598.
    6. De, R., Kundu, P., Swarnakar, S., Ramamurthy, T., Chowdhury, A., Nair, G.B. and Mukhopadhyay, A.K. (2009) Antimicrobial activity of curcumin against Helicobacter pylori isolates from India and during infections in mice. Antimicrob. Agents Chemother., 53(4), 1592–1597.
    7. Singh, M., Sasi, P., Gupta, V.H., Rai, G., Amarapurkar, D.N. and Wangikar, P.P. (2012) Protective effect of curcumin, silymarin and N-acetylcysteine on antitubercular drug-induced hepatotoxicity assessed in an in vitro model. Hum. Exp. Toxicol., 31(8), 788–797.
    8. Darvesh, A.S., Aggarwal, B.B. and Bishayee, A. (2012) Curcumin and liver cancer: a review. Curr. Pharm. Biotechnol., 13(1), 218–228.
    9. Ji, J.L, Huang, X.F. and Zhu, H.L. (2012) Curcumin and its formulations: potential anti-cancer agents. Anti-cancer Agents Med. Chem., 12(3), 210–218.
    10. Gediya, L.K. and Njar, V.C. (2009) Promise and challenges in drug discovery and development of hybrid anticancer drugs. Expert Opin. Drug Discovery, 4(11), 1099–1111.
    11. Liu, K., Zhang, D., Chojnacki, J., Du, Y., Fu, H., Grant, S. and Zhang, S. (2013) Design and biological characterization of hybrid compounds of curcumin and thalidomide for multiple myeloma. Org. Biomol. Chem., 11(29), 4757–4763.
    12. Ito, T., Ando, H. and Handa, H. (2011) Teratogenic effects of thalidomide: molecular mechanisms. Cell. Mol. Life Sci., 68(9), 1569–1579.
    13. Yang, G., Chen, W. and Wu, Y. (2013) Bortezomib, dexamethasone plus thalidomide for treatment of newly diagnosed multiple myeloma patients with or without renal impairment. Chin. J. Cancer Res. , 25(2), 155–160.

1st July 2013, Sulfamethazine


Since their discovery in the 1930s, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, including chlamydia, pneumonia, urinary tract infections and chronic ulcerative colitis. However, their side effects can include serious neurological problems such as nausea, headache, dizziness, hallucination and even psychosis. In addition, sulfonamide antibiotics can also cause allergic reactions ranging from various benign rashes to, in extreme cases, life-threatening Stevens-Johnson syndrome and toxic epidermal necrolysis. These side effects, along with growing bacterial resistance, have resulted in sulfonamide drugs being used much less frequently.

Despite several decades of in-depth analysis of the sulfonamide family, the actual molecular mechanics behind the side effects have not been fully understood until a recent study headed by chemical biologist Kai Johnsson of the Swiss Federal Institute of Technology in Lausanne reported a possible cause of some of the neurological effects [1]. The researchers found that the arylsulfonamide moiety, present in all sulfonamide drugs, binds with the active site of an enzyme called sepiapterin reductase (SPR; EC 1.1.1.153), resulting in its inhibition [2]. This enzyme takes part in the biosynthesis of tetrahydrobiopterin, a compound essential for production of several neurotransmitters, including serotonin and dopamine. By using cell-based assays, the researchers showed that interference with the biosynthetic pathway eventually depletes the neurotransmitters, which in turn is thought to trigger the neurological side effects [3]. In addition, it was shown that one sulfonamide drug, sulfamethazine (CHEBI:102265), which is known not to have any side effects, was also a very weak inhibitor of SPR. This was attributed to the two methyl groups present on the pyrimidine ring making it more difficult for the molecule to fit in to the active site. In contrast, the analogue lacking the two methyl groups, sulfadiazine, was shown to be 370 times more potent as an SPR inhibitor. These findings open up the possibility of redesigning sulfonamide drugs so that they don't fit into the active site of SPR, or combining existing sulfonamide drugs with supplements to replace neurotransmitter molecules lost by inhibition of SPR.

The background image is a Creative Commons licensed picture showing the interior of an old pharmacy at the Kraków Museum of Pharmacy.

Reference(s)

    1. Haruki, H., Pedersen, M.G., Gorska, K.I., Pojer, F. and Johnsson, K. (2013) Tetrahydrobiopterin biosynthesis as an off-target of sulfa drugs. Science, 340, 987–991.
    2. Chidley, C., Haruki, H., Pedersen, M.G., Muller, E. and Johnsson, K. (2011) A yeast-based screen reveals that sulfasalazine inhibits tetrahydrobiopterin biosynthesis. Nat. Chem. Biol., 7, 375–383.
    3. Friedman, J., Roze, E., Abdenur, J.E., Chang, R., Gasperini, S., Saletti, V., Wali, G.M., Eiroa, H., Neville, B., Felice, A., et al. (2012) Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann. Neurol., 71, 520–530.

3rd June 2013, GW 501516


This month's Entity of the Month is a failed drug candidate that has the rather unwieldy IUPAC name of {2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)­phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy} ­acetic acid. As the compound was never marketed, it has no brand or trade name and, as trials were stopped at an early stage, it also has no INN or US adopted name. Consequently, it is most commonly referred to in the primary literature by its research code [1], GW 501516 (CHEBI:73726), also GW 1516 and GSK-516.

GW 501516 resulted from a research collaboration between SmithKline Beecham (now GlaxoSmithKline, GSK) and Ligand Pharmaceuticals that dates back to 1992. The compound was found to be a potent agonist of peroxisome proliferator-activated receptors type β/δ (PPARβ/δ), a type of nuclear receptor protein involved in the regulation of the metabolism of carbohydrates and lipids [2,3]. GSK began Phase I trials in 2001, hoping that GW 50156 could be used to stimulate muscles to burn fats and so be used as a treatment for hyperlipidaemia (high levels of lipids in the blood, often resulting from diabetes). In a trial in rats, the compound was found to increase fatty acid metabolism in skeletal muscle and give protection against diet-induced obesity and type 2 diabetes, while in obese rhesus monkeys increased levels of HDL ('good') cholesterol and lower levels of LDL ('bad') cholesterol were observed [4]. Ligand Pharmaceuticals received a $1 million 'milestone' payment from GSK in 2003 as Phase I development continued, while Phase II trials started in 2004. However, concurrent animal safety testing showed problems [5,6] and GSK stopped all development work on GW 501516 in 2006.

GW 501516 did not disappear without trace, however. The observation that giving high doses increased the exercise endurance of mice, together with the knowledge that (a) it could be easily synthesised [7] and (b) it was not controlled by sports doping regulations, made GW 501516 a potential performance-enhancing drug for athletes. Accordingly, the World Anti-Doping Agency (WADA) added PPARβ/δ modulators to their prohibited list in January 2009, and methods for detecting the use of GW 501516 in routine doping control tests (based on identification of the corresponding sulfoxide and sulfone, its urinary metabolites) were developed [8,9]. Nevertheless, WADA recently became aware that GW 501516 was being sold on the black market, commonly under the name 'endurobol', and in March of this year took the rare step of issuing an alert, pointing out to potential users that development of GW501516 was stopped when "serious toxicities" were discovered in pre-clinical studies [10]. The first positive test for 'endurobol' came within a month, with the announcement that the European track cycling champion Valery Kaykov had been sacked by his team, RusVelo [11]; several other professional cyclists have since tested positive [12,13].

So what are the "serious toxicities" referred to in the WADA alert? The initial human testing of GW 501516 was done using very low doses for short periods of time and did not show up any serious adverse effects. In contrast, animal testing used considerably higher doses over a much longer period. Rats given from 5 up to 40 mg/kg/day over a 2-year period developed cancers "in multiple tissues at all doses". Tissues affected included the stomach, liver, bladder, skin, thyroid, tongue, testes, ovaries and womb [5]. Similarly grim results were obtained from tests with mice [6]. For those athletes doping with GW 501516, there are clearly other things to worry about than simply being caught cheating.

The background image is a Creative Commons licensed picture showing protesters with a 'Tour de Doping' banner demonstrating against the widespread use of doping by competitors in the 2006 Tour de France.

Reference(s)

    1. Overington, J.P. (2013) The ontogeny and evolution of compound names. The ChEMBL-og - Open Data For Drug Discovery, February 3.
    2. Berger, J. and Moller, D.E. (2002) The mechanisms of action of PPARs. Annu. Rev. Med., 53, 409–435.
    3. Wang, Y.-X., Lee, C.-H., Tiep, S., Yu, R.T., Ham, J., Kang, H. and Evans, R.M. (2003) Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell, 113(2), 159–170.
    4. Sprecher, D.L. (2007) Lipids, lipoproteins, and peroxisome proliferator activated receptor–δ. Am. J. Cardiol., 100(11, Suppl. 1), S20–S24.
    5. Geiger, L.E., Dunsford W.S., Lewis, D.J., Brennan, C., Liu, K.C. and Newsholme, S.J. (2009) Rat carcinogenicity study with GW50116, a PPAR delta agonist. The Toxicologist, Abstr. 48th Annu. Meet. Soc. Toxicol., Baltimore, March 15-19 2009, Abstr. 895.
    6. Newsholme, S.J., Dunsford W.S., Brodie, T., Brennan, C., Brown, M. and Geiger, L.E. (2009) Mouse carcinogenicity study with GW50116, a PPAR delta agonist. The Toxicologist, Abstr. 48th Annu. Meet. Soc. Toxicol., Baltimore, March 15-19 2009, Abstr. 896.
    7. Wei, Z.-L. and Kozikowski, A.P. (2003) A short and efficient synthesis of the pharmacological research tool GW501516 for the peroxisome proliferator-activated receptor δ. J. Org. Chem., 68(23), 9116–9118.
    8. Thevis, M., Moller, I., Thomas, A., Bueck, S., Rodchenkov, G., Bornatsch, W., Geyer, H. and Schanzer, W. (2010) Characterization ot two major urinary metabolites or the PPARδ-agonist GW1516 and implementation of the drug in routine doping controls. Anal. Bioanal. Chem., 396(7), 2479–2491.
    9. Thevis, M., Moller, I., Bueck, S. and Schanzer, W. (2013) Synthesis, mass spectrometric characterization, and analysis of the PPARδ agonist GW1516 and its major human metabolites: targets in sports drug testing. Methods Mol. Biol., 952, 301–312.
    10. WADA issues alert on GW501516. Play True magazine March 21 2013.
    11. Stokes, S. (2013) First cycling positive for GW501516, Rusvelo's Valery Kaykov provisionally suspended. Velonation News, April 11.
    12. Stokes, S. (2013) GW501516 positives confirmed, three of four riders are from same BCR Pizza Hut team. Velonation News, April 15.
    13. Stokes, S. (2013) Marlon Perez latest rider to test positive for GW501516. Velonation News, May 03.

7th May 2013, omacetaxine mepesuccinate


The plant alkaloid homoharringtonine (INN: omacetaxine mepesuccinate, CHEBI:71019), isolated from Cephalotaxus harringtonia (a slow-growing shrub or small tree, commonly known as the Japanese cow's tail pine, due to the shape of the leaves, or as the Japanese plum yew because of its plum-like fleshy fruits), was originally identified more than 35 years ago as a possible treatment for chronic myeloid leukaemia (CML, a cancer of the white blood cells accounting for up to a fifth of all cases of leukaemia in adults) and initial studies showed promising activity. However, the introduction of imatinib and related tyrosine kinase inhibitors (TKIs) halted the clinical development of homoharringtonine as a treatment for CML [1]. The advent of resistance to TKIs in some patients has led to renewed interest in homoharringtonine and in October 2012, the compound was approved by the US Food and Drug Administration (FDA) for treatment of CML in adults with resistance to established TKIs [2].

Further potential for homoharringtonine in cancer treatment, this time in combination therapy with with tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), has been demonstrated in a recent publication by research groups headed by Petr Bartunek and Ladislav Andera at the Academy of Sciences of the Czech Republic in Prague [3]. TRAIL is under consideration as a potential anti-tumour agent. However, most primary human tumours are resistant to treatment with TRAIL alone, hence the need for combination therapy with drugs targeting the resistance. In high-throughput screening for novel agents that could sensitise TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis (programmed cell death), the researchers found homoharringtonine to be a highly effective enhancer of TRAIL-mediated apoptosis of these resistant cells. The combination of TRAIL and homoharringtonine also led to the strong suppression of growth in tumours implanted into immunodeficient mice.

The background image is a Creative Commons licensed picture of Cephalotaxus harringtonia green fruits.

Reference(s)

    1. Wetzler, M. and Segal, D. (2011). Omacetaxine as an anticancer therapeutic: what is old is new again. Curr. Pharm. Des., 17, 59–64.
    2. FDA approves Synribo for chronic myelogenous leukemia (FDA press release), Oct 26, 2012.
    3. Beranova, L., Pombinho, A.R., Spegarova, J., Koc, M., Klanova, M., Molinsky, J., Klener, P., Bartunek, P. and Andera, L. (2013). The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms. Apoptosis, 18, 739–750.

2nd April 2013, (–)-epigallocatechin 3-gallate


Alzheimer's disease (AD), as first described in 1906 by the German psychiatrist and neuropathologist Alois Alzheimer, is a progressive and fatal neurodegeneration of the brain manifested by symptoms of dementia and decline in cognition that escalate in severity as the disease advances, leading to impairment of everyday activities and neuropsychiatric symptoms [1–3].

According to the amyloid cascade hypothesis for AD [4], the deposition or aggregation of the β-amyloid (Aβ) in the brain parenchyma is a central event in the disease pathology. The Aβ is a product of the cleavage of the amyloid precursor protein and has the natural propensity to aggregate and fold with a β-pleated sheet configuration and then stack on each other to form long fibrils and clumps known as senile plaques, in a process called cerebral amyloid angiopathy or congophilic angiopathy [5]. Additionally, elevated levels of transition metals such as Cu, Zn and Fe, essentially involved in homeostasis and proper neurological functioning of the brain, are also found in considerable concentrations in the amyloid plaque [6]. It is proposed that these metals have a relation to AD neuropathogenesis, namely in the aggregation of Aβ and the formation of reactive oxygen species which lead to oxidative stress and further neuronal death. Consequently, a number of potential therapeutic strategies to treat AD are based on the premise that utilizing novel bifunctional compounds that contain elements for metal chelation and Aβ interactions would provide anti-amyloidogenic effects [7,8].

According to a paper published recently by Mi Hee Lim and an interdisciplinary team of researchers at the University of Michigan, the extracts from green tea, Camellia sinensis, may block the formation of the Aβ plaques [9]. Their attention was drawn to (–)-epigallocatechin 3-gallate (EGCG, CHEBI:4806), a major catechin found in the leaves of the green tea, which has antioxidant [10], anti-cancer [11], anti-HIV [12] and neuroprotective activities [13]. The authors propose that not only does EGCG prevent the formation of aggregates but that it also breaks down existing aggregate structures in the proteins that contained metals – specifically copper, iron and zinc. The studies also suggest that the overall reactivity of EGCG with a metal-free or metal-associated Aβ species is associated with its ability to influence formation of the compact conformation of Aβ and ternary complexes containing Aβ, Cu or Zn and EGCG in multiple stoichiometries. The study essentially aims at building a structure-based mechanism for EGCG action towards Aβ and builds a platform for development and application of small molecules as therapeutic agents for AD.

The background image is a Creative Commons licensed picture showing a Chinese teapot.

Reference(s)

    1. Berchtold, N.C. and Cotman, C.W. (1998) Evolution in the conceptualization of dementia and Alzheimer�s disease: Greco-Roman period to the 1960s. Neurobiol. Aging, 19(3), 173–189.
    2. Boller, F. and Forbes, M.M. (1998) History of dementia and dementia in history: An overview. J. Neurol. Sci., 158(2), 125–133.
    3. Tran, M., Bédard, M., Dubois, S., Weaver, B. and Molloy, D.W. (2013) The influences of psychotic symptoms on the activities of daily living of individuals with Alzheimer disease: a longitudinal analysis. Aging Ment. Health, 17, in press.
    4. Karran, E., Mercken, M. and De Strooper, B. (2011) The amyloid cascade hypothesis for Alzheimer�s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug. Discov., 10(9), 698–712.
    5. Weller, R.O., Preston, S.D., Subash, M. and Carare, R.O. (2009) Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease. Alzheimers Res. Ther., 1(2), 6.
    6. Pithadia, A.S. and Lim, M.H (2012) Metal-associated amyloid-β species in Alzheimer�s disease. Curr. Opin. Chem. Biol., 16(1–2), 67–73.
    7. Wu, W.H., Lei, P., Liu, Q., Hu, J., Gunn, A.P., Chen, M.S., Rui, Y.F., Su, X.Y., Xie, Z.P., Zhao, Y.F., Bush, A.I. and Li, Y.M. (2008) Sequestration of copper from &beta-amyloid promotes selective lysis by cyclen-hybrid cleavage agents. J. Biol. Chem., 283(46), 31657–31664.
    8. Ono, K., Hasegawa, K., Naiki, H. and Yamada, M. (2004) Curcumin has potent anti-amyloidogenic effects for Alzheimer's β-amyloid fibrils in vitro. J. Neurosci. Res., 75(6), 742–750.
    9. Hyung, S.J., Detoma, A.S., Brender, J.R., Lee, S., Vivekanandan, S., Kochi, A., Choi, J.S., Ramamoorthy, A., Ruotolo, B.T. and Lim, M.H. (2013) Insights into antiamyloidogenic properties of the green tea extract (–)-epigallocatechin-3-gallate toward metal–associated amyloid-β species. Proc. Natl. Acad. Sci. U. S. A., 110(10), 3743–3748.
    10. Wang, Y., Zhao, Y., Andrae-Marobela, K., Okatch, H. and Xiao, J. (2013) Tea polysaccharides as food antioxidants: An old woman's tale? Food Chem., 138(2–3), 1923–1927.
    11. Fang, M.Z., Wang, Y., Ai, N., Hou, Z., Sun, Y., Lu, H., Welsh, W. and Yang, C.S. (2003) Tea polyphenol (–)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res., 63(22), 7563–7570.
    12. Williamson, M.P., McCormick, T.G., Nance, C.L and Shearer, W.T. (2006) Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy. J. Allergy Clin. Immunol., 118(6), 1369–1374.
    13. Itoh, T., Imano, M., Nishida, S., Tsubaki, M., Mizuguchi, N., Hashimoto, S., Ito, A. and Satou, T. (2012) (–)-Epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury. J. Neural Transm., 119(8), 877–890.

4th March 2013, gedunin


The Indian neem tree, Azadirachta indica, is a quick-growing evergreen member of the Meliaceae (mahogany) family which is native to the Indian subcontinent and has been introduced to many other areas in the tropics. Also known as known as 'Heal all' and 'Nature's pharmacy', it has long been used in traditional Indian medicine. Among the pharmacologically active metabolites produced by the tree is gedunin (CHEBI:65954) [1,2], a pentacyclic tetranortriterpenoid isolated from the bark, which has been shown to possess antimalarial [3], insecticidal [4], and anticancer activity [5]. The latter has been shown to result from the inhibition of the 90 kDa heat shock protein (Hsp90) [6,7].

Hsp90 is among the most important of chaperone proteins (proteins that help other proteins to fold and unfold properly): it has been estimated that the Hsp90 protein-foldingmachine may handle up to 10% or all cellular proteins [8]. Furthermore, it is required for the stability and function of a number of conditionally activiated signalling proteins and mutated proteins that promote cancer cell growth and survival [9]. Consequently, inhibiting the action of Hsp90 has become an important strategy for the development of novel cancer treatments in recent years [10] and a number of Hsp90 inhibitors are in clinical trials for cancer treatment [11–14]. However, the clinical efficacy of most Hsp90 inhibitors has been disappointing for, in addition to inhibiting Hsp90, the compounds have inadvertently caused the overexpression of Hsp70 and Hsp27, which protect cancer cells from apoptosis (programmed cell death), and this has reduced the benefit of inhibiting the action of Hsp90.

Now a group of scientists led by Ahmed Chadli at Georgia Regents University Cancer Center have found that gedunin inhibits Hsp90 indirectly [15]. Hsp90 works in combination with a number of chaparones and co-chaperones (helper proteins). Chadli's group has shown that gedunin binds directly to a co-chaperone of Hsp90 called p23, resulting in the Hsp90 machine being deactivated without the undesired production of the anti-apoptotic proteins.

Their discovery opens up new possibilities for cancer treatments, in which Hsp90 is targeted indirectly through targeting its co-chaperones; over twenty co-chaperone proteins have so far been shown to regulate the Hsp90 machine. It is thought that their findings will be particularly relevant for future drug development for hormone-dependent cancers, including breast, prostate, and endometrial cancers.

The background image is a Creative Commons licensed picture showing a neem tree at Rawanjana Dungar railway station, Rajastan.

Reference(s)

    1. Akisanya, A., Bevan, C.W.L., Hirst, J., Halsall, T.G. and Taylor, D.A.H. (1960) Petroleum extracts from the genus Entandrophragma. J. Chem. Soc., 3827–3829.
    2. Akisanya, A., Bevan, C.W.L., Halsall, T.G., Powell, J.W. and Taylor, D.A.H. (1961) Some reactions of gedunin. J. Chem. Soc., 3705–3708.
    3. Khalid, S.A., Duddeck, H. and Gonzalez-Sierra, M. (1989) Isolation and characterization of an antimalarial agent of the neem tree Azadirachta indica. J. Nat. Prod., 52(5), 922–926.
    4. Nathan, S.S., Kalaivani, K., Chung, P.G. and Murugan, K. (2006) Effect of neem limonoids on lactate dehydrogenase (LDH) of the rice leaffolder, Cnaphalocrocis medinalis (Guenée) (Insecta: Lepidoptera: Pyralidae). Chemosphere, 62(8), 1388–1393 .
    5. Uddin, S.J., Nahar, L., Shilpi, J.A., Shoeb, M., Borkowski, T., Gibbons, S., Middleton, M., Byres, M. and Sarker, S.D. (2007) Gedunin, a limonoid from Xylocarpus granatum, inhibits the growth of CaCo-2 colon cancer cell line in vitro. Phytother. Res., 21(8), 757–761.
    6. Lamb, J., Crawford, E.D., Peck, D., Modell, J.W., Blat, I.C., Wrobel, M.J., Lerner, J., Brunet, J.P., Subramanian, A., Ross, K.N., Reich, M., Hieronymus, H., Wei, G. and Carr, S.A. (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science (Washington, DC, U. S.), 313, 1929–1935.
    7. Hieronymus, H., Lamb, J., Ross, K.N., Peng, X.P., Clement, C., Rodina, A., Nieto, M., Du, J., Stegmaier, K., Raj, S.M., Maloney, K.N., Clardy, J., Hahn, W.C., Chiosis, G. and Golub, T.R. (2006) Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell, 10(4), 321–330.
    8. Picard, D. (2012) Preface to Hsp90. Biochim. Biophys. Acta, Mol. Cell Res., 1823(3), 605–606.
    9. Neckers, L. (2007) Heat shock protein 90: the cancer chaperone. J. Biosci, 32(3), 517–530.
    10. Sidera, K. and Patsavoudi, E. (2013) HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat. Anti-Cancer Drug Discovery, 8, in press.
    11. Blagg, B.S. and Kerr, T.D. (2006) Hsp90 inhibitors: small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation. Med. Res. Rev., 26(3), 310–338.
    12. Xiao, L., Lu, X. and Ruden, D.M. (2006) Effectiveness of Hsp90 inhibitors as anti-cancer drugs. Mini-Rev. Med. Chem., 6(10), 1137–1143.
    13. Kim, Y.S., Alarcon, S.V., Lee, S., Lee, M.J., Giaccone, G., Neckers, L. and Trepel, J.B. (2009) Update on Hsp90 inhibitors in clinical trial. Curr. Top. Med. Chem., 9(15), 1479–1492.
    14. Trepel, J., Mollapour, M., Giaccone, G. and Neckers, L. (2010) Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer, 10(8), 537–549.
    15. Patwardhan, C.A., Fauq, A., Peterson, L.B., Miller, C., Blagg, B.S. and Chadli, A. (2013) Gedunin inactivates the co-chaperone p23 causing cancer cell death by apoptosis. J. Biol. Chem., 288, in press.

4th February 2013, caffeine


In recognition of the copious amounts of caffeine consumed by various members of the ChEBI team throughout the first 99 releases, caffeine (CHEBI:27732) has been selected as our entity of the month to commemorate the 100th release of ChEBI.

Caffeine is the common name for 1,3,7-trimethylxanthine. The word "caffeine" originates from the German "kaffee" and the French "café", each meaning coffee. In purified form, caffeine exists as a white powder with a distinctive bitter flavour. Caffeine is naturally found in certain leaves, beans, and fruits of over 60 plants worldwide, where it acts as a natural pesticide. Caffeine is synthesised in plants from the purine nucleotides AMP, GMP, and IMP. These in turn are transformed into xanthosine, then theobromine and eventually caffeine [1]. In humans, caffeine acts as a central nervous system stimulant, temporarily warding off drowsiness and enhancing alertness. The most common sources of caffeine in the human diet are coffee, tea, soft drinks, energy drinks and chocolate derived from cocoa beans [2].

The long term effects of moderate caffeine consumption (up to 300 mg per day, equivalent to about three cups of coffee) are thought to be a reduction in the risk of developing Parkinson's disease, type 2 diabetes, hepatic diseases, cardiovascular disease and some forms of cancer. However, heavy consumption (more than 500-600 mg per day) may have negative effects in some users, such as insomnia, anxiety, mood swings, nausea, palpitations, headaches and muscle tremors. Fatal caffeine overdoses in adults are relatively rare and require the ingestion of a large quantity of the drug, typically in excess of 5 g [3].

Two recent reports have served to highlight both the positive and negative effects of caffeine consumption. Ronald Postuma of McGill University in Montreal, Canada, and co-workers have recently studied the effects of regular caffeine consumption on patients who already have the symptoms of Parkinson's disease. They gave 61 people with the disease a six-week course of pills containing the caffeine equivalent of about three cups of coffee every day, or a placebo. Only people in the caffeine group showed significant improvement in tests for motor problems, such as the severity of tremors, and general mobility [4].

Unlike many other psychoactive substances, caffeine is both legal and unregulated in nearly all parts of the world. Energy drinks, which at present are not regulated as they are classed as nutritional supplements, have been under scrutiny because of their high caffeine content. In October 2012, parents from Maryland filed a wrongful death lawsuit against an energy drink manufacturer after their 14-year-old daughter died of cardiac arrest. She had reportedly consumed two 24-ounce cans of the beverage within a 24-hour period. It is thought that she suffered from an hereditary heart condition which may have been triggered by the sudden rush of caffeine [5]. In November 2012, The US Food and Drug Administration (FDA) released incident reports describing several deaths that may have occurred following the consumption of energy drinks. The filing of such reports with the FDA does not prove that a product was directly responsible for a death or an injury. In a released statement, the FDA stated that it was likely to seek advice from outside experts to help determine whether energy drinks posed particular risks to teenagers or people with underlying health problems [5]. In Canada, an independent panel made several recommendations, including that such beverages are labelled as �stimulant drug-containing drinks� and new regulations have been put in place to limit caffeine levels in energy drinks to 180 mg [6].

Reference(s)

    1. Ashihara, H., Monteiro, A.M., Gillies, F.M. and Crozier, A. (1996). Biosynthesis of caffeine in leaves of coffee. Plant Physiol., 111, 747–753.
    2. http://www.howstuffworks.com/caffeine.htm
    3. Kerrigan, S. and Lindsey T. (2005). Fatal caffeine overdose: two case reports. Forensic Sci. Int., 153, 67–9.
    4. Postuma, R.B., Lang A.E., Munhoz, R.P., Charland, K., Pelletier, A., Moscovich, M., Filla L., Zanatta, D., Romenets, S.R., Altman, R., Chuang, R. and Shah, B. (2012). Caffeine for treatment of Parkinson disease. A randomized controlled trial. Neurology, 79, 651–659.
    5. http://features.blogs.fortune.cnn.com/2013/01/23/energy-drinks-brace-for-caffeine-crash/
    6. http://www.hc-sc.gc.ca/fn-an/legislation/pol/energy-drinks-boissons-energisantes-eng.php

7th January 2013, Acrylamide


Acrylamide (CHEBI:28619) is an industrially produced reactive molecule widely used as a chemical intermediate in the preparation of polymers such as polyacrylamide,a polymer which can be synthesised in both linear-chain and cross-linked forms and is utilized in many processes including the synthesis of dyes, the preparation of copolymers for contact lenses and in sealant grouts in the construction of dam foundations, tunnels and sewers. However, despite its widespread utility, acrylamide has been shown to be a potent neurotoxin in both humans and animals. Acrylamide also acts as a reproductive toxin, genotoxin and carcinogen in rodents [1]. In addition, based on several cohort studies of cancers in humans with potential for occupational exposure to acrylamide, the chemical is also classified as 'probably carcinogenic to humans' (class 2A) by the International Agency for Research on Cancer [2].

Acrylamide toxicity became a major concern when a Swedish study announced the discovery of considerable levels of the compound in starch-based foods such as potato crisps, french fries, bread and other foodstuffs. Acrylamide is formed during high-temperature cooking via the Maillard reaction involving the reaction of a reducing sugar with the amino acid L-asparagine [3]. However a link between the dietary intake of acrylamide and cancer could not be confirmed until a Dutch epidemiological survey, involving around 62,000 women over a period of 11 years, concluded that women who ingested 40 �g per day of acrylamide via their diet were twice as likely to develop womb or ovarian cancer than women who had eaten only 9 �g per day [4]. This has evoked several research efforts aimed at reducing the dietary levels of the chemical in foodstuffs through new farming and food-processing techniques.

One of the ways to reduce acrylamide formation in potatoes is by developing new cultivars that are low in the acrylamide precursors – L-asparagine and the reducing sugars. As a part of these efforts, a team of researchers led by Nigel Halford from Rothamsted Research, UK, measured the levels of acrylamide precursors in nine different varieties of potatoes along with the amount of acrylamide formed during frying. The precursor–acrylamide relationship was found to be dependent on the strain of the potato used [5].

The study proposed that the two crisp-potato varieties Lady Clare and Saturna showed acrylamide formation that was consistently below the European Commission's ideal of 1000 ppb. However the complexity of the precursor–acrylamide relationships and the sensitivity of the potatoes to seasonal variations make it difficult to identify specific targets for breeding programmes. Nevertheless, researchers continue to aim at developing more efficient tools to produce low-acrylamide varieties of potatoes to comply with possible harsher regulatory limits.

The background image is that of potatoes frying in oil, during which process the Maillard reaction gives rise to acrylamide.

Reference(s)

    1. Parzefall, W. (2008) Minireview on the toxicity of dietary acrylamide. Food Chem. Toxicol., 46(4), 1360–1364.
    2. IARC Monograph (1994) Acrylamide. IARC Monogr. Eval. Carcinog. Risks Hum., 60, 389–433.
    3. Svensson, K., Abramsson, L., Becker, W., Glynn, A., Hellen�s, K.-E., Lind, Y. and Ros�n, J. (2003) Dietary intake of acrylamide in Sweden. Food Chem. Toxicol., 41(11), 1581–1586.
    4. Hogervorst, J. G., Schouten, L. J., Konings, E. J., Goldbohm, R. A. and van den Brandt, P. A. (2007) A prospective study of dietary acrylamide intake and the risk of endometrial, ovarian, and breast cancer.Cancer Epidemiol., Biomarkers Prev., 16, 2304–2313.
    5. Halford, N. G., Muttucumaru, N., Powers S. J., Gillatt, P. N., Hartley, L., Elmore, J. S. and Mottram, D. S. (2012) Concentrations of free amino acids and sugars in nine potato varieties: effects of storage and relationship with acrylamide formation. J. Agric. Food Chem., 60(48), 12044–12055.



2012

3rd December 2012, Antibiotic


This month's entity is not an individual compound, but rather a class of compounds. So what is an antibiotic? One of the most quoted of the early definitions was published by Selman A. Waksman (the co-discoverer of streptomycin) in 1947. His definition was 117 words in length but, in short, 'antibiotic' was described as any substance produced by a microorganism that killed or inhibited the growth of bacteria or other microorganisms [1]. Most published definitions still limit the meaning of 'antibiotic' to microbial natural products [2], despite the fact that most scientists find the distinction 'rather academic' [3]. The term 'antibiotic' is now commonly used to include semisynthetic modifications of natural compounds, such as many of the penicillins and cephalosporins, as well as compounds produced entirely by chemical synthesis, for example the sulfonamides.

The medical profession has now had an extensive arsenal of antibiotics available for the treatment of infectious diseases for well over 50 years. Consequently, it has become difficult to envisage just how rapidly microorganisms could overwhelm the body's defences and just how precarious life could be before antibiotics became available. A perfectly healthy individual could die of septicaemia from a simple cut, a case in point being that of Calvin Coolidge Jr., the youngest son of the 30th President of the United States who, during the afternoon of June 30th 1924, while playing tennis with his older brother, developed a blister on his right foot. Septicaemia developed, and the best medical practitioners in the nation's capital couldn't save him; he died aged 16 at the Walter Reed Army General Hospital just seven days later [4]. Many other bacterial infections, most notably tuberculosis, were also routine killers.

The introduction of the first sulfonamides (in 1935) and, particularly, penicillins (in 1940) caused the mortality rate associated with bacterial infections to plummet. However, the power of these new antibiotics soon began to wane owing to the ability of bacteria to develop resistance to them.

Alexander Fleming, the discoverer of penicillin, warned against misusing antibiotics at the end of his acceptance speech for the 1945 Nobel Prize for Physiology or Medicine [5]. "The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant." The warning has been repeated regularly over the years; for example the Alliance for the Prudent Use of Antibiotics (APUA), a non-profit group based at Tufts University Medical School, has been promoting appropriate antibiotic use to contain drug resistance for over thirty years. Despite this, the warnings have been largely ignored.

For many years, the problem was masked by a seemingly endless supply of new and better antibiotics from the major pharmaceutical companies. Thus between 1940 and 1962, more than 20 new classes of antibiotics were marketed, so that when bacteria developed resistance to one antibiotic there was always another one available to take its place [6]. Since 1962, however, only four new classes have entered the market, while the number of large pharmaceutical companies engaged in the discovery of antibiotics has fallen markedly. It typically takes only two years between the introduction of a new antibiotic and the observance of resistance to it, but the process of developing a new antibiotic is long (around ten years) and expensive (typically over $300 million). Combined with the emergence of multi-drug-resistant bacteria, the result is that insufficient new classes of antibiotics or new members of existing classes are reaching the market to keep pace with the development of resistant bacteria. The need for antibiotics targeting Gram-negative bacteria is particularly acute.

In cases of severe infections, antibiotic treatment has to start 'blind' until the infecting bacteria have been identified in the laboratory, which can take two days. As bacterial resistance increases, so does the likelihood that the 'blind' treatment will not work. Where there is blood poisoning (sepsis) this delay in fighting the infection doubles the risk of death. Doctors are increasingly having to use carbapenems, the 'reserve' antibiotics kept for use when other treatments have failed. Now the spread of resistance to carbapenems is being seen as well.

While it is still almost always possible to find an antibiotic to treat any bacterial infection, the situation is far from ideal. Alternative antibiotics are often more expensive than the 'normal' treatments and can take much longer to work, as they are often not as good at killing the bacteria; they can also cause serious side effects. Thus the cost of treating one person suffering from multi-drug-resistant tuberculosis (MDR-TB) can be as much as 200 times that of treating someone with the non-resistant variety. The burden of this cost is likely to fall disproportionately on poor countries - of the 310,000 cases of MDR-TB reported in the world in 2011, almost 60% were in India, China or the Russian Federation [7].

As part of an on-going effort to reduce the unnecessary use of antibiotics and so cut down the development and spread of resistance, the U.K. Health Protection Agency (HPA) chose 18th November 2012, European Antibiotics Awareness Day (EAAD), to urge people to think twice before they ask for antibiotics from their medical practitioners to treat cold and flu symptoms - colds and influenza are viral infections, while antibiotics are active against bacteria, not viruses [8]. However, this is only one aspect of a much bigger problem.

In many parts of the world, antibiotics can be purchased 'over the counter', without the need for any diagnosis or recommendations for proper use. Antibiotics are also readily available via the internet, where effective regulation to limit supplies to cases where they are needed is virtually impossible, increasing still further the number of human incubators from which resistant strains of bacteria can evolve. For many years, antibiotics were routinely given to many farm animals, not because they were sick, but simply to promote growth. Denmark, the world's biggest exporter of pork, began phasing out the practice more than 15 years ago, and an EU-wide ban was introduced at the start of 2006; however, the practice continues elsewhere, including in the United States. Congresswoman Louise Slaughter, the only microbiologist in Congress, has calculated from FDA figures that up to 80% of all of the antibiotics used in the U.S. are given to livestock, mostly as growth promotion agents.

Our image is a Creative Commons licensed picture of a Faroe Islands postage stamp issued in 1983, depicting Sir Alexander Fleming.

Reference(s)

  1. Waksman, S.A. (1947) What is an antibiotic or antibiotic substance? Mycologia, 39, 565–569.
  2. Bentley, R. and Bennett, J.W. (2003) What is an antibiotic? Revisited. Adv. Appl. Microbiol., 52, 303–331.
  3. Pratt, W.B. and Fekety, R. (1986) "The antimicrobial drugs." Oxford University Press, New York.
  4. President's son, Calvin Jr., 16, dies as parents watch. New York Times, July 8th, 1924.
  5. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleming-lecture.pdf
  6. Coates, A.R., Halls, G. and Hyu, Y. (2011) Novel classes of antibiotics or more of the same? Br. J. Pharmacol, 163(1), 184–194.
  7. Tuberculosis. World Health Organisation Factsheet 104 (October 2012).
  8. Antibiotics and you. Health Protection Agency Press Release, November 14th 2012.

5th November 2012, dinitrogen


Having part of one's stomach removed is perhaps not the way one would celebrate a coming of age. Nevertheless, owing to the misuse of liquid nitrogen (CHEBI:17997), this was the fate of British teenager Gaby Scanlon, who suffered a perforated stomach after drinking a cocktail prepared with liquid nitrogen [1]. Scanlon, who was out with friends in Lancaster on her 18th birthday, was reported to have become breathless and developed severe stomach pains before being taken to the Royal Lancaster Infirmary for life-saving surgery. The procedure, a gastrectomy, involves connecting the oesophagus to the small intestine. As a result Scanlon is likely to have to alter her diet, such as by eating smaller meals more frequently and taking multivitamin supplements.

Liquid nitrogen is a cryogenic fluid which boils at -196°C at atmospheric pressure and starts to evaporate the moment it comes into contact with room temperature air, creating a dramatic dry-ice effect caused by condensation of water vapour in the air. But if the nitrogen has not boiled away fully, as a liquid it has the power to freeze objects in a matter of seconds. If swallowed, liquid nitrogen can cause cold burns to the mouth, throat and stomach, killing the tissue. As the frozen vapour hits the stomach it rapidly warms, releasing large volumes of air which can burst the stomach. As a result of the accident, the Food Standards Agency has issued a warning about the dangers of liquid nitrogen [2] and David Morris, the Member of Parliament for the constituency of Morecambe and Lunesdale, has called on the UK Parliament to ban liquid nitrogen cocktails [3].

Reference(s)

  1. http://www.guardian.co.uk/uk/2012/oct/08/teenager-stomach-liquid-nitrogen-cocktail
  2. http://www.food.gov.uk/news-updates/news/2012/oct/nitrogen#.UI_Wv2cdpQI
  3. http://www.guardian.co.uk/uk/2012/oct/12/mp-ban-liquid-nitrogen-cocktails

1st October 2012, everolimus


Over the last few decades, major improvements have been achieved in the management of breast cancer, mirrored by a significant decrease in the mortality rate despite an increasing prevalence of the disease. However, metastatic breast cancer (also known as secondary breast cancer) remains common and is the cause of death in nearly 12,000 women annually in the UK [1]. It occurs when the breast cancer cells spread from the first primary tumour in the breast to another distant part of the body (metastasis) which happens through the blood stream or lymphatic system. This type of spread is also referred to as advanced breast cancer or stage 4 cancer.

Adjuvant endocrine therapy [2] that employs the use of a selective estrogen receptor antagonist such as tamoxifen or an aromatase inhibitor has been a cornerstone of treatment for patients diagnosed with metastatic breast cancer in recent years. However, patients generally tend to develop resistance to such hormone therapy. Apparently, the mechanism for this resistance is over-activation of the mTOR (mammalian transporter of rapamycin) pathway which regulates cell growth, proliferation, motility and survival and is over-active in many forms of cancer [3].

At the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium held last month in San Francisco, Prof. Hope Rugo, Director of Breast Oncology and Clinical Trials Education and Professor of Medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, presented the updated 18-month results of the pivotal phase III Breast Cancer Trials of Oral Everolimus (BOLERO-2) [4]. The trials indicate that treatment with everolimus (CHEBI:68478), a derivative of sirolimus, used in combination with the aromatase inhibitor exemestane, extended median progression-free survival in patients to 7.8 months compared with 3.2 months for the control group treated with exemestane alone. These progression-free survival benefits were stable for all the subgroups studied including age and geography.

Everolimus acts as an mTOR inhibitor, modulating the progression of the tumour. Given the positive results, everolimus has entered National Comprehensive Cancer Network (NCCN) 2012 guidelines and has been approved as a drug for advanced breast cancer by the FDA [5].

We have chosen everolimus as our entity of month in support of Macmillan Cancer Support, one of the largest cancer support charities in the UK, who have recently organised the World�s Biggest Coffee Morning, a fundraising event spread over numerous locations in the UK, including our Hinxton Campus.

The background image is a Creative Commons licensed picture of a giant pink ribbon in a market in Louisville, Kentucky, for Breast Cancer awareness.

Reference(s)

  1. Coleman, R.E., Bertelli, G., Beaumont, T., Kunkler, I., Miles, D., Simmonds, P.D., Jones, A.L. and Smith, I.E. (2011) UK guidance document: Treatment of metastatic breast cancer. Clin. Oncol., 24(3), 169–176.
  2. Smith, I.E. and Dowsett, M.(2003) Aromatase inhibitors in breast cancer. N. Engl. J. Med., 348(24), 2431–2442.
  3. (2012) Everolimus approved for HR-positive breast cancer. Cancer Discovery, 2(9), 756.
  4. Azvolinsky A. (2012) Everolimus for advanced breast cancer: An update from the BOLERO-2 Trial. CancerNetwork, September 18.
  5. FDA approves Afinitor for advanced breast cancer (FDA press release), July 20, 2012.

3rd September 2012, β-Carotene


Vitamin A deficiency is of public health significance in the developing world. Approximately half a million children in Africa and Asia go blind every year due to their diet being deficient in vitamin A, which is important for vision and the immune system. β-Carotene (CHEBI:17579), a red-orange pigment abundant in plants and fruit, is the primary dietary source of vitamin A worldwide. In the body, β-carotene is converted into vitamin A, which can exist in several forms (retinol, retinal, retinoic acid and retinyl esters). The role of vitamin A in the visual cycle is specifically related to the retinal form. Within the eye, 11-cis-retinal is bound to rhodopsin (rods) and iodopsin (cones) at conserved lysine residues. As light enters the eye, the 11-cis-retinal is isomerised to the all-trans form. This isomerisation induces a nervous signal along the optic nerve to the visual centre of the brain. The all-trans-form is subsequently recycled via a series of enzymatic reactions.

A variety of sweet potato bred naturally to contain four to six times the amount of β-carotene than the average sweet potato has helped to stave off vitamin A deficiency in parts of Africa [1]. In a two year project headed by Christine Hotz at the International Food Policy Research Institute in Washington DC involving 10,000 households in Uganda, it was found that vitamin A intake doubled in women and young children who ate the biofortifed sweet potatoes compared with families that continued eating regular varieties [2]. Additionally, by the end of the study almost 90% of the children who ate the new strain had escaped vitamin A deficiency, compared with only 50% in a control group.

More controversial than the naturally bred sweet potatoes is Golden Rice, a variety of Oryza sativa rice produced via genetic engineering to be rich in β-carotene, of which ordinary white rice contains none. Critics of the modified rice, including Greenpeace, have claimed that the rice is impractical as people would need to consume huge amounts in order to obtain sufficient quantities of β-carotene. A recent study carried out by Guangwen Tang and co-workers at Tufts University in Boston, Massachusetts, has compared the vitamin A value of β-carotene in Golden Rice and in spinach with that of pure β-carotene in oil when consumed by children [3]. Analyses showed that the β-carotene in Golden Rice was as effective as pure β-carotene in oil and superior to that in spinach at providing vitamin A to children. A bowl of 100–150 grams of cooked Golden Rice (50 grams dry weight) can provide approximately 60% of the recommended daily intake of vitamin A. Although the results seem to counter the criticism, several obstacles will have to be overcome before Golden Rice becomes widely available.

Reference(s)

  1. http://www.newscientist.com/article/17-08-2012.
  2. Hotz, C., Loechl, C., Lubowa, A., Tumwine, J.K., Ndeezi, C., Masawi, A.N., Baingana, R., Carriquiry, A., de Brauw, A., Meenakshi, J.V. and Gilligan, D.O. (2012), Introduction of β-carotene-rich orange sweet potato in rural Uganda results in increased vitamin A intakes among children and women and improved vitamin A status among children. J. Nutr., doi:10.3945/jn.111.151829, published online 8 August 2012.
  3. Tang, G., Hu, Y., Yin S.-a., Wang, Y., Dallal, G.E., Grusak M.A. and Russell, R.M. (2012), β-Carotene in Golden Rice is as good as β-carotene in oil at providing vitamin A to children. Am. J. Clin. Nutr., 56, 658–664.

6th August 2012, thionitrous acid


Until the mid-1980s, nitric oxide (NO) – a short-lived, highly reactive, toxic gas – was best known as an air pollutant from internal combustion engines (but produced for and used on a huge scale in the Ostwald process for the manufacture of nitric acid). The independent discovery by Robert Furchgott, Louis Ignarro and Ferid Murad that nitric oxide was endogenously produced and acted as a signalling molecule between cells, playing a vital role in regulating blood pressure and circulation, was completely unexpected and opened up new areas of biomedical research. For their breakthrough, Professors Furchgott, Ignarro and Murad shared the Nobel Prize in Physiology or Medicine in 1998. During his Nobel acceptance speech, Furchgott noted the irony that Alfred Nobel, celebrated for his work with nitroglycerin and dynamite, had suffered from angina, for which he was prescribed nitroglycerin [1]. Furchgott, Ignarro and Murad's work led researchers to the explanation of why nitroglycerin is so effective in treating heart pain: it is actually a prodrug, being converted by mitochondrial aldehyde dehydrogenase (EC 1.2.1.3) in the body into nitric oxide, which is a natural vasodilator [2].

More recently, hydrogen sulfide (H2S) – another reactive, toxic gas – has also been recognised as an important signalling molecule, with similar physiological effects to nitric oxide [3]. Now, work led by Milos R. Filipović of the Department of Chemistry and Pharmacy at the University of Erlangen-Nürnberg in Germany suggests that the effects of nitric oxide and hydrogen sulfide may be linked by thionitrous acid, HSNO (CHEBI:65308) [4], a molecule so reactive it has previously only been isolated and spectroscopically identified in an argon matrix at –261°C [5].

One important signalling pathway for nitric oxide involves S-nitrosation of the thiol groups of cysteine residues in proteins, affording S-nitrosated proteins. To date, over 3000 S-nitrosoproteins have been reported [6], and S-nitrosation is being seen to be as important as phosphorylation. Filipović and co-workers have shown that S-nitrosated proteins can react with hydrogen sulfide to produce thionitrous acid, which can be metabolised to produce NO(+), NO, and NO(–) species, each of which evokes distinct physiological responses. In addition, the group have shown that thionitrous acid can freely diffuse through membranes, so facilitating the transfer of nitroso groups from one protein to another in signalling pathways. Not only does their study explain some of the physiological effects ascribed to hydrogen sulfide, it suggests that thionitrous acid may play a key role in cellular redox regulation.

The background image is a Creative Commons licensed picture showing the production and diffusion of nitric oxide (NO) (white) in the cytoplasm (green) of clusters of conifer cells one hour after mechanical agitation [7]. NO diffuses into the culture medium around cell clusters. The large dark green circle inside each cell is the nucleus. Some nuclei may contain a nucleolus (light green). The small and irregular dark areas outside the nucleus and in the cytoplasm represent the vacuoles (laser confocal photomicrograph x400). NO was visualised with a fluorescent probe DAF-2 DA (diaminofluorescein diacetate). NO is derived from L-arginine and oxygen by nitric oxide synthase (NOS, EC 1.14.13.39) activity in conifers and humans.

Reference(s)

  1. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/furchgott-speech_en.html
  2. Chen, Z., Foster, M.W., Zhang, J., Mao, L., Rockman, H.A., Kawamoto, T., Kitagawa, K., Nakayama, K.I., Hess, D.T. and Stamler, J.S. (2005), An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc. Natl. Acad. Sci. U. S. A., 102(34), 12159–12164.
  3. Wagner, C.A. (2009), Hydrogen sulfide: a new gaseous signal molecule and blood pressure regulator. J. Nephrol., 22(2), 173–176.
  4. Filipovic, M.R., Miljkovic, J.Lj., Nauser, T., Royzen, M., Klos, K., Shubina, T., Koppenol, W.H., Lippard, S.J. and Ivanović-Burmazović, I. (2102), Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols. J. Am. Chem. Soc., 134(29), 12016–12027.
  5. Nonella, M., Huber, J.R. and Ha, T.-K. (1987), Photolytic preparation and isomerization of thionyl imide, thiocyanic acid, thionitrous acid, and nitrogen hydroxide sulfide in an argon matrix: an experimental and theoretical study. J. Phys. Chem., 91(20), 5203–5209.
  6. Hess, D.T. and Stamler, J.T. (2012), Regulation by S-nitrosylation of protein post-translational modification. J. Biol. Chem., 287(7), 4411–4418.
  7. Durzna, D.D. (2009), Arginine, scurvy and Cartier's "tree of life". J. Ethnobiol. Ethnomed., 5:5.

2nd July 2012, L-phenylalanine


L-Phenylalanine (CHEBI:17295; more commonly know just as 'phenylalanine' and abbreviated as Phe or F) is one of the twenty common DNA-encoded amino acids used in protein formation. It is also a precursor for L-tyrosine which is in turn converted into the signalling molecules dopamine, (R)-noradrenaline and (R)-adrenaline.

The inability of an individual to metabolise L-phenylalanine is one of the characteristics of the genetic disorder phenylketonuria (PKU). Individuals who suffer from PKU have a mutation in the gene for the hepatic enzyme phenylalanine 4-monooxygenase (phenylalanine hydroxylase, PAH, EC 1.14.16.1) and must carefully regulate their intake of L-phenylalanine in order to avoid high levels accumulating in the blood as their bodies break down proteins into their component amino acids. PKU has all the characteristics of amyloid diseases, disorders characterised by inappropriate folding and aggregation of proteins and peptides to form toxic protein fibrils. Such disorders include the age-related neurodegenerative diseases Alzheimer's and Parkinson's. Aromatic amino acids such as L-phenylalanine are known to be important for accelerating the amyloid assembly process and, especially when the amyloid beta protein (Aβ) contains two adjacent L-phenylalanine residues, these seem to mediate the intermolecular reactions between polypeptide chains needed for fibril assembly as seen in Alzheimer's disease.

Now, in a recent publication in Nature Chemical Biology [1] a team from Tel-Aviv University led by Ehud Gazit, in collaboration with researchers from the University of Zurich, report a direct connection between PKU and Alzheimer's disease by demonstrating that L-phenylalanine can by itself form toxic fibrils. They found that at concentrations that exist in PKU, L-phenylalanine self-assemblies into amyloid-like fibrils. Gazit's team worked with mice genetically modified to have a PKU-like condition. These expressed antibodies against L-phenylalanine fibrils which were not found in non-diseased mice. Use of fluorescent antibody probes allowed unambiguous detection of the L-phenylalanine fibrils.

Gazit's results provide a greater understanding of the molecular nature of PKU amyloid diseases, and suggest that antibody-led approaches currently being developed to treat Alzheimer's and Parkinson's by targeting fibrils should work also with PKU. The team is currently seeking a partner in the pharma industry to help in their further investigations.

The background image is of Alzheimer's beta-amyloid fibrils, based on PDB ID 2BEG and rendered with the open-source PyMol visualisation system.

Reference(s)

  1. Adler-Abramovich, L., Vaks, L., Carny, O., Trudler, D., Magno, A., Caflisch, A., Frenkel, D. and Gazit, E. (2012) Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nature Chemical Biology advance online publication, 17 June 2012 (doi:10.1038/nchembio.1002).

1st June 2012, auranofin


Amoebiasis (previously known as entamoebiasis) is an infection of the intestines caused by ingestion of the amoeba Entamoeba histolytica. The infection is spread through ingestion of the cyst-form of the parasite, generally through ingestion of food or water contaminated with human faecal matter. Amoebiasis is therefore often endemic in areas of the world lacking modern sanitation systems.

An estimated 90% of the 40 to 50 million people in the world infected by E. histolytica do not show any symptoms; the amoeba simply eats and digests bacteria and food particles in the intestine, which is protected from attack by a layer of mucus. However, as the Latin name histolytica suggests (histo-lytic = tissue destroying), the amoeba can be far from benign. If it does come into contact with the cells lining the intestine, it secretes the same substances it uses to digest bacteria, so destroying the cell membranes and resulting in penetration and digestion of human tissues. Symptoms range from fatigue, abdominal cramps and watery or bloody diarrhoea through to fever and vomiting. The insidious onset of symptoms (typically two to four weeks after initial infection) and their variability make diagnosis particularly difficult [1]. Once amoebae enter the bloodstream, they may be carried to other organs in the body, particularly the liver, causing liver abscess. In 1998, the World Health Organisation estimated that amoebiasis resulted in about 70,000 deaths annually, making it the fourth leading cause of death and the third leading cause of morbidity due to protozoan infections worldwide [2].

Non-invasive amoebiasis is commonly treated using paromomycin, but this is poorly absorbed from the gastrointestinal tract (most of the dose is eliminated unchanged in the faeces) so another antiprotozoal, metronidazole, is used to treat invasive amoebiasis. However, metronidazole has adverse effects [3], while potential resistance of E. histolytica to the drug is a growing problem [4,5].

Now, a collaboration of scientists from the University of California (UC), San Francisco, UC San Diego, Wake Forest School of Medicine at Winston-Salem, North Carolina, the University of Utah, Salt Lake City and the Centre for Research and Advanced Studies of the National Polytechnic Institute in Mexico City has developed an automated high-throughput screen to test a 910-member library consisting of both FDA-approved and unapproved bioactive compounds for activity against E. histolytica [6]. This involved overcoming the problems that E. histolytica is an anaerobe and that no rapid readout assay was available. The group found that auranofin (CHEBI:2922), a drug approved by the FDA 25 years ago for the treatment of rheumatoid arthritis, was ten times more potent against E. histolytica than metronidazole. In a mouse model of amoebic colitis and a hamster model of amoebic liver abscess, auranofin markedly decreased the number of parasites, damage from inflammation, and the size of liver abscesses.

The fact that auranofin has already been approved by the FDA for use in humans means that years of expensive development can be saved. The U.S. National Institutes of Health has granted auranofin "orphan-drug" status (used to identify a significant, newly developed or recognized treatment for a disease which affects fewer than 200,000 persons in the U.S.) and the UC San Diego hopes to conduct clinical trials in the near future.

The background image shows Trophozoites (the active, feeding stage) of Entamoeba histolytica with ingested erythrocytes.

Reference(s)

  1. Haque, R., Huston, C.D., Hughes, C.D., Houpt, E. and Petri, W.A., Jr. (2003), Amebiasis. N. Engl. J. Med., 348(16), 1565–1573.
  2. The world health report 1998 - Life in the 21st century: A vision for all. (World Health Organisation, Geneva, 1998).
  3. Krogstad, D.J. and Cedeno, J.R. (1988), Problems with current therapeutic regimens. In Ambiasis: Human Infection by Entamoeba histolytica (ed. Ravdin, J.I.) 741–748 (John Wiley & Sons, New York).
  4. Samarawickrema, N.A., Brown, D.M., Upcroft, J.A., Thammapalerd, N. and Upcroft, P. (1997), Involvement of superoxide dismutase and pyruvate:ferredoxin oxidoreductase in mechanisms of metronidazole resistance in Entamoeba histolytica. J. Antimicrob. Chemother., 40(6), 833–840.
  5. Wassmann, C., Hellberg, A., Tannich, E., and Bruchhaus, I. (1999), Metronidazole resistance in the protozoan parasite Entamoeba histolytica is associated with increased expression of iron-containing superoxide dismutase and peroxiredoxin and decreased expression of ferredoxin 1 and flavin reductase. J. Biol. Chem., 274(37), 26051–26056.
  6. Debnath, A., Parsonage, D., Andrade, R.M., He, C., Cobo, E.R., Hirata, K., Chen, S., García-Rivera, G., Orozco, E., Martínez, M.B., Gunatilleke, S.S., Barrios, A.M., Arkin, M.R., Poole, L.B., McKerrow, J.H., and Reed, S.L. (2012), A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nature Medicine, doi:10.1038/nm.2758, published online 30 May 2012.

8th May 2012, Imidacloprid


The recent decline in bee population, known as colony collapse disorder, is causing great concern amongst scientists because of the valuable ecosystem service they provide [1]. Two recent studies have indicated that a group of widely used pesticides may be partially to blame for declining bee populations. Neonicotinoids are a class of insecticides chemically related to nicotine and emerged in the mid-1990s as a relatively less toxic alternative to human-damaging pesticides. They are used to protect major crops and have become the world's most commonly used group of pesticides. However, exposure to sub-lethal amounts can also cause harm to non-target organisms, such as bees.

In a study by David Goulson and co-workers at the University of Stirling, UK, colonies of the bumble bee Bombus terrestris were exposed in the laboratory to sub-lethal amounts of the neonicotinoid imidacloprid (CHEBI:5870) and subsequently allowed to develop naturally under field conditions [2]. The pesticide-dosed colonies were found to have gained significantly less weight and produced 85% fewer new queens compared with control colonies. A separate study headed by Mickaël Henry at the National Institute for Agricultural Research in Avignon, France, offers a possible explanation for these findings [3]. They fed low levels of another neonicotinoid, thiamethoxam, to European honey bees Apis mellifera and tagged the bees with radio-frequency identification microchips to monitor their movements. The researchers found that the dosed bees were much more likely to die away from their hives, and suggested that the pesticide caused impairment of the bees' navigation abilities so they could not find their way home.

While the findings don't conclusively explain global bee declines they are expected to add weight to the call for the use of neonicotinoids to be banned or regulated. Germany, France and Slovenia already have strict limits on their use, and US beekeepers recently petitioned the Environmental Protection Agency to ban another neonicotinoid, clothianidin. Regulatory agencies are considering new guidelines for risk assessment of pesticides to bees and conducting tests in conditions that mimic nature as close as possible. Currently, tests are typically done in the laboratory and only focus on whether the pesticides kill the bees, but do not detect other subtle effects that can prove critical in the wild.

Reference(s)

  1. Stokstad, E. (2012), Field research on bees raises concern about low-dose pesticides. Science, 335, 1155–1156..
  2. Whitehorn, P.R., O'Connor, S., Wackers, F.L. and Goulson D. (2012), Neonicotinoid pesticide reduces bumble bee colony growth and queen production. Science, 336, 351–352.
  3. Henry, M., Béguin, M., Requier, F., Rollin, O., Odoux, J.-F., Aupinel, P., Aptel, S., Tchamitchian, S. and Decourtye, A., (2012), A common pesticide decreases foraging success and survival in honey bees. Science, 336, 348–350.

2nd April 2012, 4-methylimidazole


4-Methylimidazole (CHEBI:40035) is produced commercially by cyclocondensation of formaldehyde and ammonia with methylglyoxal. It is used as a chemical intermediate, starting material, or component in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation and from the browning of certain foods through the Maillard reaction between carbohydrates and organic amino-containing compounds. In particular, it is found in types of caramel colouring produced using ammonia-based processes. It has also been detected in mainstream and sidestream tobacco smoke. Because of its high potential for human exposure, a decade ago 4-methylimidazole was nominated by the US National Cancer Institute for a long-term study.

The results of the two-year feed studies that were carried out, published in a 278-page report in 2007 [1] and subsequently in a 2008 paper [2], concluded that although there was no evidence of carcinogenic activity of 4-methylimidazole in male rats, there was equivocal evidence of such activity in female rats based on increased incidences of mononuclear cell leukaemia. There was also clear evidence of carcinogenic activity in both male and female mice based on increased incidences of alveolar/bronchiolar neoplasms.

It was largely on the basis of this report that in January 2011 the State of California added 4-methylimidazole to its list of probable carcinogens [3] and stipulated the "No Significant Risk Level" intake to be 16 μg per day, an amount considerably less than that ingested by regular drinkers of the carbonated beverage cola. Hence on March 8th 2012 both the two main producers of cola, Coca-Cola and PepsiCo, announced [4] that they had lowered levels of 4-methylimidazole in the caramel colouring used in the manufacture of their drinks so as to avoid having to label their products with a cancer warning to comply with Californian law. However, both manufacturers insist that the drinks pose no health threats to humans and that, with the exception of the reduction in 4-methylimidazole content for the US market, recipes will not change. Indeed, the recipes are not changing in Europe at all, as there are no similar restrictions there on acceptable levels of 4-methylimidazole.

Reference(s)

  1. National Toxicology Program (2007) Toxicology and Carcinogenesis Studies of 4-Methylimidazole (CAS No. 822-36-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 535. NIH Publication No.05-4471. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health; Research Triangle Park, NC.
  2. Chan P.C., Hill G.D., Kissling G.E. and Nyska A. (2008) Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice. Arch. Toxicol., 82, 45–53.
  3. California Office of Environmental Health Hazard Assessment (2011) Proposition 65. Chemical listed effective January 7, 2011 as known to the State of California to cause cancer: 4-methylimidazole.
  4. The Coca-Cola Company, Coca-Cola Statement Regarding Caramel in our Beverages, press release, March 9, 2012.

5th March 2012, Ethanol


In one of the more unusual quirks of nature, an insect species has been found to use alcohol (ethanol, CHEBI:16236) for self-medication to ward off a blood-borne parasite [1]. Fruit flies of the species Drosophila melanogaster have developed an extremely high tolerance to alcohol over evolutionary time owing to their living in and feeding on rotting and fermented fruit. A recent study carried out by a research team headed by Todd Schlenke at Emory University (Atlanta, Georgia) has shown that the flies actually seek out and utilise the alcohol to help prevent predation from tiny parasitic wasps, which are their major killers [2]. The wasp mothers deposit their eggs on the inside of fruit fly larvae along with a venom to suppress their hosts' immune response. The hatchlings then eat the young flies from the inside out, eventually emerging as adult wasps from the remains of the fruit fly pupae. Fortunately for the flies, the high alcohol concentration in their bodies is harmless to them but deadly to the wasps.

Schlenke and his team released healthy and wasp-infected fruit fly larvae into Petri dishes that contained both regular food and food laced with alcohol, allowing them to freely move to either side. After 24 hours, 80% of the infected larvae were on the alcohol side of the dish, compared with only 30% of the non-infected ones. With infected fruit flies that had consumed alcohol-laced food, the wasps were killed in approximately 60% of the cases, but grew normally in all flies that fed on regular food. Furthermore, the wasps were found to be discouraged from laying their eggs into alcohol-soaked larvae. The team repeated the experiment using the species of wasp (Leptopilina boulardi) that lays its eggs specifically in D. melanogaster rather than the generalist wasp (L. heterotoma). Here, the alcohol diet was less effective, killing the specialist wasps in only 10% of the cases. These results indicate that the specialist wasp has also been able to adapt to the alcohol-fused habitat of D. melanogaster. The researchers hope that their data will lead to further studies of the protective effects of alcohol consumption in other organisms, including humans.

The background image shows a specimen of the fruit fly Drosophila melanogaster.

Reference(s)

  1. http://www.newscientist.com/article/dn21493-parasiteplagued-flies-selfmedicate-on-booze.html
  2. Milan, N.F., Kacsoh, B.Z. and Schlenke, T.A. (2012), Alcohol consumption as self-medication against blood-borne parasites in the fruit fly. Current Biology, doi:10.1016/j.cub.2012.01.045, published online 16 February 2012.

6th February 2012, (+)-artemisinin


There are five species of Plasmodium protazoan parasites which cause malaria in humans, of which Plasmodium falciparum is the deadliest [1,2], being responsible for almost all of the estimated 655,000 deaths from malaria in 2010 [3], the majority being of young children. Around 90% of the malaria-related deaths occur in sub-Saharan Africa, where P. falciparum is the cause of more than 75% of malarial infections.

As part of a secret anti-malarial drug discovery project set up by the Chinese army in 1967, Tu Youyou, a medical scientist at the Academy of Chinese Medicine (now the China Academy of Chinese Medical Research), in Beijing, screened over 2,000 recipes for traditional Chinese medicines. By 1971, her team had prepared 380 extracts from 200 herbs. They then assessed whether the substances could clear Plasmodia from the bloodstream of infected mice. One of the preparations she tested, described in a fourth century book titled Handbook of Prescriptions for Emergencies, used leaves of Artemisia annua (sweet wormwood, a common herb found in many parts of the world). Initially it was ineffective, as it had been extracted with boiling water which had destroyed the active ingredient. By extracting at lower temperatures using ether as the solvent, however, the preparation completely cleared Plasmodium from the blood in both mice and monkeys [4]. By the end of 1972, she and her team had isolated the active ingredient. This substance, named qinghaosu by the Chinese, remained unknown in the west until 1979 [5]. Artemisinin (CHEBI:223316), as the drug is best known in the west, has since saved millions of lives. It is the most effective treatment currently available for multi-drug-resistant forms of malaria, and artemisinin combination therapies (ACTs) are recommended as first-line drugs by the World Health Organisation [3]. Tu Youyou was awarded the prestigious Lasker-DeBakey Clinical Medical Research Award for her discovery in 2011.

Although a total synthesis of artemisinin has been described [6], it is not considered to be a viable route for satisfying the demand for artemisinin, which is now one of the few high-volume drugs to be entirely produced from a plant-based source. As Artemisia annua is an annual, supplies of artemisinin are seasonal and the price fluctuates widely. ACT drugs are consequently more expensive than other malaria treatments, even though Novartis and Sanofi provide the former on a non-profit basis [7]. By using artemisinic acid, a much less complex, bicyclic precursor as a starting point for synthesis, however, artemisinin could soon become cheaper and more readily available. Artemisinic acid is also obtainable from Artemisia annua, though in higher yields than artemisinin. Better still, artemisinic acid can be produced by engineered yeast, using a process invented by a group led by Jay D. Keasling at the University of California, Berkeley [8] and developed commercially by Amyris. Amyris have licensed their technology to Sanofi, who aim to bring artemisinin-based drugs to the market by 2013 [9]. The large-scale transformation of artemisinic acid to artemisinin is still a massive challenge, however, requiring the creation of three of the artemisinin's rings and the generation of the endoperoxide group that is crucial to the antimalarial activity.

Thanks to a recent publication by François Levésque and Peter H. Seeberger at the Max-Planck Institute for Colloids and Interfaces in Germany [10], however, the task could have been made considerably easier. They describe the combination of three separate steps in the transformation into a single continuous flow process. Of particular note is an oxidation step requiring the photochemical generation of singlet dioxygen. Reactions involving this highly reactive species are very difficult to perform on a large scale in conventional batch systems, due to the low rate of mass transfer of oxygen gas into the solution and the formation of potentially explosive hydroperoxides. However, Seeberger and Levésque have shown that they can generate singlet dioxygen on a preparative scale by simply wrapping the tubing containing the reactant flow around a cooled mercury lamp [11]. Their setup can now produce around 800 g of artemisin per day, meaning that the entire world demand for the drug, estimated at roughly 225 million doses, could be met by just 400 such reactors [9].

The background image shows an Anopheles gambiae mosquito feeding.

Reference(s)

  1. Perlmann, P. and Troye-Blomberg, M. (2000), Malaria blood-stage infection and its control by the immune system. Folia Biol. (Prague, Czech. Repub.), 46(6), 210–218.
  2. Snow, R.W., Guerra, C.A., Noor, A.M., Myint, H.Y. and Hay, S.I. (2005), The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature, 434, 214–217.
  3. World Malaria Report 2011.(World Health Organisation, Geneva, 2011).
  4. Miller, L.H. and Su, X. (2011), Artemisinin: discovery from the Chinese herbal garden. Cell, 146(6), 855–858.
  5. Qinghaosu Antimalarial Coordinating Research Group (1979), Chin. Med. J., 12, 811–816.
  6. Schmid, G. and Hofheinz, W. (1983), J. Am. Chem. Soc.,, 105, 625–627.
  7. Artemisinin combination therapies,(The CNAP Artemisia Research Project, University of York).
  8. Ro, D.-K., Paradise, E.M., Ouellet, M., Fisher, K.J., Newman, K.L., Ndungu, J.M., Ho, K.A., Eachus, R.A., Ham, T.S., Kirby, J., Chang, M.C.Y., Withers, S.T., Shiba, Y., Sarpong, R., and Keasling, J.D. (2006), Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature, 440, 940–943.
  9. Halford, B. (2012), Artemisinin goes with the flow. Chem. Eng. News, 90(4), 4.
  10. Levésque, F. and Seeberger, P.H. (2012), Continuous-flow synthesis of the anti-malaria drug artemisinin. Angew. Chem., Int. Ed., 51, in press.
  11. Levésque, F. and Seeberger, P.H. (2011), Highly efficient continuous flow reactions using singlet oxygen as a “green” reagent. Org. Lett., 13, 5008–5011.

9th January 2012, Mercury


Mercury (CHEBI:16170) is the only metallic element that is a liquid at standard temperature and pressure. Along with most of its compounds it is extremely toxic, causing both chronic and acute poisoning. Moreover, it has a tendency to accumulate in organisms and increase in concentration up through the food chain, and therefore monitoring of its levels in the environment is vitally important.

For this reason Aurore Aubail, working at the National Environmental Research Institute of Denmark, together with colleagues from France and Norway, have studied the temporal changes in mercury pollution exposure over the period 1964 to 2003 using polar bear teeth as a measure of the mercury exposure, and they now report their findings in the latest issue of Journal of Environmental Monitoring [1]. Polar bears sit on top of the Arctic food chain and are therefore particularly susceptible to accumulating high levels of mercury within tissues. Their teeth are regarded as an especially good matrix of the mercury exposure as, unlike soft tissue, they are not remodelled throughout the animal’s life.

Teeth from 87 polar bear skulls were therefore analysed using solid sample atomic absorption spectrophotometry. In addition the relative abundances of carbon (13C/12C) and nitrogen (15N/14N) stable isotopes were measured using isotope-ratio mass spectrometry to provide information about any changes in feeding habits or habitats. The results showed (i) a significant decrease in mercury concentrations in the dental tissue over the four decades and (ii) that there was no significant temporal trend in the δ15N or δ 13C signatures, thus eliminating variations in feeding habits or habitats. Aubail and her co-workers suggest that this decreasing temporal trend for mercury levels in the dental tissue may result from an overall decrease in mercury emissions from Europe and North America. When interviewed for Chemistry World, Aubail expressed the hope that the use of polar bear teeth to study mercury would continue as one of the methods of studying long-term trends of pollutants [2].

Reference(s)

  1. Aubail, A., Dietz, R, Rigét, F., Sonne, C., Wiig, Ø and Caurant, F. (2012), Temporal trend of mercury in polar bears (Ursus maritimus) from Svalbard using teeth as a biomonitoring tissue. J. Environment. Monit., 14, 56–63.
  2. Arctic biting back over mercury pollution, Chemistry World, 9 December 2011.



2011

5th December 2011, Pyrrolidin-2-one


Although spiders seem safe in their webs, in some parts of the world they are vulnerable to attack from armies of marauding ants. Surprisingly, ants are rarely found on the webs spun by batik golden web spiders (Nephila antipodiana), which live alongside many predatory ant species in south-east Asia [1]. Mark Elgar at the University of Melbourne, Australia, and Daiqin Li at the National University of Singapore analysed the webs of 21 batik golden web spiders and found that their silk contained pyrrolidin-2-one (CHEBI:36592). After stripping strands of the silk of chemicals, ants were lured with bait across a bridge constructed from the stripped thread. After reapplying pyrrolidin-2-one to the stripped thread, the ants were then deterred from following a trail of food back over it [2].

Furthermore, the chemical is only produced by adult and large juvenile spiders, while small and immature spiders, whose threads are sufficiently thin to make them inaccessible to ants, do not produce any. This suggests that production of pyrrolidin-2-one is actually a chemical response to the threat of predation, rather than a simple by-product of silk synthesis. These findings could pave the way for development of new insect repellents for humans.

Other current applications of pyrrolidin-2-one include use in industry as a high boiling non-corrosive polar solvent and as an intermediate in the manufacture of polymeric compounds, such as poly(vinylpyrrolidone).

Reference(s)

  1. http://www.newscientist.com/article/mg21228405.600-spider-webs-protected-by-chemical-ants-hate.html
  2. Zhang, S., Koh, T.H., Seah, W.K., Lai, Y.H., Elgar, M.A. and Li D. (2011), A novel property of spider silk: chemical defence against ants. Proc. R. Soc. B, doi:10.1098/rspb.2011.2193, published online 23 November 2011.

7th November 2011, Acetylsalicylic acid


The contributions of Dr. Thomas John MacLagan (1838–1903) to medicine were at one time ranked as equivalent to those of Joseph Lister and James Young Simpson, but have been largely forgotten [1]. MacLagan was a medical superintendent at Dundee Royal Infirmary from 1864 to 1866, during which time he had to cope with a major fever epidemic and became noted for pioneering the clinical use of thermometers. While working as a medical practitioner in Dundee (1869–1779), he carried out research into the use of salicin, a chemical extracted from willow bark. In 1874 he began using salicin for the treatment of rheumatism, and was the first to use salicin to cure acute articular rheumatism. His work was taken up by researchers in Germany, and in 1897 chemists at Bayer AG produced a synthetically altered version of salicin, acetylsalicylic acid (CHEBI:15365) (which had actually been prepared over forty years earlier by a French chemist, Charles Frédéric Gerhardt [2], though in a rather impure form). Bayer AG sold acetylsalicylic acid around the world under the trade name by which it is now best known, Aspirin. Although its use declined following the introduction of more effective alternatives (e.g. paracetamol, also known as acetaminophen, in 1956; ibuprofen in 1969), it rose again in the 1990s when it was shown to be effective as an anticoagulant agent and so was used as a preventative treatment for heart attack and stroke. In 2002, worldwide use was estimated as 40,000 tonnes – equivalent to around 120 billion tablets – per year [3].

More recently, it has become apparent that aspirin may find a potential new use as an agent for the prevention of colorectal cancer. Also known as bowel cancer, this is the second most common cancer in developed countries, with about 1 million new cases and over 600,000 deaths worldwide each year. Late last year, a 20-year follow-up of five pooled randomised trials of cardiovascular disease prevention assessing the effect of aspirin on incidence and mortality of colorectal cancer suggested that a daily dose of at least 75 mg of aspirin taken for several years reduced the 20-year risk of the cancer by 24%, while associated mortality was reduced by 35% [4]. However, a final conclusion on the ability of aspirin to prevent colorectal cancer still required a randomised trial of aspirin with colorectal cancer as the primary target. Now, the results of a study involving 861 carriers of the most common inherited colorectal cancer, Lynch syndrome (often called hereditary nonpolyposis colorectal cancer or HNPCC), have now been described in a major report by Sir John Burn and colleagues [5] which has generated international news coverage. Their study showed that carriers who took a daily dose of 600 mg of aspirin per day for an average of 25 months suffered significantly fewer cancers than those in the control group. Combined, these results and previous evidence suggest that aspirin should be seriously considered for the prevention of colorectal cancer, particularly in those who are at high risk of developing the disease.

The background image shows willows, a source of salicin, on the River Avon, east of Stratford-upon-Avon.

Reference(s)

  1. Stewart, W.K. and Fleming, L.W. (1987) Perthshire pioneer of anti-inflammatory agents (Thomas John Maclagan). Scott. Med. J., 32(5), 141–146. PMID: 3327165.
  2. Gerhardt, C. (1853) Untersuchungen über die wasserfreien organischen Säuren. Ann. Chem., 87(2), 149–179.
  3. Warner, T.D. and Mitchell, J.A. (2002) Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum? PNAS, 99(21), 13371–3373.
  4. Rothwell, P.M., Wilson, M., Elwin, C.-E., Norrving, B., Algra, A., Warlow, C.P. and Meade T.W. (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet, 376, 1741–1750.
  5. Burn, J., Gerdes, A.-M., Macrae, F., Mecklin, J.-P., Moeslein, G., Olschwang, S., Eccles, D., Evans, D.G., Maher, E.R., Bertario, L., Bisgaard, M.-L., Dunlop, M.G., Ho, J.W.C., Hodgson, S.V., Lindblom, A., Lubinski, J. Morrison, P.J., Murday, V., Ramesar, R., Side, L., Scott, R.J., Thomas, H.J.W., Vasen, H.F., Barker, G., Crawford, G., Elliott, F., Movahedi, M., Pylvanainen, K., Wijnen, J.T., Fodde, R., Lynch, H.T., Mathers, J.C. and Bishop, D.T. (2011) Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet, doi:10.1016/S0140-6736(11)61049-0, published online 28 October 2011.

3rd October 2011, Aminocyclopyrachlor


Aminocyclopyrachlor (CHEBI:62952) was developed as a selective low-toxicity herbicide by the major American chemical company DuPont and was marketed by them as its potassium salt under the trade name Imprelis. However, in August of this year [less than a year following approval by the US Environmental Protection Agency (EPA)], DuPont voluntarily began a recall programme following several thousands of complaints that the product had caused significant damage to trees, particularly Norway spruce (Pinus abies) and the various species of white pine (e.g. Pinus strobus) [1].

Aminocyclopyrachlor is a synthetic auxin with a substituted pyrimidine structure. Although the mechanism of its action has not been fully established, one theory is that it works in a manner similar to that of other synthetic herbicides such as clopyralidand aminopyralid, namely by interfering with a plant's hormonal balance in order to override its ability to control cellular metabolism at the most active growth points (shoots and roots) [2]. DuPont had been marketing Imprelis to provide preemergent and/or postemergent control of broadleaf weeds on non-food use sites, such as rights of way, wildlife management areas and recreational areas (e.g. golf courses), as well as in commercial properties such as turf farms. It is possible that the method of application, involving treatment of the grassland at a time when adjacent conifers are growing and metabolising at high rates, may be one of the main causes for the detrimental effect on the conifers, effects principally characterised by such symptoms as browning of tree shoots and needles and stunting of fresh growth.

The EPA issued an order halting the sale of Imprelis two weeks after DuPont's voluntary withdrawal of the product [3].

Reference(s)

  1. E. I. du Pont de Nemours and Company, Imprelis Facts information sheet, August 2011.
  2. Trusty, S. (2011) Industry Advancements: What«s New in Weed Control. Sports Field Management, January 2011.
  3. U.S. Environmental Protection Agency, News release, EPA Issues Stop Sale Order to DuPont on Sale and Distribution of Imprelis Herbicide, August 11, 2011.

5th September 2011, Tetraethyllead


The recently deceased Emeritus Professor Derek Bryce-Smith had a long and distinguished career at the University of Reading, spanning a wide variety of interests including organometallic chemistry, radical chemistry and photochemistry. However, he will arguably be best remembered for alerting the world to the dangers of tetraethyllead (CHEBI:30182), which was used for several decades as an anti-knock additive in petrol. Ridiculed by the oil industry and marginalised for several years, he lived to see the eventual banning of leaded fuel in almost every country. "It was a very lonely battle for a very long time," he said. "A lot of my colleagues looked at me sideways, because many research chemists are in debt to the oil industry, which provides them with money for research."

Tetraethyllead consists of a lead atom bonded to a tetrahedral arrangement of four ethyl groups. The C-Pb bond is relatively weak, and in the hot environment of an internal combustion engine it undergoes fission to produce lead, a potent and insidious neurotoxin, and ethyl radicals which can help terminate the combustion process by radical reactions and prevent "knocking" (uncontrolled pre-ignition of fuel causing a pinging noise in the engine, which reduces efficiency and leads to eventual damage) [1]. The lead formed on combustion is subsequently dispersed into the atmosphere via the exhaust. The discovery of the environmental and health damage caused by the lead, as well as the incompatibility of lead with catalytic converters, resulted in the phasing out of leaded fuel and development of replacement anti-knock additives, such as MTBE, ferrocene, toluene and isooctane.

Reference(s)

  1. Seyferth, D. (2003), The rise and fall of tetraethyllead. 2. Organometallics 22, 5154–5178.

1st August 2011, Roxarsone


The antiprotozoal (coccidiostat) properties of roxarsone (CHEBI:35817), an organoarsenic compound first synthesised over a hundred years ago [1], were responsible for it becoming, on March 21st 1944, the first arsenic-based product approved for use in animal feeds by the U.S. authorities. For over half a century, roxarsone (also known by its trade name, 3-NitroTM) has been used as a feed additive in the poultry industry to control coccidiosis (a parasitic disease that infects the intestinal tract of poultry) and promote growth, particularly in broiler chickens.

In its original organic form, the arsenic in roxarsone is relatively benign, being non-carcinogenic and less toxic than the inorganic forms of arsenic, arsenite and arsenate, which are now classed as human carcinogens by the U.S. Environmental Protection Agency, and can cause immunological and neurological problems on long-term exposure [2]. Very little roxarsone is retained in the chicken meat (the U.S. Food and Drug Administration (FDA) limit is 0.5 ppm in chicken muscle tissue), and nearly all is excreted unchanged, meaning that in the U.S. alone, an estimated 1,000-2,000 tonnes of roxarsone and its degradation products have been added to the environment each year by the disposal of poultry litter, which is either spread on agricultural fields near the chicken houses, or made into fertilizer pellets for use on domestic lawns and gardens [3].

Recognition that roxarsone was ultimately converted by bacteria into inorganic (and hence water-soluble) forms of arsenic in the environment [4–7], resulted in increased public concern over the use of roxarsone, as well as law suits contending that arsenic in poultry litter had caused ill effects in humans. The European Union banned the use of arsenic in animal feeds in 1999 [8], while in the U.S., Tyson Foods, the country's largest poultry producer, stopped using arsenic compounds in 2004. Even so, roxarsone remained part of the diet for the majority of the 9 billion broiler chickens produced in the U.S. each year [3]. In a recent FDA study [9], scientists found that levels of inorganic arsenic in the livers of chickens treated with roxarsone were increased relative to levels in the livers of the untreated control chickens. Even though the levels found are not thought to pose any risk to health, on June 8, 2011 Alpharma, LLC, (now a part of Pfizer Animal Health), who are the U.S. manufacturers, announced that they would voluntarily suspend sales of roxarsone within 30 days, so giving animal producers time to move to other treatment strategies [10,11]. It now seems likely that the future of nitarsone (trade name HistostatTM, also manufactured by Alpharma), a compound closely related to roxarsone and now the last remaining organoarsenic feed additive, is in the balance.

The background image shows five-day-old Cornish-Rock (Cornish Cross) broiler chicks in a brooder.

Reference(s)

  1. Benda, D. and Bertheim, A. (1911) Über Nitro-oxy-aryl-arsinsäuren. Ber., 44, 3445–3448.
  2. http://www.epa.gov/ttn/atw/hlthef/arsenic.html.
  3. Hileman, B. (2007), Arsenic in chicken production. Chem. Eng. News, 85(15), 34–35.
  4. Garbarino, J.R., Bednar, A.J., Rutherford, D.W., Beyer, R.S. and Wershaw, R.L. (2003), Environmental fate of roxarsone in poultry litter. I. Degradation of roxarsone during composting. Environ. Sci. Technol., 37, 1509–1514.
  5. Rutherford, D.W.,Bednar, A.J., Garbarino, J.R., Needham, R., Staver, K.W.,Wershaw, R.L. (2003), Environmental fate of roxarsone in poultry litter. Part II. Mobility of arsenic in soils amended with poultry litter. Environ. Sci. Technol.,, 37, 1515–1520.
  6. Cortinas, I., Field, J.A., Kopplin, M., Garbarino, J.R., Gandolfi, A.J. and Sierra-Alvarez, R. (2006), Anaerobic biotransformation of roxarsone and related N-substituted phenylarsonic acids. Environ. Sci. Technol., 40, 2951–2957.
  7. Stolz, J.F., Perera, E., Kilonzo, B., Kail, B., Crable, B., Fisher, E., Ranganathan, M., Wormer, L. and Partha Basu, P. (2007), Biotransformation of 3-nitro-4-hydroxybenzene arsonic acid (roxarsone) and release of inorganic arsenic by Clostridium species. Environ. Sci. Technol., 41, 818–823.
  8. Commission Directive 2009/141/EC.
  9. FDA Study 275.30 (2011), Arsenic speciation in broiler chickens. a) Summary Final Report. b) Amendments to final report. c) Analyst's report. d) Statistician's Report.
  10. Pfizer To Suspend Sale of 3-Nitro (Roxarsone) in the United States (Alpharma news release), June 8, 2011.
  11. FDA: Pfizer will voluntarily suspend sale of animal drug 3-Nitro (FDA press release), June 8, 2011

4th July 2011, Bendroflumethiazide


One of the more recent controversies involving the use of performance-enhancing drugs in sport has involved Manchester City footballer Kolo Touré. In February 2011, the player tested positive for a specified substance, subsequently found to be the banned diuretic bendroflumethiazide (CHEBI:3013), which he blamed on the use of dietary water tablets belonging to his wife. Touré admitted the offence, which contravened Regulation 3 of the Football Association Doping Regulations 2010-11 and was suspended from all footballing activities for six months [1], escaping the recommended two-year ban because the Football Association's independent regulatory commission ruled his intent was not to mask drug use, but instead to control his weight [2].

Bendroflumethiazide belongs to a group of drugs called thiazide diuretics. These act inside the kidney, removing water from the blood and turning it into urine, through increasing the removal of salts such as potassium and sodium salts from the blood. This removal of salts causes water to be drawn out of the blood and into the kidneys, at a faster rate. Thiazides are also used to treat hypertension, although the mechanism of action is not fully understood.

Reference(s)

  1. http://news.bbc.co.uk/sport1/hi/football/teams/m/man_city/9498185.stm.
  2. http://www.telegraph.co.uk/sport/football/teams/manchester-city/8567138/Manchester-City-defender-Kolo-Toure-banned-for-taking-dietary-supplements-was-obsessed-with-his-belly.html.

6th June 2011, Electron


Knowing something as apparently simple as whether electrons are round or egg-shaped has far-reaching ramifications for testing some of the theories of particle physics and for the types of particles that could be detected at high-energy accelerators, such as the Large Hadron Collider. The Standard Model of particle physics predicts that the electron (CHEBI:10545) should behave as though it were almost perfectly spherical, with the distortion from a perfect sphere being far too small to detect. However, this cannot account for the observed predominance of matter over antimatter in the universe, and so has led physicists to propose extensions and refinements to the Standard Model, known as supersymmetry, in which the electron would have a much more distorted shape than the Standard Model suggests - so much so, that the distortion should be detectable.

Recently, a team from Imperial College in London has reported on an experiment spanning more than a decade and resulting in the most accurate measurements of the shape of the electron yet [1]. Their findings suggest that the electron differs from being perfectly round by less than 1 x 10-27 cm, meaning that if the electron were magnified to the size of the solar system, it would still appear spherical to within the width of a human hair. Although the findings do not support the theory of supersymmetry, they do not rule it out. The researchers are now refining their methods to improve the precision of their measurements still further.

The image shows a beam of electrons moving in a circle (cyclotron motion) within a glass bulb.

Reference(s)

  1. Hudson, J.J., Kara, D.M., Smallman, I.J., Sauer, B.E., Tarbutt, M.R., and Hinds, E.A. (2011), Improved measurement of the shape of the electron. Nature, 473, 493–496.

4th May 2011, Choline


Choline (CHEBI:15354) is a water-soluble, semi-essential nutrient similar to the B-vitamins. Long recognised as an important promoter of good health, it is synthesised by the body, but dietary supplementation is required to ensure adequate intake. Sources of choline include soybeans, egg yolk, beef, cauliflower and navy beans. A lipotropic agent, choline is essential in the brain development of foetuses and infants [1]. It has also been shown to improve cognitive function in adults; to enhance alertness and mood; and to support liver and cardiovascular health [2]. It is used in the treatment of liver disorders, Alzheimer's Disease, bipolar disorder and atherosclerosis (fat build-up in the arteries). Its most commonly available form is lecithin, a phospholipid mixture containing 20-90% active ingredient phosphatidylcholine, but healthy amounts of choline and its metabolites trimethylamine N-oxide (TMAO) and glycine betaine [3] occur in fruits, and direct-to-consumer dietary supplements are freely available for human consumption, as well as for use in livestock feed.

Cardiovascular disease is the world's largest killer, with many risk factors which interact in myriad ways. Recent ground-breaking work in metabolomics (the study of global metabolite profiles in an organism under a given set of conditions) sheds some light on how these factors may interact differentially to produce the variable susceptibilities to heart disease experienced by different individuals, even while on identical diets. In particular, the Hazen group at the Lerner Research Institute in Cleveland has reported its discovery of a pathway linking dietary lipid intake and intestinal flora with increased risk of heart disease [4,5,6]. Eighteen small molecules were found to be associated with atherosclerotic plaque build-up in the arteries, three of which - choline, TMAO and betaine - were especially good predictors of atherosclerosis. This finding represents a unique addition to cardiovascular disease pathogenesis in implicating not just the common dietary supplements choline and its metabolites, but also in identifying intestinal flora as obligatory participants in atherogenesis. The findings suggest that, since these molecules can serve as heart disease markers, a blood test for any of them may be able to identify those at greater risk for heart disease.

A caveat in the interpretation of these results: the mice in the Hazen study were of a breed already genetically prone to heart disease, and were fed huge amounts of choline, much more than would normally be consumed in day-to-day living. Nevertheless, the study is useful in raising the question of the need to consider risk vs. benefits of some commonly used supplements. It also offers the prospect of the potential design of healthy-promoting yoghurt that acts by changing the demographics of intestinal probiotics, or drugs to block the production of harmful metabolites.

In conclusion, metabolomics studies have identified, through the discovery of novel heart disease markers, potential tools for improved diagnosis, prevention and treatment of heart disease.

Reference(s)

  1. Sentongo, T.A., Kumar., P., Karza, K., Keys, L., Iyer, K. and Buchman, A.L. (2010), Whole-blood-free choline and choline metabolites in infants who require chronic parenteral nutrition therapy. J. Pediatr. Gastroenterol. Nutr. 50, 194-9.
  2. Ueland, P.M. (2010), Choline and betaine in health and disease. J. Inherit. Metab. Dis. 34, 3-15.
  3. Babb, S.M., Ke, Y., Lange, N., Kaufman, M.J., Renshaw, P.F. and Cohen, B.M. (2004), Oral choline increases choline metabolites in human brain. Psychiatry Res. 130, 1-9.
  4. Wang, Z., Klipfell, E., Bennett, B.J., Koeth, R., Levison, B.S., DuGar, B., Feldstein, A.E., Britt, E.B., Fu, X., Chung, Y.M., Wu, W., Schauer, P., Smith, J.D., Allayee, H., Tang, W.H.W., DiDonato., J.A., Lusis, A.J. and Hazen, S.L. (2011), Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57-63.
  5. Carr, E. (2011), A role for gut flora in cardiovascular disease: you are what they eat. Cambridge Medicine Journal.
  6. Lerner Research Institute (2011), Common dietary fat and intestinal microbes linked to heart disease. ScienceDaily.

4th April 2011, Amphotericin B


Amphotericin B (ChEBI:2682) is a highly potent antifungal drug, which has been in widespread clinical use since the 1960's [1]. Its mode of action involves formation of molecular pores on fungal cell membranes. These transmembrane channels allow ions to leak from the cell, resulting in its death. The presence of a sterol, such as cholesterol or ergosterol, in the cell is required for formation of the ion channels. However, it is the exact nature and extent of the interaction between the fungicide and sterols in the cell that has hitherto baffled scientists for more than 50 years [2].

Recent work carried out by a team of scientists from the University of Illinois at Urbana-Champaign led by Martin Burke have solved this mystery by performing a highly sensitive isothermal titration calorimetry assay [3], which has proved that direct binding between fungicide and sterol definitely occurs. By using intricate synthetic techniques, the researchers prepared several derivatives of amphotericin lacking the carboxylic acid and sugar functional groups [3], which were thought to be involved in sterol binding. By repeating the isothermal titration calorimetry assay with the synthetic derivatives, it was proved unequivocally that the sugar group alone is required for sterol binding to form ion channels and destroy fungal cells.

The enhanced understanding of the mode of action has potential to reduce the toxic side-effects of amphotericin B, which include chills, fever, hypotension, nausea and headaches. In addition, there is also the possibility to develop new drugs to replace faulty proteins in human cells and to correct ion-channel dysfunction, which is responsible for several diseases, including cystic fibrosis.

Reference(s)

  1. Sanglard, D. and Odds, F.C. (2002), Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2, 666–669.
  2. http://www.rsc.org/chemistryworld/News/2011/March/09031102.asp.
  3. Palacios, D.S, Dailey, I., Siebert, D.M., Wilcock, B.C. and Burke M.D. (2011), Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities. Proc. Natl. Acad. Sci. U.S.A. doi:10.1073/pnas.1015023108.

9 March 2011, Thiopental sodium


Over 75 years has elapsed since thiopental sodium (CHEBI:9561) was first used clinically as an intravenous anaesthetic. Also called sodium thiopental and more commonly known in the UK as sodium thiopentone, it is a barbiturate, so acts on the GABAA receptors to cause a marked decrease in neuronal activity. For this reason, overdoses can be fatal, and were initially an important factor in mortality associated with the use of the drug, particularly for trauma patients who were in a state of shock. For many years, it was widely believed that at the Japanese attack on the American bases in Hawaii in December 1941, ..."i.v. anaesthesia was the cause of more fatalities among the servicemen at Pearl Harbor than were the enemy bombs" [1]. Only decades later, with the release of hospital records through U.S. freedom of information legislation, did it become clear that the rumoured death rate was greatly exaggerated. For example, of 344 wounded admitted to Tripler Army Hospital during the morning of December 7th 1941, only 13 did not survive [2]. With the publication of improved dosing procedures for trauma cases in January 1943 [3], thiopental sodium became an invaluable drug for the rapid induction (30 seconds) of general anaesthesia in both humans and animals. (It is not used to maintain anaesthesia due to prolonged recovery times; this is normally done with an inhaled anaesthetic agent.) It is still used to provide general anaesthesia hundreds of thousands of times each year in the U.K. alone [4].

Thiopental sodium was first synthesised in the early 1930s by Ernest H. Volwiler and Donalee L. Tabern at Abbott Laboratories in Illinois. Abbott manufactured the drug until 2004, when its Hospital Products division was spun off as Hospira. Following difficulties in obtaining raw materials, Hospira ceased manufacturing the drug in the U.S. in 2010, resulting in a world shortage, and bringing a darker side of thiopental sodium to public prominence. For in over 30 states of the U.S., thiopental sodium is used as part of the protocol for capital punishment by lethal injection. An initial injection of a very large dose of the drug is used to ensure rapid loss of consciousness, and is followed sequentially by injection of the muscle relaxant pancuronium bromide, which causes paralysis and stops breathing, and potassium chloride, which stops the heart. The states of Ohio and Washington have used thiopental sodium alone in cases where the normal procedure failed due to the inability to locate suitable veins. The shortage of thiopental sodium has therefore caused problems for the U.S. prison authorities, who have been looking abroad for supplies. For Arizona State Prison Complex, Florence, success was found in the U.K. last September: in Horn Lane, Acton, in west London, a small office is home to a driving school and a pharmaceutical wholesalers named Dream Pharma Ltd. [5], who supplied thiopental sodium apparently obtained from the British license holder, Archimedes Pharma UK [6]. Following a public outcry and a legal challenge, the British government reversed an initial decision and imposed export controls on the drug in late November 2010 to prevent its use in executions.

Hospira was originally planning to move production of thiopental sodium from the U.S. to Italy. However, the Italian parliament would only allow the drug to be made there if Hospira could guarantee that it would not be used in capital punishment. Since Hospira typically distributes the drug through wholesalers, the end use would be difficult to guarantee, so Hospira have recently decided to abandon attempts to resume production of the drug [6,7]. So now U.S. prison authorities must look elsewhere for supplies, or change to a different drug and face the inevitable legal challenges. In the meantime, it seems likely that the number of prisoners on "death row" in the U.S. (there are currently over 300 in Texas alone) will continue to rise.

Reference(s)

  1. Payne, J.P. (1994) Awareness and its medicolegal implications. Br. J. Anaesth., 73, 38–45.
  2. Bennetts, F.E. (1995) Thiopentone anaesthesia at Pearl Harbor. Br. J. Anaesth., 75, 366–368.
  3. Adams, R.C. and Gray, H.K. (1943) Intravenous anesthesia with Pentothal sodium in the care of gunshot wounds associated with accompanying severe traumatic shock and loss of blood: report of a case. Anesthesiology, 4, 70–73.
  4. Price, D. (2011) The case for sodium thiopental (letter) The Times, February 16 (Issue 70184), page 23.
  5. http://news.bbc.co.uk/today/hi/today/newsid_9342000/9342976.stm.
  6. http://www.guardian.co.uk/world/2011/jan/23/lethal-injection-sodium-thiopental-hospira?INTCMP=SRCH.
  7. Hospira Statement Regarding PentothalTM (sodium thiopental) Market Exit (Hospira news release), Jan. 21, 2011.

7 February 2011, Clenbuterol


One of the most recent high-profile allegations of the use of performance-enhancing drugs in sport involves the Spanish winner of the 2010 Tour de France cycle race, Alberto Contador. Following detection of a small amount of the sympathomimetic amine clenbuterol (CHEBI:174690) in a urine sample taken during a rest day of the 2010 Tour, Contador has been given a provisional one-year ban from racing by the Royal Spanish Cycling Federation and could be stripped of his 2010 Tour title by the Union Cycliste Internationale, the world governing body for cycle racing. Throughout the proceedings, Contador has continued to protest his innocence, claiming the source of the drug to have been contaminated meat.

Clenbuterol is most commonly available as its hydrochloride salt and is used principally by sufferers of breathing disorders as a decongestant and bronchodilator. It is a β-adrenergic agonist with some structural and pharmacological similarities to adrenaline (epinephrine) and albuterol (salbutamol). Its effect in increasing the rate at which body fat is metabolised has led to its use in livestock to increase the muscle-to-body ratio and thus obtain leaner meat, a practice that is banned in the European Union and many other countries. In the USA, incidences of localised food contamination led its use being restricted in 2006 to the treatment of horses, while in China two cases of widespread poisoning have occurred, thought to be due to the consumption of meat infected with clenbuterol [1,2].

Reference(s)

  1. AFP News Release, September 19, 2006.
  2. China Daily, February 23rd, 2009.



2010

6 December 2010, Coenzyme Q10


Coenzyme Q10 (ChEBI:46245, also known as ubiquinone-10, CoQ10, CoQ, Q10 or simply Q) is a ubiquinone containing 10 isoprenoid units. First discovered in 1957 by Crane et al. [1], its chemical structure was determined by Karl Folkers [2], who later won the Priestley medal from the American Chemical Society. This oil-soluble, vitamin-like micronutrient forms part of the electron transport chain which, in the process of aerobic respiration, generates 95% of the human body's energy as ATP [3].

Coenzyme Q10 is synthesized de novo by every cell in the body, but levels decrease with age, in several clinical disorders, and in patients administered certain drugs such as hydroxymethylglutaryl-CoA reductase inhibitors (commonly known as statins). With cardiovascular disease being a leading cause of death in the West, evidence that oral supplements of coenzyme Q10 can benefit patients suffering from heart disease is of increasing appeal. Evidence is also accumulating for its effective treatment of other ailments including mitochondrial disorders and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington's disease and Parkinson's disease.

Coenzyme Q10 is one of the best-selling dietary supplements worldwide, available over the counter from health food shops and pharmacies. Its popularity may be due to the wide-ranging claims made for its effectiveness in a myriad of human health issues: it is marketed as an energy booster; a periodontal health promoter; an agent for maintaining normal blood-cholesterol levels; an enhancer of cognitive function; a remedy for hypertension, migraine headaches, radiation injury and cancer; and a superdrug capable of delaying or even reversing the effects of aging. However, perusal of the scientific literature reveals that, while data supporting some claims are forthcoming (such as in the case of heart disease and mitochondrial function), coenzyme Q10 is neither panacea nor elixir [4,5].

References

  1. Crane, F.L., Hatefi, Y., Lester, R.L. and Widmer, C. (1957) Isolation of a quinone from beef heart mitochondria. Biochim. Biophys. Acta 25, 220–221.
  2. Wolf, D.E., Hoffman, C.H., Trenner, N.R., Arison, B.H., Shunk, C.H., Linn, B.O., McPherson, J.F. and Folkers, K. (1958) Coenzyme Q. I. Structure studies on the coenzyme Q group. J.Am. Chem. Soc. 80, 4752.
  3. Ernster, L. and Dallner, G. (1995) Biochemical, physiological and medical aspects of ubiquinone function. Biochim. Biophys.Acta 1271, 195–204.
  4. Watts, T.L. (1995), Coenzyme Q10 and periodontal treatment: is there any beneficial effect? Br. Dent. J. 178, 209–213.
  5. European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies (2010), Scientific Opinion on the substantiation of health claims related to coenzyme Q10 and contribution to normal energy-yielding metabolism (ID 1508, 1512, 1720, 1912, 4668), maintenance of normal blood pressure (ID 1509, 1721, 1911), protection of DNA, proteins and lipids from oxidative damage (ID 1510), contribution to normal cognitive function (ID 1511), maintenance of normal blood cholesterol concentrations (ID 1721) and increase in endurance capacity and/or endurance performance (ID 1913) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J. 8, 1793–1819.

1 November 2010, Graphene


The discovery of graphene (ChEBI:36973) has unusual origins in pencil lead and adhesive tape. In 2004, two scientists at the University of Manchester, UK attached adhesive tape to a piece of graphite then repeatedly peeled it back until they had the thinnest layer possible [1]. This was then attached to an oxidised silicon plate and the ultrathin layers observed using an electron microscope. Because graphene is so thin, it is virtually transparent and is the strongest material known to science [2]. It conducts electricity better than copper and also outperforms all other known materials as a conductor of heat.

The two scientists, Andre Geim and Konstantin Novoselov have shared the 2010 Nobel Prize for Physics for their "groundbreaking experiments regarding the two-dimensional material graphene".

The breakthrough has led to an explosion of interest in graphene. The best-known potential use for graphene is as a replacement for silicon in computer chips. Graphene's electrons move 100 to 1,000 times faster than those of silicon meaning less power will be required for the same computing capacity. this could result in a new generation of faster smaller computers. The incredible strength of graphene provides the possibility of mixing small amounts into other materials and using the resulting composites to produce stronger and lighter materials. The major hold-up for progress is finding a way to produce graphene on an industrial scale. The process using adhesive tape and graphite known as 'exfoliation' is slow and labour intensive but has been scaled up with some companies currently able to produce graphene by the ton [3].

References

  1. Novoselov, K.S., Geim, A.K., Morozov, S.V., Jiang, D., Zhang, Y., Dubonos S.V., Grigorieva I.V. and Firsov, A.A. (2004), Electric field effect in atomically thin carbon films. Science 306, 666–669.
  2. Lee, C., Wei X., Kysar, J.W. and Hone J. (2008) Measurement of the elastic properties and intrinsic strength of monolayer graphene. Science 321, 385–388.
  3. Segal, M. (2009) Selling graphene by the ton. Nature Nanotechnology 4, 612–614.

4 October 2010, Aldicarb


Aldicarb (CHEBI:2555) is a systemic insecticide, acaricide (a substance that kills ticks and mites), and nematocide (a substance that kills parasitic nematodes). It is commonly used under the trade name Temik, a granular mix containing 10–15% of the active ingredient, which is a mixture of E and Z isomers (it is not certain which is the more active).

After the granules are applied to the soil, aldicarb dissolves in water present in the soil and is then taken up by the roots of the plants being protected. First described in the 1960s [1,2], it was introduced to the market in 1970 by Union Carbide Corporation and has since been used for the control of pests on a wide variety of crops, including bananas, beans, carrots and parsnips, citrus, cotton, onions, pecans, potatoes, sorghum, soya, sugar beet, and sweet potatoes.

One of the carbamate class of pesticides, aldicarb is an acetylcholinesterase inhibitor. It thus acts as a nerve poison by disrupting nerve impulses. Although not thought to be teratogenic, mutagenic or carcinogenic, it is the most toxic widely used pesticide. LD50 values for aldicarb administered in liquid form to rats, mice, and rabbits range from just 0.5 to 1 mg/kg; though less poisonous, the granules are still classed as highly toxic [3]. Moreover, because of its moderate solubility in water it can leach through soil into groundwater, and thus, perhaps unsurprisingly, its use has been beset by controversy.

Aldicarb is manufactured by the addition of 2-methyl-2-(methylsulfanyl)propanaldoxime to methyl isocyanate. In 1984, a leak of methyl isocyanate at a Union Carbide factory in Bhopal, India, making aldicarb and the related pesticide carbaryl for the Indian cotton crop, killed over 3,000 local residents; some estimates of the death toll exceed 15,000 [4]. (Union Carbide subsequently sold its worldwide agrochemical division to Rhône-Poulenc, who became part of Aventis CropScience GmbH in 1999 and were in turn acquired by Bayer in 2002 to form part of Bayer CropScience AG, the current manufacturer). In the U.S. in the mid-1980s, several incidents in which misapplication of aldicarb resulted in contaminated cucumbers and watermelons occurred, causing adverse effects in people. Subsequent reviews resulted in reductions in the levels of permitted residues and increased restrictions on the conditions under which use of aldicarb was allowed. Despite protests from farmers that alternative products were much less effective, its use was effectively banned in Europe in 2007 [4].

Now, 40 years after it was first registered, aldicarb is approaching the end of the road. Bayer CropScience has recently announced that it is to remove it voluntarily from the market worldwide by the end of 2014. In an agreement with the U.S. Environmental Protection Agency [5], U.S. farmers must stop using aldicarb on citrus and potatoes by the end of 2011, and on other crops by September 2018.

References

  1. Payne, L.K. Jr and Weiden, M.H.J. (1965) 2-Hydrocarbylthio-sulfinyl and sulfonylalkanal carbamoyloximes. U.S. Pat., US3217037.
  2. Payne, L.K. Jr, Stansbury H.A. Jr and Weiden, M.H.J. (1966) The synthesis and insecticidal properties of some cholinergic trisubstituted acetaldehyde O-(methylcarbamoyl)oximes. J. Agric. Food Chem., 14, 356–365.
  3. Risher, J.F., Mink, F.L. and Stara, J.F. (1987) The toxicologic effects of the carbamate insecticide aldicarb in mammals: a review. Environ. Health Perspect., 72, 267–281.
  4. http://www.pesticides.gov.uk/approvals.asp?id=2065
  5. U.S. Environmental Protection Agency (2010) Agreement to Terminate All Uses of Aldicarb, http://www.epa.gov/oppsrrd1/REDs/factsheets/aldicarb_fs.html

6 September 2010, Melamine


The search for a rapid and effective test for melamine (CHEBI:27915) became important following the contaminated milk scandal in China in 2008, when milk powder deliberately tainted with melamine killed six infants and sickened an estimated further 300,000.

Melamine (1,3,5-triazine-2,4,6-triamine) is an organic base, produced as a white, crystalline powder. It is only slightly soluble in water and is usually used to make melamine formaldehyde resin, fertilizer, flame retardants and other products. Its use as an additive in food or related ingredients is prohibited, as excessive ingestion of melamine will cause insoluble melamine cyanurate crystals to form in the kidneys leading to acute renal failure. Melamine's high nitrogen content (66% N by mass) gives it the analytical characteristics of protein molecules in some simple tests for protein used in the food industry, and it is this feature that has led to its illegal use as a food adulterant

Currently the most common tests for melamine are liquid chromatography–tandem mass spectrometry (LC–MS/MS) and gas chromatography–mass spectrometry (GC–MS). Other tests have been developed, e.g. capillary zone electrophoresis (CZE) and micellar electrokinetic chromatography (MEKC), but all of these tests, although highly sensitive, are time-consuming and labour-intensive. Now, Chinese scientists funded by the Chinese Ministry of Health have announced in the peer-reviewed journal Talanta that they have developed a quick and simple colorimetric testing method to detect melamine in milk products [1]. The method uses gold nanoparticles which, as they approach each other and aggregate, experience a colour change from wine-red to purple or blue. The presence of melamine in the tested product causes this aggregation approach to commence. The new test, which can be completed within 30 minutes, is low-cost, is visible to the naked eye and requires no pre-treatment, can be used on-site to test for melamine in both infant formula and liquid milk, with sufficient sensitivity for detection at the levels required by regulatory bodies.

Reference

  1. Guo, L., Zhong, J., Wu, J., Fu, F, Chen, G. and Lin, S. (2010) Visual detection of melamine in milk products by label-free gold nanoparticles. Talanta, doi:10.1016/j.talanta.2010.07.035.

2 August 2010, Oxytocin


Oxytocin (ChEBI:7872), sometimes known as the "love molecule" or the "trust molecule" plays an important role in many processes. These include uterine contractions during childbirth, sexual arousal, lactation, puberty, orgasm, facial recognition, trust, memory formation and pair bonding.

Oxytocin is a cyclic peptide hormone with just nine amino acids in sequence (CYIQNCPLG) that also acts as a neurotransmitter in the brain [1] where it is produced in the hypothalamus. It was the first ever polypeptide hormone to be sequenced and synthesized biochemically [2], work for which the American biochemist Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry.

Together with the neuropeptide argipressin (arginine vasopressin), it is believed to influence social cognition and behaviour. First shown in mice, recent studies have shown that also in humans simply sniffing a spray containing oxytocin increases a person's level of trust in others. [3].

References

  1. Lee, H.J., Macbeth, A.H., Pagani, J.H. and Young, W.S. (2009) Oxytocin: the great facilitator of life. Prog. Neurobiol. (Amsterdam, Neth.) 88, 127–151.
  2. du Vigneaud, V., Ressler, C., Swan, J.M., Roberts, C.W., Katsoyannis, P.G. and Gordon, S. (1953) The synthesis of an octapeptide amide with the hormonal activity of oxytocin. J. Am. Chem. Soc. 75, 4879–4880..
  3. Kosfeld, M., Heinrichs, M., Zak, P.J., Fischbacher, U. and Fehr, E. (2005) Oxytocin increases trust in humans. Nature 435, 673–676.

5 July 2010, Edaxadiene


Tuberculosis is a contagious pulmonary disease that is on the increase, killing 1.5 to 2 million people worldwide annually. It is caused by the pathogen Mycobacterium tuberculosis, but details about the virulence and infectivity of this organism are still only partly understood. This has in turn slowed progress towards the development of new drugs to combat the disease.

In 2009, a team of scientists from Iowa State, Illinois and Cornell Universities led by Professor Reuben Peters isolated from M. tuberculosis a halimane-type diterpenoid which they named edaxadiene, [1]. They found that the compound was produced by M. tuberculosis as a defence mechanism against attack by human macrophage cells, cells which aim to engulf and destroy infectious microbes. Peters' team proposed for the new molecule a structure consisting of a tricyclic core with five adjacent stereocentres.

Elsewhere, during an attempt to synthesise edaxadiene so as to be able to study it in more depth, Erik Sorensen and his colleagues at Princeton University deduced on the basis of spectral evidence that the molecule contained only a bicyclic core and had a longer side-chain. This alternative structure for edaxadiene, now confirmed following a successful synthesis of the molecule by Sorensen's team [2], forms our Entity of the Month and is shown as CHEBI:59685 In fact, a molecule with this same structure had been isolated some 6 years earlier from a sponge, Raspailia sp., collected from the Nosy Be island of Madagascar by a team led by Yoel Kashan of Tel-Aviv University and named appropriately by them as nosyberkol, [3].

The correct identification and successful synthesis of edaxadiene/nosyberkol should enable sufficient quantities of this compound to be prepared in order to elucidate more precisely its role in the infectivity and virulence of M. tuberculosis. It thus looks set to make a significant impact on our understanding of, and ability to treat, tuberculosis.

The background image shows a close-up of a culture of M. tuberculosis, revealing the organism's colonial morphology.

References

  1. Mann, F.M., Prisic, S., Hu, H., Xu, M., Coates, R.M. and Peters, R.J. (2009), Characterization and inhibition of a Class II diterpene cyclase from Mycobacterium tuberclosis - Implications for tuberculosis. J. Biol. Chem., 284, 23574–23579.
  2. Spangler, J.E., Carson, C.A. and Sorensen, E.J. (2010) Synthesis enables a structural revision of the Mycobacterium tuberculosis-produced diterpene, edaxadiene. Chem. Sci., DOI: 10.1039/c0sc00284d.
  3. Rudi, A., Aknin, M., Gaydou, E. and Kashman, Y. (2004) Asmarines I, J, and K and nosyberkol: four new compounds from the marine sponge Raspailia sp. J. Nat. Prod., 67, 1932–1935.

2 June 2010, 6-acetyl-2,3,4,5-tetrahydropyridine


Chemistry, like most other fields of human endeavour, has a tremendous capacity for both good and evil. However, arguably one of the best and most delightful reactions in chemistry is the Maillard reaction. It occurs when amino acids are heated together with sugar and is therefore a prominent reaction when baking bread or brewing beer: many of the reaction products provide the characteristic flavours of these foods, which we all enjoy so much.While the chemical structures and identities of most of the products of this form of "non-enzymatic browning" are only poorly characterised or unknown, our Entity of the Month 6-acetyl-2,3,4,5-tetrahydropyridine (CHEBI:59533) is an exception. It is a well known aromatic compound, which is responsible for the flavour of white bread, popcorn and tortillas and has an extremely low odour threshold, between 0.02 and 0.06 ng l–1.[1] It exists in a tautomeric equilibrium with 6-acetyl-1,2,3,4-tetrahydropyridine, the two forms usually occurring in foods in a 1:2 ratio.

The compound can be synthesized in a simple three-step procedure. In a first step, BOC-protected 2-piperidone is treated with 1-ethoxy-1-lithioethene in a bid to build up the acetyl side-chain. This results in ring opening and the formation of a linear ketone which, after treatment with toluene-p-sulfonic acid, reforms the heterocycle in the form of an ene-carbamate. Treatment of the latter with potassium hydroxide yields the final product [1].

The Maillard Reaction is named after Louis Camille Maillard, a precocious French physiologist, who first described it in the 1910s. Maillard is also known for his contributions towards the diagnosis of kidney disorders.

Our background image shows freshly toasted bread – and the brown colour (the Maillard reaction is a method for non-enzymatic browning) is indicative of the reaction having taken place.

Reference

  1. Harrison, T.J. and Dake, G.R. (2005) An expeditious, high-yielding construction of the food aroma compounds 6-acetyl-1,2,3,4-tetrahydropyridine and 2-acetyl-1-pyrroline. J. Org. Chem. 70, 10872–10874.

5 May 2010, Mephedrone


Mephedrone (CHEBI:59331) is a synthetic central nervous system stimulant and entactogen drug chemically related to cathinone, the psychoactive alkaloid present in the khat plant (Catha edulis, family Celastraceae). It can be synthesised from 4-methylpropiophenone by an initial bromination at the β-carbon followed by replacement of the bromine by a methylamino group derived from methylamine hydrochloride. Although it was probably not available until 2007, by 2009 mephedrone had become the fourth most popular street drug in the UK, behind cannabis, cocaine and ecstasy. Little is currently known regarding its pharmacology or toxicology, although one recent report suggests the likelihood that it stimulates the release of, and then inhibits the reuptake of, monoamine neurotransmitters [1].

Although already listed as a prohibited substance in many countries, in others it has varying degrees of legality (notably the USA where it is currently unscheduled under the Controlled Substances Act). In the UK, a decision by the Home Secretary to classify mephedrone as illegal caused the resignation of two members of the Advisory Council on the Misuse of Drugs (ACMD) which has led in turn to a general questioning of UK drugs policy. Mephedrone finally became classified as a Class B drug in the UK on April 16, 2010 – prior to this time it was often sold openly under the guise of a 'plant food' (although having no known use as such).

Reference

    1. Winstock, A., Marsden, J. and Micheson, L. (2010). What should be done about mephedrone? BMJ [Br. Med. J.] 340, c1605.

7 April 2010, 8-OHdG


8-Hydroxy-2'-deoxyguanosine (8-OHdG, ChEBI:40304) is an important molecule in oxidative stress used as a biomarker of many processes involving reactive oxygen species. Also known as 8-oxo-dG (this abbreviation derived from its tautomeric name 8-oxo-7,8-dihydro-2'-deoxyguanosine) and as HMDB03333 in the Human Metabolome Database [1], it has been used especially as a sensitive marker of the DNA damage caused by hydroxyl radical attack at C-8 of guanine. This damage, if left unrepaired, has been proposed to contribute to mutagenicity and cancer promotion [2]. This use of 8-OHdG as a biomarker for DNA damage extends over a wide range of scenarios [3,4,5,6], because it is one of the major products of DNA oxidation.

More recent work by Junko Fujihara and his colleagues at Shimane University in Japan has demonstrated how 8-OHdG can be used as a possible marker for arsenic poisoning, since antiquity a method of dispatch frequent in homicide and suicide cases [7]. Fujihara's study however focuses principally on the use of arsenic in medicine, and specifically in demonstrating a relationship between concentrations of 8-OHdG and various arsenic compounds in the urine of a patient with acute promyelocytic leukaemia being treated with arsenic trioxide. Their conclusions that 8-OHdG in urine can be used therapeutically as a key biomarker for arsenic compounds may also find application in the diagnosis of arsenic poisoning when arising from the consumption of seafood such as fish, shrimp, oysters and seaweeds, organisms known to contain appreciable amounts of arsenic compounds.

References

  1. Wishart, D.S., Knox, C., Guo, A.C., Eisner, R., Young, N., Gautam, B., Hau, D.D., Psychogios, N., Dong, E., Bouatra, S. et al. (2009). HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 37 (Database issue), D603–610.
  2. Kuchino, Y., Mori, F., Kasai, H., Inoue, H., Iwai, S., Miura, K., Ohtsuka, E. and Nishimura, S. (1987). Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature 327 (6117), 77–79.
  3. Wu, L.L., Chiou, C.C., Chang, P.Y. and Wu, J.T. (2004). Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clin. Chim. Acta339, 1–9.
  4. Schriner, S.E., Linford, N.J., Martin, G,M., Treuting, P., Ogburn, C.E., Emond, M., Coskun, P.E., Ladiges, W., Wolf, N., Van Remmen, H. et al. (2005). Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911.
  5. Sumida, S. et al (1997). Effect of a single bout of exercise and beta-carotene supplementation on the urinary excretion of 8-hydroxy-deoxyguanosine in humans. Free radical research 27 (6), 607-618. PMID:9455696
  6. Tarng, D.-C., Huang, T.-P., Wei, Y.-H., Liu, T.-Y., Chen, H.-W., Chen, T.W. and Yang, W.-C. (2000). 8-Hydroxy-2'-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients. Am. J. Kidney Dis. 36, 934–944.
  7. Fujihara, J., Agusa, T., Tanaka, J., Fujii, Y., Moritani, T., Hasegawa, M., Iwata, H., Tanabe, S. and Takeshita, H. (2009).8-Hydroxy-2'-deoxyguanosine (8-OHdG) as a possible marker of arsenic poisoning: a clinical case study on the relationship between concentrations of 8-OHdG and each arsenic compound in urine of an acute promyelocytic leukemia patient being treated with arsenic trioxide. Forensic Toxicol. 27, 41–44.

3 March 2010, Sildenafil citrate


Few chemical compounds are better known to the general public than sildenafil citrate (CHEBI:58987), traded under the name of "Viagra".The compound was first synthesised by chemists working at Pfizer, with a view to using it for the treatment of hypertension and angina pectoris. Whilst having been found to be ineffective against angina in clinical trials, it has been observed to induce penile erections and was therefore marketed by Pfizer as a drug for the treatment of erectile dysfunction. A number of synthetic routes for the preparation of the parent sildenafil have been reported [1]. A common industrial synthetic route is through reaction of 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide and 2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylbenzoic acid followed by subsequent cyclisation to sildenafil through heating under acidic conditions.

Sildenafil has been shown to be an inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5, an enzyme which is responsible for the degradation of 3',5'-cyclic GMP (cyclic guanosine monophosphate, cGMP) in the corpus cavernosum. This leads to the presence of increased levels of cGMP, which, in turn causes vasodilation of the helicine arteries and thus increased blood flow into the spongy tissue of the penis [2].

Apart from the treatment of sexual dysfunction, sildenafil is also used in the treatment of pulmonary arterial hypertension and works again through relaxation of the arterial wall, which leads to a decrease in arterial resistance [3]. Furthermore – and arguably most interestingly – sildenafil has been found to decrease the time necessary for the re-entrainment of circadian rhythms after phase advances in the light–dark cycle (such as occur on transmeridian eastbound flights) in members of the Cricetidae family [4]. The discovery was rewarded with the award of an Ig Nobel Prize in Aviation in 2007.

Creative Commons licensed picture of Sildenafil crystals taken from Wellcome Trust Images.

References

  1. Dunn, P.J. (2005) Synthesis of commercial phosphodiesterase(v) inhibitors. Org. Process Res. Dev. 9, 88–97.
  2. David, J.W., Stephen, F., Michael, J.A. and Gary, J.M. (1999) Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am. J. Cardiol. 83 (5, Suppl. 1), 21–28.
  3. Richalet, J.-P., Gratadour, P., Robach, P., Pham, I., Dechaux, I., Joncquiert-Latarjet, A., Mollard, P., Brugniaux, J. and Cornolo, J. (2005) Sildenafil inhibits altitude-induced hypoxemia and pulmonary hypertension. Am. J. Respir. Crit. Care Med. 171, 275–281.
  4. Agostino, P.V., Plano, S.A. and Golombek, D.A. (2007) Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules. Proc. Natl. Acad. Sci. U. S. A. 104, 9834–9839.

3 February 2010, Ferrocene


Ferrocene (CHEBI:30672) is not only an intensely useful chemical entity which has found applications in such diverse fields such as anti-cancer therapy and materials science, but it has also brought together a number of the most eminent chemical researchers of the century and led to the discovery of a new type of bonding. The orange compound was, as is often the case, discovered accidentally by Pauson (of Pauson–Khand reaction fame) and Kealy, who attempted synthesis of fulvalene through oxidative coupling of cyclopentadienyl magnesium bromide and iron(III) chloride [1]. The result was an orange powder, which proved to be extremely stable and whose structure remained, for a while at least, a mystery: Pauson and Khand initially suggested that two cyclopentadienyl moieties, which were bound to the iron(II) in an η1 fashion rather than in the η5-motif we know to be correct today. The new bonding motif caused a little sensation in the structural chemistry community when it was postulated [2].

The correct metallocenic structure was independently determined/deduced by Woodward and Wilkinson [3] as well as by E.O. Fischer [4], who subsequently extended the series of known metallocene compounds considerably. Significant amounts of work were also done by Myron Rosenblum, Woodward's student and one of the co-authors on their original paper reporting the ferrocene structure. Many accounts of the beginning and further development of ferrocene research have since been written [5–9].

Ferrocene is a remarkably stable organometallic compound and shows chemistry which is very similar to that of 'classical' aromatic compounds. It readily undergoes Friedel-Crafts chemistry [10] and can also be lithiated [11], thus showing a wide spectrum of interaction with both electrophiles and nucleophiles. This, in turn, means that a large number of derivatives can be prepared, which opens the material up to a wide range of applications. Chemical examples include the use of ferrocene as a backbone in ligand systems and as an oxidising agent. Ferrocene can be polymerised through derivatisation to vinylferrocene and subsequent polymerisation to give poly(vinylferrocene) [12].

The compound has use as an anti-knock agent, replacing the much more toxic tetraethyllead. Furthermore, ferrocenyl analogues of tamoxifen, an estrogen receptor antagonist, have also been reported in the literature [13].

References

  1. Kealy, T.J. and Pauson, P.L. (1951) A new type of organo-iron compound. Nature 168, 1039–1040.
  2. Lazlo, P. and Hoffmann, R. (2000) Ferrocene: Iron-clad history or Rashomon Tale? Angew. Chem., Int. Ed. 39, 123–124.
  3. Wilkinson, G., Rosenblum, M., Whiting, M.C. and Woodward, R.B. (1952) The structure of iron bis-cyclopentadienyl. J. Am. Chem. Soc. 74, 2125–2126.
  4. Fischer, E.O. and Pfab, W. (1952) Zur Kristallstruktur der Di-Cyclopentadienyl-Verbindungen des zweiwertigen Eisens, Kobalts und Nickels. Z. Naturforsch., B 7, 377–379.
  5. Fischer, E.O. and Jira, R. (2001) How metallocene chemistry and research began in Munich. J. Organomet. Chem. 637–639, 7–12.
  6. Pauson, P.L. (2001) Ferrocene—how it all began. J. Organomet. Chem. 637–639, 3–6.
  7. Rosenblum, M. (2001) The early ferrocene days—a personal recollection. J. Organomet. Chem. 637–639, 13–15.
  8. Whiting, M.C. (2001) Recollections of the arrival of ferrocene. J. Organomet. Chem.637–639, 16–17.
  9. Cotton, F.A. (2001) Cyclopentadienyl–metal chemistry in the Wilkinson Group, Harvard, 1952–1955. J. Organomet. Chem. 637–639, 18–26.
  10. Wang, R., Hong, X. and Shan, Z. (2008) A novel, convenient access to acyl ferrocenes: acylation of ferrocene with acyl chlorides in the presence of zinc oxide. Tetrahedron Lett. 49, 636–639 and references therein.
  11. Ueberbacher, B.J., Griengl, H. and Weber, H. (2008) Ortho-lithiation of free ferrocenyl alcohols: a new method for the synthesis of planar chiral ferrocene derivatives. Chem. Commun., 3287–3289.
  12. Hudson, R.D.A. (2001) Ferrocene polymers: current architectures, syntheses and utility. J. Organomet. Chem. 637–639, 47–69.
  13. Top, S., Vessieres, A., Leclercq, G., Quivy, J., Tang, J., Vaissermann, J., Huche, M. and Jaouen, G. (2003) Synthesis, biochemical properties and molecular modelling studies of organometallic specific estrogen receptor modulators (SERMs), the ferrocifens and hydroxyferrocifens: evidence for an antiproliferative effect of hydroxyferrocifens on both hormone-dependent and hormone-independent breast cancer cell lines. Chem.—Eur. J. 9, 5223–5236.

6 January 2010, (+)-Abscisic acid


(+)-Abscisic acid (CHEBI:2365), known commonly just as abscisic acid or ABA, is a ubiquitous isoprenoid plant hormone which is synthesized in the methylerythritol phosphate (MEP) pathway (also known as the non-mevalonate pathway) by cleavage of C40 carotenoids. First identified and characterised in 1963 by Fredrick Addicott and his associates at the University of California, Davis [1], ABA was originally believed to play a major role in abscission of fruits (hence its early name of 'abscisin II'). This is now known to be true for only a small number of plants, a wider role being to act as a regulator of plant responses to a variety of environmental stresses such as drought, extremes of temperatures, and high salinity. Such responses include stimulating the closure of stomata, inhibiting shoot growth while not affecting root growth, and inducing seeds to synthesise storage proteins.

Because of its essential function in plant physiology, targeting the ABA signalling pathway holds considerable promise for future applications in agriculture. Now, in a recent issue of Nature, Ning Zheng and his co-worker Laura Sheard from the University of Washington summarise recent converging studies which reveal the details of how ABA transmits its message [2]. In particular, an article by an international team led by Eric Xu of the Van Andel Research Institute describes how their crystallographic work on unbound ABA and ABA bound to some of its receptors, together with extensive biochemical studies from elsewhere, identify a conserved gate–latch–lock mechanism underlying ABA signalling [3].

References

  1. Okhuma, K., Lyon, J.L., Addicott, F.T. and Smith O.E. (1963) Abscisin II, an abscission-accelerating substance from young cotton fruit. Science 142, 1592–1593.
  2. Sheard, L.B. and Ning Zheng (2009) Plant biology: Signal advance for abscisic acid. Nature 462, 575–563.
  3. Melcher K. et al. (2009) A gate–latch–lock mechanism for hormone signalling by abscisic acid receptors. Nature 462, 602–608.



2009

3 December 2009, Adrenaline


Adrenaline (CHEBI:33568), also known as epinephrine, is a catecholamine that acts as a hormone and neurotransmitter. It was first isolated from an extract of the suprarenal (adrenal) gland as its mono-benzoyl derivative by the American biochemist and pharmacologist John Jacob Abel in 1889 [1] who later also crystallised it as a hydrate. The pure compound was produced in 1901 by the Japanese industrial chemist Jokichi Takamine [2] and patented as 'Adrenalin'. Two chemists, Stolz and Dakin, independently reported the synthesis of the compound in 1904 [3,4].

Adrenaline is a potent 'fight-or-flight' hormone, which is produced in stress situations. When produced in the body, it leads to an increase in heart-rate, vasodilation and the supply of both glucose and oxygen to the muscles and the brain, thus preparing the body for rapid action if needed. The increase in glucose supply is achieved through the binding of adrenaline to β-adrenergic receptors in the liver. This triggers the adenylate cyclase pathway, which, in turn, leads to increased glycogenolysis activity. On the other hand, adrenaline suppresses both digestive processes as well as immune responses. As such, it can be used in the treatment of anaphylactic shock [5] as well as for the treatment of cardiac arrest and cardiac disrythmias [6].

The biosynthesis of adrenaline is regulated by the central nervous system. It is ultimately derived from L-tyrosine, which is converted into L-dihydroxyphenylalanine (L-DOPA) by the action of tyrosine 3-monooxygenase (EC 1.14.16.2). Adrenaline is produced through the conversion of L-DOPA into dopamine into noradrenaline into adrenaline itself. Adrenaline crystallises in star-shaped needles (see background picture).

References

  1. Abel, J.J. (1899) Ueber den blutdruckerregenden Bestandtheil der Nebenniere, das Epinephrin. Z. Physiol. Chem. 18, 318–324.
  2. Takamine, J., (1902) The isolation of the active principle of the suprarenal gland. J. Physiol. 27 (Suppl), xxix–xxx.
  3. Stolz, F. (1904) Ueber Adrenalin und Alkylaminoacetobrenzkatechin. Ber. Dtsch. Chem. Ges. 37, 4149–4154.
  4. Dakin, H.D. (1905) The synthesis of a substance allied to noradrenaline. Proc. Roy. Soc. Lon. Ser. B 76, 491–497.
  5. Anchor, J. and Settipane, R.A. (2004) Appropriate use of epinephrine in anaphylaxis. Am. J. Emerg. Med. 22, 488–490
  6. Rainer, T.H. and Robertson, C.E. (1996) Adrenaline, cardiac arrest and evidence based medicine. J. Accid. Emerg. Med. 13, 234–237

4 November 2009, Artemether


Artemether (CHEBI:195280) is a lipid-soluble antimalarial for the treatment of multi-drug resistant strains of  Plasmodium falciparum malaria. First prepared in 1979 [1], it is a methyl ether of the naturally occurring sesquiterpene lactone (+)-artemisinin, which is isolated from the leaves of Artemisia annua L. (sweet wormwood), the traditional Chinese medicinal herb known as Qinghao. However, because of artemether's extremely rapid mode of action (it has an elimination half-life of only 2 hours, being metabolized to dihydroartemisinin which then undergoes rapid clearance), it is used in combination with other, longer-acting, drugs.  One such combination, licensed in April of this year by the WHO, is Coartem in which the artemether is mixed with lumefantrine – a racemic mixture of a synthetic fluorene derivative known formerly as benflumetol – which has a much longer and pharmacologically complementary terminal half-life of 3–6 days, allowing the two drugs to act synergistically against Plasmodium.

The molecule of artemether is interesting because of its extreme rigidity, with very few rotational bonds. Unlike quinine class antimalarial drugs, it has no nitrogen atom in its skeleton.  However, an important chemical feature (and unique in drugs) is the presence of an O–O endoperoxide bridge which is essential for its antimalarial activity, as it is this bridge which is split in an interaction with heme, blocking the conversion into hemozoin and thus releasing into the parasite heme and a host of free radicals which attack the cell membrane.

Artemether is fully Rule-of-Five compliant and has recently also been under investigation as a possible candidate for cancer treatment [2,3].

References

  1. Li, Y. et al. (1979) K'o Hsueh T'ung Pao, 24, 667 [Chem. Abstr., 91, 211376u (1979)].
  2. Singh, N.P. and Panwar, V.K. (2006) Case report of a pituitary macroadenoma treated with artemether. Integrative Cancer Therapies 5,391–394.
  3. Zhi-ping Wu et al. (2009)  Inhibitive effect of artemether on tumor growth and angiogenesis in the rat C6 orthotopic brain gliomas model. Integrative Cancer Therapies 8, 88–92.

7 October 2009, Chloroquine


Chloroquine (CHEBI:3638) is a 4-aminoquinoline drug which has been used in the prevention or treatment of malaria since the 1930s. However, despite being originally cheap, safe and effective, its efficacy has declined gradually owing to the emergence and spread of chloroquine-resistant Plasmodium falciparum malaria parasites, such that in some areas of the world the drug is totally ineffective.

P. falciparum feeds on haemoglobin protein, during the breakdown of which one or more of the various forms of the toxic and soluble molecule heme is produced. The parasite protects itself against destruction by the heme by biocrystallizing it to form the non-toxic pigment hemozoin which then collects in the organism's digestive vacuole. Chloroquine works by stopping this protective conversion of heme, causing a buildup of toxic iron waste which eventually causes cell lysis and death of the parasite.

In 2000 malarial resistance to chloroquine was linked to mutations in the P. falciparum Chloroquine Resistance Transporter (PfCRT) gene [1,2], but just how the PfCRT protein caused the resistance remained unclear. Now Dr Rowena Martin and her colleagues at the Australian National University, reporting in the journal Science [3], have studied PfCRT's function by isolating it in unfertilised eggs of the African Clawed Frog (Xenopus laevis). Martin's team were then able to show that PfCRT works by transporting the chloroquine out of the parasite's digestive vacuole, preventing it from reaching the concentrations it needs to work. Furthermore, tests with verapamil, a known 'resistance reversing' drug known to stop PfCRT's effects, showed that this actually blocked the chloroquine exit route, raising the possibility of producing future combinations of drugs of this type for more effective malarial treatments.

References

  1. Fidock, D.A. et al. (2000) Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol. Cell 6, 861–871.
  2. Sidhu, A.B., Verdier-Pinard, D. and Fidock, D.A. (2002) Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298 , 210–213.
  3. Martin, R.E., Marchetti, R.V., Cowen, A.I., Howitt, S.M., Bröer, S. and Kirk, K. (2009) Chloroquine transport via the malaria parasite's Chloroquine Resistance Transporter. Science 325, 1680–1682.

26 August 2009, Cocaine


The notion of us all carrying cocaine (ChEBI:27958) in our wallets, purses or packets may not be as outrageous or unlikely as we might think! In what researchers describe as the largest, most comprehensive analysis to date of cocaine contamination in banknotes, scientists are reporting that 95% of dollar bills in Washington DC bear traces of the illegal drug cocaine, with high levels also oberved in other big cities, such as Baltimore, Boston and Detroit [1]. Researchers at the University of Massachusetts in Dartmouth tested notes from more than 30 cities from five countries (United States, Canada, Brazil, China and Japan). "To my surprise, we're finding more and more cocaine in banknotes," said lead researcher Yuegang Zuo. He suggested the rise may be due to the economic downturn, "with stressed people turning to cocaine".

The U.S. and Canada were found to have the highest levels, with an average contamination rate of between 85 and 90 percent, while China and Japan had the lowest, between 12 and 20 percent contamination [1]. In the U.S. the cleanest bills were collected from Salt Lake City, home of the Church of Jesus Christ of Latter-Day Saints, better known as the Mormons [1].

Scientists have known for years that paper money can become contaminated with cocaine during drug deals and directly via snorting cocaine through rolled bills. Large-scale contamination is thought to take place when the notes are stacked together in currency-counting machines. In the new study, Zuo and colleagues used a modified form of a gas chromatograph-mass spectrometer for their measurements [2]. This allowed a faster, simpler and more accurate measurement of cocaine contamination than other methods, without destroying the currency. Amounts found in the 234 U.S. banknotes analysed ranged from .006 micrograms (thousands of times smaller than a single grain of sand) to over 1,240 micrograms of cocaine, or the equivalent of about 50 grains of sand, per bill. Zuo downplayed any health or legal concerns linked to the handling of contaminated notes. "For the most part, you can't get high by sniffing a regular banknote, unless it was used directly in drug uptake or during a drug exchange", Zuo said. "It also won't affect your health and is unlikely to interfere with blood and urine tests used for drug detection". The study, Zuo said, could help increase public awareness of cocaine use and help curb its abuse by assisting law enforcement agencies and forensic specialists to identify how the drug is used in a given community.

References

  1. U.S. banknotes show cocaine traces. news.bbc.co.uk. 17 August 2009.
  2. Zuo Y,, Kai Zhang K., Wu J., Rego C. and Fritz J. (2008)
    An accurate and non-destructive GC method for determination of cocaine on U.S. paper currency. J. Separation Sci. 31, 2444–2450.

29 July 2009, Copernicium


Thirteen years after its discovery [1], element 112 has finally been given the proposed name 'copernicium' (ChEBI:33517) with the symbol Cp, in honour of the astronomer Nicolaus Copernicus. Copernicus deduced that the planets revolved around the sun and finally refuted the then accepted belief that the Earth was the centre of the universe. His finding was pivotal in the discovery of gravitational force, and led to the conclusion that the stars are incredibly far away and the universe inconceivably large, as the size and position of the stars does not change even though the Earth is moving.

The International Union of Pure and Applied Chemistry (IUPAC) will officially endorse the new element's name in January 2010 in order to give the scientific community time to discuss the suggested name 'copernicium' prior to the IUPAC naming. Currently the element has the IUPAC systematic element name of Ununbium and the temporary symbol Uub used until the element gets an accepted name. Scientists from the Centre for Heavy Ion Research (GSI) in Germany, led by Professor Sigurd Hofmann, discovered copernicium during fusion experiments in 1996. "After IUPAC officially recognised our discovery, we agreed on proposing the name because we would like to honour an outstanding scientist" said Professor Hofmann.

Element 112 is the heaviest element in the periodic table, 277 times heavier than hydrogen. It is produced by a nuclear fusion, when bombarding zinc ions on to a lead target [1] in a heavy ion accelerator. As the element decays after a split second [1], its existence can only be proved with the assistance of extremely fast and sensitive analysis methods. Isolation of an observable quantity has never been achieved and may well never be. Since 1981, scientists at GSI have discovered six new chemical elements carrying atomic numbers 107-112 and have named five of them: element 107 is called bohrium (Bh), 108 is hassium (Hs), 109 is meitnerium (Mt), 110 is darmstadtium (Ds) and element 111 is called roentgenium (Rg).

Reference

  1. Hofmann S., Ninov, V., Hessberger, F.P., Armbruster, P., Folger, H., Münzenberg, G., Schött, H.J., Popeko, A.G., Yeremin, A.V., Saro, S., Janik, R., and Leino M. (2006) The new element 112. Zeitsch rift für Physik:A Hadrons and Nuclei. 354, 229–230.

24 June 2009, Capecitabine


Capecitabine (CHEBI:31348) is a chemotherapy drug that is administered as a treatment for a variety of cancer types, including bowel cancer, stomach cancer, breast cancer and oesophageal cancer. It acts as a prodrug, undergoing a three-step enzymic conversion into 5-fluorouracil in the tumour, where it inhibits DNA synthesis and thus slows growth of tumour tissue. Capecitabine can be synthesized from the readily available starting materials D-ribofuranose and cytosine [1].

When capecitabine is used for long-term treatment of recurrent cancers, one of the side-effects can be the onset of hand-foot syndrome, which eventually can lead to total eradication of the patients fingerprints [2]. This has recently proved rather inconvenient for one unsuspecting patient. A recent report [3] describes an instance where a patient on capecitabine for over three years went to the USA to visit relatives in December 2008. He was detained for 4 hours as his fingerprints could not be detected by immigration officials and was only allowed to enter after the officers were entirely satisfied that he posed no threat to security. As a result, all patients taking capecitabine long-term are being advised to travel with a letter from an oncologist stating condition and treatment being received to account for their lack of fingerprints.

As a final aside, recent reports suggest that the actual purpose of fingerprints is to enhance sensitivity rather than friction.

References

  1. Moon, B.S., Shim, A.Y., Lee, K.C., Lee, H.J., Lee, B.S., An, G.I., Yang, S. D., Chi, D.Y., Choi, C.W., Lim, S.M. and Chun, K.S. (2005) Synthesis of F-18 labeled capecitabine using [18F]F2 gas as a tumor imaging agent. Bull. Korean Chem. Soc. 26, 1865–1868.
  2. Chua, D., Wei, W.I., Sham, J.S.T. and Au, G.K.H. (2008) Capecitabine monotherapy for recurrent and metastatic nasopharyngeal cancer. Jpn. J. Clin. Oncol. 38, 244–249.
  3. Wong, M., Choo, S.-P. and Tan, E.-H. (2009) Travel warning with capecitabine. Annals of Oncology Advance Access May 26th 2009/doi:10.1093/annonc/mdp278.

27 May 2009, Oseltamivir


Oseltamivir (CHEBI:7798) is an ethyl ester prodrug which requires hydrolysis to the corresponding carboxylate to be physiologically active. It is marketed as an antiviral drug for the treatment of both Influenzavirus A and Influenzavirus B infection in the form of its phosphate salt by Hofmann-La Roche (trade name Tamiflu). Oseltamivir inhibits the neuraminidase protein on the viral surface and interferes with virus particle aggregation and release.

Oseltamivir is synthesized commercially from shikimic acid, the low availability of which is a major bottleneck in its production. Shikimic acid is only effectively isolated from Chinese star anise (Illicium verum) which is grown solely in four provinces of China and one in Vietnam. Some 90% of the annual harvest is used in the production of oseltamivir. For this reason, several alternative routes for shikimic acid production are being actively sought by a number of commercial companies. In addition, some alternative synthetic routes to oseltamivir which do not involve the intermediacy of shikimic acid have appeared in the literature [1–5].

The onset of the H5N1 avian influenza epidemic in Southeast Asia in 2005 led to fears of a pandemic and subsequent stockpiling of oseltamivir by several nations. However, although affluent countries like Japan, Britain and the USA are thought to have enough oseltamivir to reach about one quarter to a half of their populations, a recent press report highlights the situation with developing countries which may well have enough for only about 1 percent of their people or less. The 2009 outbreak in Mexico of a new strain of the influenza type A H1N1 virus (commonly called 'swine flu') has renewed fears of a pandemic and these, together with the high costs of stockpiling and maintaining expensive medicines for future epidemics that may never develop, have highlighted again the possibility that those countries with low supplies of oseltamivir may suffer higher death rates if swine flu becomes more lethal outside of Mexico.

References

  1. Yeung, Y.-Y., Hong, S. and Corey, E.J. (2006) A short enantioselective pathway for the synthesis of the anti-influenza neuramidase inhibitor oseltamivir from 1,3-butadiene and acrylic acid. J. Am. Chem. Soc. 128, 6310–6311.
  2. Fukuta, Y., Mita, T., Fukuda, N., Kanai, M. and Shibasaki, M. (2006) De novo synthesis of Tamiflu via a catalytic asymmetric ring-opening of meso-aziridines with TMSN3 J. Am. Chem. Soc. 128, 6312–6313.
  3. Mita, T., Fukuda, N., Roca, F.X., Kanai, M. and Shibasaki, M. (2007) Second generation catalytic asymmetric synthesis of Tamiflu: allylic substitution route. Org. Lett. 9, 259–262.
  4. Satoh, N., Akiba, T., Yokoshima, S. and Fukuyama., T. (2007) A practical synthesis of (–)-oseltamivir Angew. Chem. Int. Ed. 46, 5734–5736.
  5. Trost, B.M. and Zhang, T. (2008) A concise synthesis of (–)-oseltamivir Angew. Chem. Int. Ed. 47, 1–4.

29 April 2009, Ethyl formate


Ethyl formate (CHEBI:52342), a low-molecular-weight volatile compound produced by many fruits and vegetables, has an important role as a flavour and aroma component. It has also been used as a fumigant possessing insecticidal and fungicidal properties [1]. The compound can potentially degrade to biogenic levels in the tissues of treated commodities in contrast to conventional chemicals which can persist as residues in food products. Ethyl formate was evaluated as a fumigant for stored grain as a potential alternative to the ozone-depleting fumigant methyl bromide (CHEBI:39275) and to phosphine (CHEBI:30278), which is under pressure owing to the development of strong resistance in stored grain insects [2]. Recently, astronomers have found ethyl formate in a giant dust cloud at the heart of the Milky Way [3]. While scouring their data, the team also found evidence for the lethal chemical propyl cyanide (CHEBI:51937) in the same cloud. The two molecules, whose sizes are comparable to the simplest amino acid, glycine (CHEBI:15428), are the largest yet discovered in deep space. Finding amino acids in interstellar space would raise the possibility of life emerging on other planets as they are one of the building blocks of life.

References

  1. Simpson, T., Bikoba, V. and Mitcham, E.J. (2004) Effects of ethyl formate on fruit quality and target pest mortality for harvested strawberries. Postharvest Biology and Technology 34, 313–319.
  2. Haritos, V.S., Damcevski, K.A. and Dojchinov, G. (2006) Improved efficacy of ethyl formate against stored grain insects by combination with carbon dioxide in a 'dynamic' application. Pest Manag. Sci. 62, 325–333.
  3. Galaxy's centre tastes of raspberries and smells of rum, say astronomers. guardian.co.uk. Tuesday 21 April 2009

25 March 2009, lycorine


Daffodil is the common English name for Narcissus, the botanic name of a genus of mainly spring-flowering bulbs in the family Amaryllidaceae. Daffodil bulbs, often confused with onions, contain lycorine (CHEBI:6601), a highly poisonous crystalline alkaloid which might be lethal when ingested in certain quantities. Traditionally, lycorine has been obtained from plant extracts [1] but its total synthesis was recently accomplished using chiral ligand-controlled asymmetric cascade conjugate addition methodology [2]. Several studies have highlighted the capacity of lycorine to inhibit protein synthesis, most probably by acting at the level of termination [3]. Other published articles suggest a role as an inhibitor of ascorbic acid biosynthesis [4]. The most recent studies also indicate a possible role of lycorine as an anticancer drug bearing apoptosis-mediated antiprolifereative effects [5–7].

References

  1. Heliang, F., Ning, W. and Xuanwang, H. (2003) Method for separating lycorine from plant extract. Patent CN1611504.
  2. Yamada, K.I., Yamashita, M., Sumiyoshi, T., Nishimura, K. and Tomioka, K. (2009) Total synthesis of (–)-lycorine and (–)-2-epi-lycorine by asymmetric conjugate addition cascade. Org. Lett. Publication Date (Web): February 25, 2009/DOI: 10.1021/ol9003564 .
  3. Vrijsen, R., Vanden Berghe, D.A., Vlietinck, A.J. and Boeyé, A.(1986) Lycorine: a eukaryotic termination inhibitor? J. Biol. Chem. 261, 505–507.
  4. Arrigoni, O., Arrigoni Liso, R. and Calabrese, G. (1975) Lycorine as an inhibitor of ascorbic acid biosynthesis. Nature 256, 513–514.
  5. Liu, J., Hu, W.-X., He, L.-F., Ye, M. and Li, Y. (2004) Effects of lycorine on HL-60 cells via arresting cell cycle and inducing apoptosis. FEBS Lett. 578, 245–250.
  6. Liu, X.-S., Jiang, J., Jiao, X.-Y., Wu, Y., Lin, J.-H. and Cai, Y.-M. (2008) Lycorine induces apoptosis and down-regulation of Mcl-1 in human leukemia cells. Cancer Lett. 274, 16–24 .
  7. Evidente, A., Kireev, A.S., Jenkins, A.R., Romero, A.E., Steelant, W.F., Van Slambrouck, S. and Kornienko, A. (2009) Biological evaluation of structurally diverse Amaryllidaceae alkaloids and their synthetic derivatives: discovery of novel leads for anticancer drug design. Planta Med. Publication Date (Web): February 23, 2009/DOI: 10.1055/s-0029-1185340.

25 February 2009, N'-bis(2,3-dihydroxybenzoyl)-N''-hexanoyltren


There is much interest in identifying compounds that transport anions, especially chloride (Cl), across lipid membranes. Reports that catechol binds Cl in organic solvents [1] have inspired Berezin and Davis [2] to use catechols for the synthesis of novel anion transporters. In a first step, two 2,3-dihydroxybenzoic acid residues were attached to a tris(2-aminoethyl)amine (tren) scaffold. In a second step, a hexanoyl group was linked to tren's third amino group to yield N,N'-bis(2,3-dihydroxybenzoyl)-N''-hexanoyltren (CHEBI:51950). The authors show that the selectivity of ionic permeability across the membrane in the presence of this bis-catechol compound follows a Hofmeister series [3] with the anion influx rate decreasing in the order ClO4 > I > NO3 > Br > Cl. The authors also have observed a non-linear dependence of the rate constant for anion transport on the concentration of the transporter. The authors suggest that self-association of the bis-catechol transporter in the membrane increases the anion permeability across the bilayer without requiring complete dehydration of the transported anion. While bacterial siderophores and synthetic analogues use catecholates to transport iron(3+) ions across membranes, this is the first report of catechols facilitating transmembrane transport of anions.

References

  1. Winstanley, K.J., Sayer, A.M. and Smith, D.K. (2006) Anion binding by catechols — an NMR, optical and electrochemical study. Org. Biomol. Chem. 4, 1760–1767.
  2. Berezin, S.K. and Davis, J.T. (2009) Catechols as membrane anion transporters. J. Am. Chem. Soc. 131, 2458–2459.
  3. Hofmeister, F. (1888) Zur Lehre von der Wirkung der Salze. Arch. Exp. Pathol. Pharmacol. 24, 247–260.

28 January 2009, Cucurbit[7]uril


In 1905, Behrend, Meyer and Rusche described the reaction between glycoluril and formaldehyde which yielded a cross-linked amorphous polymer. Treatment of this substance with hot concentrated sulfuric acid produced a crystalline precipitate [1]. Some 75 years after the Behrend et al. paper, the crystal structure of this compound (now known as cucurbit[6]uril or CB[6]) was solved by Freeman et al. The footnote to their paper [2] says: "The trivial name cucurbituril is proposed because of a general resemblance of 2 to a gourd or pumpkin (family Cucurbitaceae), and by devolution from the similarly named (and shaped) component of the early chemists' alembic."
Now, the term cucurbituril refers to any macrocycle consisting of repeating cis-glycoluril residues linked by methylene groups, with the number of repeated units in the macrocycle denoted by the "n" in the cucurbit[n]uril (CB[n]) name. By virtue of their shape, cucurbiturils can form stable inclusion compounds and thus are now employed for molecular recognition, self-assembly, and nanotechnology [3]. In addition to that of CB[6], the structures of CB[5], CB[7], CB[8] and CB[10] have been determined. Unlike CB[6] or CB[8], which are sparingly soluble in water, CB[7] (CHEBI:51434) has a moderate solubility in water which prompted Jeon et al. to study its inclusion of drugs and explore its potential as a drug carrier [4]. CB[7] forms a stable 1:1 complex with the anticancer drug oxaliplatin in aqueous solution. The authors suggest that the encapsulation of the drug not only increases the stability of the drug, but also reduces the unwanted side effects of oxaliplatin.

References

  1. Behrend, R., Meyer, E. and Rusche, F. (1905) Ueber Condensationsproducte aus Glycoluril und Formaldehyd. Liebigs Ann. Chem. 339, 1–37.
  2. Freeman, W.A., Mock, W.L. and Shih, N.-Y. (1981) Cucurbituril. J. Am. Chem. Soc. 103, 7367–7368.
  3. Lagona, J., Muchophadyay, P., Chakrabarti, S. and Isaacs, L. (2005) The cucurbit[n]uril family. Angew. Chem. Int. Ed. 44, 4844–4870.
  4. Jeon, Y.J., Kim, S.-Y., Ko, Y.H., Sakamoto, S., Yamaguchi, K. and Kim, K. (2005) Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug. Org. Biomol. Chem. 3, 2122–2125.



2008

17 December 2008, Epicocconone

The ascomycete fungus Epicoccum nigrum is known to be a source of natural fluorescent compounds. One of them, epicocconone (CHEBI:51226) [1], also known as "Deep Purple" and "Lightning Fast", is a water-soluble, low molecular mass molecule based on a polyketide skeleton. It has a weak green fluorescence in water (λem = 520 nm), which shifts to red (λem = 610 nm) with a concomitant increase in quantum yield in the presence of a protein. Its cell permeability, low cytotoxicity and large Stokes' shift make it a highly useful fluorochrome for live cell imaging [2]. Recently, a epicocconone-based assay that allows the rapid and accurate determination of protease enzyme kinetic parameters (KM, Vmax) as well as inhibition constants through the measurement of fluorescence anisotropy on the actual protease substrates [3] has been developed. This novel assay will be suitable for high-throughput applications in drug development and biotechnology.

References

  1. Bell, P.J.L. and Karuso, P. (2003) Epicocconone, a novel fluorescent compound from the fungus Epicoccum nigrum. J. Am. Chem. Soc. 125, 9304–93045.
  2. Choi, H.-Y., Veal, D.A. and Karuso, P. (2005) Epicocconone, a new cell-permeable long Stokes' shift fluorescent stain for live cell imaging and multiplexing. J. Fluoresc. 16, 475–482.
  3. Cleemann, F. and Karuso, P. (2008) Fluorescence anisotropy assay for the traceless kinetic analysis of protein digestion. Anal. Chem. 80, 4170–4174.

26 November 2008, Irgarol 1051

Biologically active triazine compounds have been extensively used as herbicides for over five decades [1]. Their generally high toxicity and persistence have aroused growing environmental and public health concerns. In recent years, Irgarol 1051 (CHEBI:5962), a highly specific methylthioltriazine compound which inhibits photosynthesis, has been used in long-life antifouling coatings for marine applications to prevent the growth of algae [2]. The degradation and transformation of Irgarol-1051 in natural coastal seawater has been studied [3] and two major degradation processes have been identified: microbial metabolism and photolysis. Irgarol 1051 main degradation product, which is biologically less toxic, is known as M1 or GS265751 (CHEBI:51079). A number of other transformation products, such as M2 (CHEBI:51112) and M3 (CHEBI:51083), have been identified; however, only the descyclopropyl transformation product M1 is being consistently found in natural waters [4]. Recently, the occurrence and persistence of Irgarol 1051 and its main metabolite in the coastal waters of Southern England were researched. The results indicated organic rich sediments and paint residues as major sites of storage for Irgarol 1051, and that Irgarol 1051 may be classified as a persistent organic pollutant due to its long half-life [5].

References

  1. Lam, K.-H., Cai, Z., Wai, H.-Y., Tsang, V.W.-H., Lam, M.H.-W., Cheung, R.Y.-H., Yu, H. and Lam, P.-K. (2005) Identification of a new Irgarol-1051 related s-triazine species in coastal waters. Environmental Pollution 136, 221-230.
  2. Ciba® IRGAROL® 1051 factsheet.
  3. Lam, K.-H., Lei, N.-Y., Tsang, V.W.-H., Cai, Z., Leung, K.M.Y. and Lam, M.H.-W. A mechanistic study on the photodegradation of Irgarol-1051 in natural seawater. Mar. Pollut. Bull., in press.
  4. Lam, K.-H., Wai, H.-Y., Leung, K.M.Y., Tsang, V.W.-H., Tang, C.-F., Cheung, R.Y.-H. and Lam, M.H.-W. (2006) A study of the partitioning behavior of Irgarol-1051 and its transformation products. Chemosphere 64, 1177-1184.
  5. Zhou, J.L. (2008) Occurrence and persistence of antifouling biocide Irgarol 1051 and its main metabolite in the coastal waters of Southern England. Sci. Total. Environ. 406, 239-246.

29 October 2008, PP121

A pyrazolopyrimidine, known simply as PP121 (CHEBI:50915), has been found to block simultaneously two key enzymes involved in the growth of cancer cells. In a recent publication [1], Kevan Shokat, of the University of California at Berkeley, and collaborators report that PP121 is highly effective in inhibiting both oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases [PI(3)Ks], two protein families that are currently among the most intensely pursued cancer drug targets. The enzymes are involved in cell signalling pathways, alterations of which are involved in many types of cancer. This example of dual inhibition owes its effectiveness to the ability of the molecule to flex around the single bond connecting its pyrazolopyrimidine and pyrrolopyridine ring systems. Thus the molecule is able to change its shape slightly, enabling it to occupy a hydrophobic pocket in both enzyme classes. The researchers believe that the rational design approach employed by them demonstrates the possibility to identify potent, selective and drug-like molecules capable of targeting these two classes of oncogenic kinases, and in the long term to providing routes to more effective therapy for many cancers.

Reference

  1. Apsel, B., Blair, J.A., Gonzalez, B., Nazif, T.M., Feldman, M.E., Aizenstein, B., Hoffman, R., Williams, R.L., Shokat, K.M. and Knight, Z.A. (2008) Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nature Chem. Biol. 4, 691–699.

24 September 2008, Dronedarone

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia (abnormal heart rhythm). Risk increases with age, with 8% of people over 80 having AF. Historically, the most effective treatment for this disorder has been either oral or intravenous administration of the iodinated benzofuran derivative amiodarone (CHEBI:2663), a procedure which has been used safely in patients with even advanced heart failure. However the use of amiodarone has been limited by cumulative and often irreversible organ toxicity, especially in younger patients. In an effort to provide equivalent efficacy and safety with less toxicity, dronedarone (CHEBI:50659) [2], a pharmacologically related benzofuran derivative lacking the iodine moieties, has been developed [1] and subjected to clinical trials. The U.S. Food and Drug Administration (FDA) assigned priority review status to dronedarone in August 2008 following the exciting results of the ATHENA study [3], a large randomized trial which showed a significant decreased risk of cardiovascular hospitalizations or death from any cause in patients with AF treated with dronedarone. Moreover, data presented at the European Society of Cardiology Congress in September [4] suggests that dronedarone could also reduce the risk of stroke for certain elderly patients with AF.

References

  1. Laughlin, J.C. and Kowey, P.R. (2008). Dronedarone: A New Treatment for Atrial Fibrillation. J. Cardiovasc. Electrophysiol. Published Online: 13 Aug 2008.
  2. Press release Sanofi-Aventis. Paris, France 8 August 2008.
  3. Hohnloser, S.H., Connolly, S.J., Crijns, H.J., Page, R.L., Seiz, W. and Torp-Petersen, C. (2007) Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. J. Cardiovasc. Electrophysiol. 19, 69-73.
  4. Connolly, S.J. (2008) ATHENA: The effect of dronedarone on cardiovascular outcomes and stroke in patients with atrial fibrillation. European Society of Cardiology Congress 2008; Munich, Germany. Clinical trials update 3.

3 September 2008, Putrebactin

Siderophores are natural ferric chelators synthesised and excreted by microorganisms. Under aerobic conditions, iron exists mostly in oxidation state III (ferric) and tends to form highly insoluble minerals. Therefore, many microorganisms depend on siderophores for iron uptake. Putrebactin (CHEBI:50432) is a macrocyclic siderophore produced by the marine bacterium Shewanella putrefaciens [1]. It is derived from N-hydroxy-N-succinylputrescine (HSP) and is structurally similar to desferrioxamine E. It was recently shown that desferrioxamine siderophore synthetase DesD catalyses ATP-dependent trimerisation–macrocyclisation of N-hydroxy-N-succinylcadaverine to desferrioxamine E [2]. A BLAST similarity search identified a gene called pubC within a conserved five-gene cluster in several Shewanella species that encodes a homologue of DesD [1]. It was suggested that pubABC encodes the enzymes required to assemble putrebactin from putrescine, with PubA catalysing the dioxygen and FADH2-dependent hydroxylation of putrescine to N-hydroxyputrescine, PubB catalysing its succinyl-CoA-dependent succinylation to HSP, and PubC catalysing ATP-dependent dimerisation of HSP to give pre-putrebactin and its subsequent macrocyclisation to putrebactin. The pubA, pubB and pubC genes are homologous to the alcA, alcB and alcC genes, respectively, which are involved in the biosynthesis of alcaligin, a dihydroxylated analogue of putrebactin isolated from Bordetella species [3].

References

  1. Kadi, N., Arbache, S., Song, L., Oves-Costales, D. and Challis, G.L. (2008) Identification of a gene cluster that directs putrebactin biosynthesis in Shewanella species: PubC catalyzes cyclodimerization of N-hydroxy-N-succinylputrescine. J. Am. Chem. Soc. 130, 10458–10459.
  2. Kadi, N., Oves-Costales, D., Barona-Gomez, F. and Challis, G.L. (2007) A new family of ATP-dependent oligomerization-macrocyclization biocatalysts. Nature Chem. Biol. 3, 652–656.
  3. Challis, G.L. (2005) A widely distributed bacterial pathway for siderophore biosynthesis independent of nonribosomal peptide synthetases. ChemBioChem 6, 601–611.

30 July 2008, 3,3'-Diindolylmethane

3,3'-Diindolylmethane (DIM; CHEBI:50182) is a lipophilic oil-soluble natural product derived from the autolysis of glucobrassicin, a compound present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts and cauliflower. The autolytic reaction requires the enzyme thioglucosidase (EC 3.2.1.147) which is endogenous to these plants and released upon rupture of the cell wall. 3,3'-Diindolylmethane shows several biological properties such as potent antiproliferative and antiandrogenic effects [1]. Clinical trials are being run at present to confirm its therapeutic role in numerous forms of cancer. Because of its innate ability to stimulate interferon-gamma production and potentiate interferon-gamma receptors, it is also under investigation for its immune-modulating properties [2]. Finally, 3,3'-diindolylmethane and several of its analogues appear to modulate drug-metabolising enzymes such as cytochrome P450 via multiple yet distinct pathways [3, 4].

References

  1. Le, H.T., Schaldach C.M., Firestone G.L. and Bjeldanes L.F. (2003) Plant-derived 3,3'-diindolylmethane is a strong androgen antagonist in human prostate cancer cells. J. Biol. Chem. 278, 21136–21145.
  2. Xue, L., Pestka, J.J., Li, M., Firestone, G.L. and Bjeldanes, L.F. (2008) 3,3'-Diindolylmethane stimulates murine immune function in vitro and in vivo. J. Nutr. Biochem. 10, 336–344.
  3. Stresser, D.M., Bailey, G.S., Williams, D.E. and Bjeldanes, L.F. (1995) The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450. J. Biochem. Toxicol. 10, 191–201.
  4. Sanderson, J.T., Slobbe, L., Lansbergen, G.W.A., Safe, S. and van den Berg, M. (2001) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and diindolylmethanes differentially induce cytochrome P450 1A1, 1B1, and 19 in H295R human adrenocortical carcinoma cells. Toxicol. Sci. 61, 40–48.

25 June 2008, Motexafin gadolinium

Nuclear magnetic resonance imaging (MRI) is a non-invasive, non-radiative medical imaging method of growing clinical importance. Unfortunately, the difference in MRI signal between diseased and healthy tissues is often small. To enhance the visualization of the area of interest, paramagnetic contrast agents are often used, such as gadolinium compounds. "Texaphyrins" (for "Texas-size porphyrins") is the trivial name of a class of synthetic expanded porphyrins first prepared in 1988 by Jonathan Sessler and co-authors at the University of Texas at Austin [1]. The texaphyrins form stable coordination complexes with large metal cations such as lanthanoids. One such complex, the texaphyrin gadolinium(3+) complex known as motexafin gadolinium (CHEBI:50161; MGd), has been extensively studied as a potential MRI-detectable enhancer of X-ray cancer therapy. In addition, it has been found that in cancer cells MGd generates reactive oxygen species such as superoxide and induces apoptosis. In vitro studies show that MGd enhances tumour cell cytotoxicity with both ionizing radiation and a number of chemotherapeutic agents [2]. The California-based company Pharmacyclics, Inc. has been developing MGd (brand name Xcytrin®) for use in combination with radiation therapy for treatment of brain metastases from lung cancer. According to the company, "MGd has been evaluated in clinical trials involving over 1000 patients and has been found to be generally well-tolerated, without the usual side-effects seen with standard chemotherapy" [3]. Earlier this month, Pharmacyclics announced final data from a Phase 1/2 study showing a high complete response rate in patients with multiple recurrent non-Hodgkin's lymphoma who were treated with MGd in combination with an approved antibody-targeted radiation therapy.

References

  1. Sessler, J.L., Murai, T., Lynch, V. and Cyr, M. (1988) An "expanded porphyrin": the synthesis and structure of a new aromatic pentadentate ligand. J. Am. Chem. Soc. 110, 5586–5588.
  2. Magda, D. and Miller, R.A. (2006) Motexafin gadolinium: a novel redox active drug for cancer therapy. Semin. Cancer Biol. 16, 466–476.
  3. Motexafin Gadolinium: Cancer Treatment product candidate.

28 May 2008, (–)-α-Thujone

Originally formulated in Switzerland, absinthe became most popular in 19th century France. Many creative artists had their lives touched by absinthe, among them Toulouse-Lautrec, Oscar Wilde, Picasso and Vincent van Gogh. Absinthe was classically manufactured from dried wormwood (Artemisia absinthium), anise and fennel, which were steeped overnight in 85% (by volume) ethanol [1]. Popular lore has it that absinthe causes hallucinations, epileptic-like attacks, and bouts of madness for those who drink it [2]. Convulsions resembling epilepsy were observed in humans and induced in animals with toxic doses of absinthe. The essential oils were first implicated, then specifically wormwood, and finally one compound, the monoterpene (–)-α-thujone (CHEBI:9577). Despite (or maybe precisely because of) its popularity, absinthe was cast as a dangerous and addictive psychoactive drug. Between 1905 and 1913 Belgium, Switzerland, the United States, and Italy banned absinthe [1]. The bans were surprising, given that they were not supported by any scientific evidence that absinthe contained enough thujone or other compounds that could lead to "absinthism". An international research effort now offers firm scientific evidence that thujone is not the culprit behind those effects [3]. The authors conclude that the thujone concentration of preban (prior to 1915) absinthe was generally overestimated in the past. Analysis of postban (1915–1988) and modern commercial absinthes (2003–2006) shows that the encompassed thujone ranges of all absinthes are similar, disproving the supposition that a fundamental difference exists between preban and modern absinthes manufactured according to historical recipes. As the authors note, 'all things considered, nothing besides ethanol was found in the absinthes that was able to explain the syndrome "absinthism"'.

References

  1. Strang, J., Arnold, W.N. and Peters, T. (1999) Absinthe: what's your poison? BMJ 319, 1590-1592.
  2. Ritter, S. (2008) Absinthe myths finally laid to rest. C&EN 86, 42–43.
  3. Lachenmeier, D.W., Nathan-Maister, D., Breaux, T.A., Sohnius, E.M., Schoeberl, K. and Kuballa, T. (2008) Chemical composition of vintage preban absinthe with special reference to thujone, fenchone, pinocamphone, methanol, copper, and antimony concentrations. J. Agric. Food Chem. 56, 3073–3081.

30 April 2008, 2-deoxy-2-(18F)fluoro-α-D-glucose

Positron emission tomography (PET) is one of the most sensitive molecular imaging techniques today. PET imaging agents are labelled with radionuclides which decay by the emission of a positron+), the antimatter counterpart of an electron. After being emitted from the nucleus, the positron travels a short distance in the surrounding matter before it annihilates with an electron. The annihilation produces two γ-rays, which are emitted simultaneously in opposite directions and are then detected by an array of surrounding detectors. Most of the PET imaging probes applied in neurological research have been labelled with either 11C or 18F.

18F18O + β+ + νe
18F-labelled PET radiopharmaceuticals have the most favourable physical properties because the 18F nuclide has the best imaging physical characteristics due to a low positron energy. Its half-life of 110 min allows for more complex radiosynthesis, longer in vivo investigation, and commercial distribution to clinical PET centres that lack radiochemistry facilities [1]. Most important examples of 18F PET imaging probes are 6-(18F)fluoro-L-dopa, a PET ligand for probing cerebral dopamine metabolism and neuroendocrine tumors, and the glucose analogue 2-deoxy-2-(18F)fluoro-α-D-glucose (18FDG; CHEBI:31617). 18FDG is the best clinically known and successful PET tracer and one of the earliest examples of a PET molecular imaging probe feasible to visualise glucose utilisation in vivo by a metabolic trapping mechanism [2]. All experts in the field agree that there would be no clinical PET imaging today without 18FDG.

References

  1. Ametamey, S.M., Honer, M. and Schubiger, P.A. (2008) Molecular imaging with PET. Chem. Rev., in press.
  2. Kopka, K., Schober, O. and Wagner, S. (2008) 18F-labelled cardiac PET tracers: selected probes for the molecular imaging of transporters, receptors and proteases. Basic Res. Cardiol. 103, 131–143.

26 March 2008, (2-trans,6-trans)-farnesol

Nutria, or coypu (Myocastor coypus), are very large (5–9 kg) rat-like animals, originally introduced into North America, Europe, Asia and Africa from South America for their fur, but which are currently ravaging wetlands across Louisiana and the coast of the Gulf of Mexico. Because of their ability to reproduce at rapid speed (a female may have 3 litters per year of up to 13 young per litter), they are unwieldy to control if released into the wild. Now, Professor Athula Attygalle and his team at the Stevens Institute of Technology, New Jersey, in collaboration with groups at Cornell University and the University of Iowa, have identified several volatile compounds, including terpenoids, fatty alcohols, fatty acids and some of their esters, in the anal scent glands of the species. Using gas chromatographic retention times as well as electron-ionization (EI) and chemical-ionization (CI) mass spectrometry, they have identified the major terpenoid constituents as (2-trans,6-trans)-farnesol [CHEBI:16619; otherwise known as (E,E)-farnesol] and its esters. (2-trans,6-trans)-Farnesol is a sesquiterpene alcohol which is also present in many essential oils such as citronella, neroli, cyclamen, lemon grass, tuberose, rose, musk, balsam and tolu. It is also used in perfumery to emphasize the odours of sweet floral perfumes. By incorporating this compound and its esters into lures as bait, Professor Attygalle's discovery offers an environmentally friendly solution to the problem of removing nutria from sensitive coastal zones and marshlands without detrimentally affecting other species.

Reference

  1. Lee, H., Finckbeiner, S., Yu, J.S., Wiemer, D.F., Eisner, T. and Attygalle, A.B. (2007) Characterization of (E,E)-farnesol and its fatty acid esters from anal scent glands of nutria (Myocastor coypus) by gas chromatography–mass spectrometry and gas chromatography–infrared spectrometry. J. Chromatogr., A 1165, 136–143.

27 February 2008, Pseudocoenzyme B12

Sixty years ago, a crystalline compound, which provided a cure for a previously fatal disease pernicious anaemia, was isolated from liver. This compound has become known as vitamin B12 [1]. In the same year, Dorothy Crowfoot Hodgkin began her attempts to determine the structure of vitamin B12, and in 1964 was awarded the Nobel Prize in Chemistry "for her determinations by X-ray techniques of the structures of important biochemical substances", including penicillin and vitamin B12. Vitamin B12 is biosynthesised in certain bacteria, with animals obtaining their B12 from food or directly from resident B12-synthesising bacteria. All B12 cofactors are cobaltcorrinoid complexes. One of the cobalt axial ligands (designated α) is attached to the corrin nucleus via the nucleotide loop, while the other axial ligand (designated β) can vary. The coenzymatically active forms of the B12 vitamins possess an organic β-axial ligand, either methyl or 5'-deoxy-5'-adenosyl, attached via a physiologically rare carbon-to-cobalt bond. The "classic" B12 cofactors that contain 5,6-dimethylbenzimidazole (DMB) as α-axial ligands are called cobalamins. Pseudocoenzyme B12 (CHEBI:48572) is the most common example of a natural B12 cofactor with an α-axial ligand other than DMB – in this case, adenine [2]. The bacterium Salmonella enterica produces the corrin ring only under anaerobic conditions, but it can form B12 coenzymes aerobically by importing a corrinoid precursor, such as cobinamide (Cbi), and adding appropriate axial ligands. Wild-type S. enterica can use ethanolamine as an aerobic source of carbon and energy in the presence of vitamin B12. It also can synthesise vitamin B12 only when both Cbi and DMB are provided. Anderson et al. [3] have recently demonstrated that mutants of S. enterica isolated for their ability to degrade ethanolamine without added DMB can convert Cbi into pseudo-B12 cofactors. The mutations cause an increase in the level of free adenine and install adenine as cobalt α-ligand instead of DMB. Addition of DMB to these mutants stops the synthesis of pseudo-B12 cofactors and B12 cofactors are produced instead. Wild-type cells make pseudo-B12 cofactors during aerobic growth on propanediol and Cbi, and can use pseudo-B12 for all of their corrinoid-dependent enzymes.

References

  1. Rickes, E.L., Brink, N.G., Koniuszy, F.R., Wood, T.R. and Folkers, K. (1948) Crystalline vitamin B12. Science 107, 396–397.
  2. Taga, M.E. and Walker, G.C. (2008) Pseudo-B12 joins the cofactor family. J. Bacteriol. 190, 1157–1159.
  3. Anderson, P.J., Lango, J., Carkeet, C., Britten, A., Kräutler, B., Hammock, B.D. and Roth, J.R. (2008) One pathway can incorporate either adenine or dimethylbenzimidazole as an α-axial ligand of B12 cofactors in Salmonella enterica. J. Bacteriol. 190, 1160–1171.

30 January 2008, Triclocarban

The urea derivative triclocarban (TCC; CHEBI:48347) is an antibacterial and antifungal compound which for 45 years has been added in the USA and Europe to household and personal care products including bars of soap, body washes, cleansing lotions, wipes and detergents. An estimated 45,000 kg of the product are imported annually for the US market alone. The mechanism of its action involves inhibition of the enzyme enoyl-[acyl-carrier-protein] reductase (NADH) (EC 1.3.1.9), a key enzyme of the type II fatty acid synthase (FAS-II) system. Recently, a new UC Davis study, led by emeritus professor Bill Lasley, an expert on reproductive toxicology, has raised concerns by demonstrating that triclocarban can alter hormonal activity in rats and human cells in the laboratory. The study identified two key effects: in human cells triclocarban increased gene expression that is normally regulated by testosterone; and when male rats were fed triclocarban, testosterone-dependent organs such as the prostate gland grew abnormally large. Also, the mechanism by which triclocarban acts, i.e. by increasing hormone effects, is novel, as all previous studies of endocrine disruptors have found that these generally act by blocking or decreasing hormone effects. Lasley believes that the findings may lead eventually to an explanation for rises in some previously described reproductive problems that to date have been difficult to understand.

Reference

  1. Chen, J., Ahn, K.C., Gee, N.A., Mohamed, M.I., Duleba, A.J., Zhao, L., Gee, S.J., Hammock, B.D. and Lasley, B.L. (2007) Triclocarban enhances testosterone action: A new type of endocrine disruptor? Endocrinology 149, 1173–1179.



2007

19 December 2007, Salinosporamide A

Salinosporamide A (CHEBI:48045), a chlorinated natural product from the marine bacterium Salinispora tropica, is a 20S proteasome inhibitor currently in phase 1 human clinical trials for the treatment of the bone marrow cancer multiple myeloma as well as solid tumours. It is around 500 times more active than its dechloro analogue salinosporamide B. In a recent publication by researchers in La Jolla, California [1], it was reported that salL, an 849-base-pair gene in the sal biosynthetic cluster, is required for in vivo chlorination of salinosporamide A. Their work has determined that SalL protein catalyses the displacement of L-methionine from the primary metabolite S-adenosyl-L-methionine (SAM; December 2005 ChEBI Entity of the Month) to generate the intermediate 5'-chloro-5'-deoxyadenosine by a nucleophilic substitution reaction. The mechanism has similarities to a known fluorinase FlA from the soil bacterium Streptomyces cattleya [2], which proceeds via a 5'-fluoro-5'-deoxyadenosine intermediate, and is in contrast to the oxidative mechanism that predominates in biological chorinations. Through its use of such an orthogonal biological chlorination mechanism, it is likely that SalL will prove valuable for the biosynthesis of halogenated small molecules.

References

  1. Eustáquio, A.S., Pojer, F., Noel, J.P. and Moore, B.S. (2008) Discovery and characterization of a marine bacterial SAM-dependent chlorinase. Nature Chem. Biol. 4, 69–74.
  2. Dong, C., Huang, F., Deng, H., Schaffrath, C., Spencer, J.B., O'Hagan, D. and Naismith, J.H. (2004) Crystal structure and mechanism of a bacterial fluorinating enzyme. Nature 427, 561–565.

28 November 2007, A,D-di-p-benzi[28]hexaphyrin(1.1.1.1.1.1)

The German astronomer and mathematician August Ferdinand Möbius (1790–1868) is best known for his discovery (in 1858) of a non-orientable two-dimensional surface with only one side, which is now known as the Möbius band. It was independently discovered the same year by another German mathematician, Johann Benedict Listing. 100 years after its discovery, the Möbius topology caught the imagination of chemists [1]. In the 1930s, Erich Hückel predicted that annulenes which contain 4n+2 mobile electrons should be stable (aromatic), and that those with 4n electrons should be unstable (antiaromatic). However, the Hückel rule is reversed for annulenes with a 180° twist (Möbius annulenes) [2]: chemical Möbius bands with 4n electrons are aromatic and those with 4n+2 electrons are antiaromatic. Recently, Stępień et al. [3] have demonstrated that a molecule can be dynamically switched between Hückel and Möbius topologies by changing the polarity of the solvent. This effect was observed in an expanded porphyrin containing two p-phenylene groups. The compound, A,D-di-p-benzi[28]hexaphyrin(1.1.1.1.1.1) (CHEBI:47035) has 28 (i.e. 4n) mobile electrons and is antiaromatic in non-polar solvents such as hexane, as expected from the Hückel rule. However in polar solvents such as chloroform and N,N-dimethylformamide, the molecule changes conformation from “Hückel” (two-sided) to “Möbius” (one-sided) and antiaromaticity is lost. The difference in conformation is brought about by a 90° twist in one of the p-phenylene groups, which can be either parallel to the other p-phenylene group (Hückel topology) or perpendicular (Möbius topology). The two conformers possess vastly different optical signatures: the hexane solution is green and the chloroform solution is blue. Have a virtual tour over the chemical Möbius band!

References

  1. Rzepa, H.S. (2005) Möbius aromaticity and delocalization. Chem. Rev. 105, 3697–3715.
  2. Herges, R. (2007) Aromatics with a twist. Nature 450, 36–37.
  3. Stępień, M., Latos-Grażyński, S., Sprutta, N., Chwalisz, P. and Szterenberg, L. (2007) Expanded porphyrin with a split personality: a Hückel-Möbius aromaticity switch. Angew. Chem. Int. Ed. 46, 7869–7873.

31 October 2007, capsaicin

Capsaicin (CHEBI:3374) is the active component of chilli peppers, plants belonging to the genus Capsicum. First isolated in 1816 but not synthesised in the laboratory until 1930, it is one of a class of related substances known as capsaicinoids. It is an irritant for mammals and produces a sensation of burning in tissues into which it comes into contact. Capsaicin is believed to be synthesised in the interlocular septa of chilli peppers by addition of a branched-chain to vanillylamine. Biosynthesis depends on the gene Pun1 which encodes a putative acyltransferase [1]. In a recent paper [2], Clifford Woolf and his co-workers at Harvard Medical School and Massachusetts General Hospital report that capsaicin can be used in combination with QX-314, a derivative of the commonly used local anaesthetic lidocaine, to produce an anaesthetic which can completely block pain without causing numbness or paralysis. On its own, QX-314 is unable to pass through cell membranes to block their electrical activity: the role of capsaicin is to open large pores called TRPV1 ion channels, which allow the QX-314 to pass through and selectively block the cells' activity. The treatment is thought to have great potential in improving pain treatment during childbirth, dental procedures and surgery.

References

  1. Stewart, C., Jr., Kang, B.-C., Liu, K., Mazourek, M., Moore, S.L., Yoo, E.Y., Kim, B.-D, Paran, I. and Jahn, M.M. (2005) The Pun1 gene for pungency in pepper encodes a putative acyltransferase. Plant J. 42, 675–688.
  2. Binshtok, A.M., Bean, B.P. and Woolf, C.J. (2007) Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature 449, 607–610.

26 September 2007, (–)-geosmin

The chemical origin of the characteristic odour of soil was first investigated in 1891 by the French chemist and politician Marcellin Berthelot, considered by many to be one of the greatest chemists of all time. However, it was not until 1965 that the responsible agent, (–)-geosmin (CHEBI:46702), was first isolated in pure form and the structure assigned. Later investigations concluded that (–)-geosmin is generated, via germacradienol (CHEBI:46734), from the universal acyclic sesquiterpene precursor farnesyl diphosphate (FPP, CHEBI:17407) by an enzyme (UniProtKB Q9X839, IntEnz EC 4.2.3.22) that is encoded by the SCO6073 gene in the soil organism Streptomyces coelicolor A3(2). A recent study by David Cane and his team at Brown University, Rhode Island, has now shown unambiguously that the SCO6073 germacradienol-geosmin synthase of S. coelicolor is a bifunctional enzyme, in which it is the N-terminal half of the protein which converts FPP principally to geramacradienol, while the C-terminal half (previously thought to be catalytically inactive) then rebinds the germacradienol and catalyses its proton-initiated cyclisation to give the (–)-geosmin.

Reference

  1. Jiang, J., He, X. and Cane, D.E. (2007) Biosynthesis of the earthy odorant geosmin by a bifunctional Streptomyces coelicolor enzyme. Nature Chem. Biol. 3, 711–715.

29 August 2007, imatinib

Protein-tyrosine kinases represent an important class of drug targets, particularly in oncology and inflammation. In a recent study [1], a "chemical proteomics" methodology that enables the capturing of a defined sub-proteome (in this case, protein kinases) on a mixed kinase inhibitor matrix ("kinobeads"), and subsequent analysis by quantitative protein mass spectrometry, has been described. This methodology was applied to three drugs targeting the oncogenic BCR-ABL kinase, which induces chronic myelogenous leukaemia (CML). Quantitative profiling of the drug candidate bosutinib (SKI-606), which is currently undergoing clinical trials, and the marketed drugs imatinib (CHEBI:38918) and dasatinib in K562 cells confirms known targets including ABL and SRC family kinases. Unexpectedly, the receptor tyrosine kinase DDR1 and the metalloflavoprotein oxidoreductase NQO2 (EC 1.10.99.2) were also identified as potent novel targets of imatinib. The function of the "forgotten" enzyme NQO2 (discovered in 1961; re-discovered 36 years later!) is not known but it has been implicated in the detoxification of xenobiotics. It also has been shown to be inhibited by the anti-malarial drugs chloroquine and quinacrine as well as by the red wine component resveratrol [2]. Interestingly, a high expression of NQO2 is found in myeloid cells, which are also the target of imatinib in CML.

References

  1. Bantscheff, M. et al. (2007) A quantitative chemical proteomics approach reveals novel modes of action of clinical ABL kinase inhibitors. Nature Biotechnol. 25, 1035–1044.
  2. Vella, F., Ferry, G., Delagrange, P. and Boutin, J.A. (2005) NRH:quinone reductase 2: an enzyme of surprises and mysteries. Biochem. Pharmacol. 71, 1–12.

25 July 2007, water

It is a wet summer this year in Britain and so it may be an appropriate time to reflect on the unique chemical compound known as water (CHEBI:15377). Water was one of the classic "four elements" of antiquity. It was Antoine Lavoisier who showed in the late 18th century that water is composed of two elements, hydrogen and oxygen. Water covers >70% of the Earth's surface and is the only single chemical substance to give its name to a scientific discipline, that of hydrology. Water is the single most important molecule for life on Earth. Most biochemical reactions take place in aqueous solution; water also is a substrate of many of them (hydrolases, hydratases, photosystem II). Crystalline proteins contain significant amounts of water. Some proteins contain single-file water chains that are suggested to be able to conduct protons along their length ("proton wires"). Such proton wires were observed in X-ray structures of the photosynthetic reaction centre from Rhodobacter sphaeroides, bacteriorhodopsin, cytochrome f, cytochrome c oxidase and phosphatidylglycerophosphatase from Listeria monocytogenes [1 and references therein]. Water can play a structural function in proteins, as is shown by the recent X-ray structural determination of a cysteinless plant Kunitz-type protease inhibitor BbCI where a water-mediated hydrogen bond replaces the highly conserved disulfide bridge thought to be crucial for protein structure stabilisation [2].

References

  1. Kumaran, D., Bonanno, J.B., Burley, S.K. and Swaminathan, S. (2006) Crystal structure of phosphatidylglycerophosphatase (PGPase), a putative membrane-bound lipid phosphatase, reveals a novel binuclear metal binding site and two "proton wires". Proteins 64, 851–862.
  2. Hansen, D., Macedo-Ribeiro, S., Verissimo, P., Yoo Im, S., Sampaio, M.U. and Oliva, M.L.V. (2007) Crystal structure of a novel cysteinless plant Kunitz-type protease inhibitor. Biochem. Biophys. Res. Commun. 46, 735–740.
  3. Hansen, D., Macedo-Ribeiro, S., Verissimo, P., Yoo Im, S., Sampaio, M.U. and Oliva, M.L.V. (2007) Crystal structure of a novel cysteinless plant Kunitz-type protease inhibitor. Biochem. Biophys. Res. Commun. 46, 735-740.


27 June 2007, lapatinib

Lapatinib (CHEBI:38636) is a quinazolinamine-based small molecule that potently inhibits the intracellular tyrosine kinase domains of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2). In March 2007, lapatinib, in the form of its ditosylate monohydrate [Tykerb; GlaxoSmithKline (GSK)], was approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress HER2 and who have received prior therapy including an anthracycline, a taxane and trastuzumab (Herceptin), the combination of trastuzumab with taxane-based chemotherapy being currently the standard first-line treatment for HER2-positive metastatic breast cancer. GSK also last year filed an application for the drug to the European Medicines Agency and expect approval for its use within Europe later this year. Financial analysts are predicting peak sales for lapatinib of $1.5 billion [Moy, B., Kirkpatrick, P., Kar, S. and Goss, P. (2007) Lapatinib. Nature Reviews Drug Discovery 6, 431–432].


30 May 2007, chlorophyll a

Photosystem I (PSI), a protein supercomplex that contains a reaction centre and light-harvesting complexes, is involved in oxygenic photosynthesis where it is a star performer in energy-gathering terms. It is the most efficient photochemical machine in nature, with almost every photon absorbed by the PSI complex being used to drive electron transport. In a recent issue of Nature, Nathan Nelson and his team at Tel Aviv University report the X-ray crystal structure of plant PSI from pea (Pisum sativum) and reveal that, along with a small number of phylloquinones, Fe4S4 clusters and carotenoids, this huge complex binds 168 chlorophyll molecules, with most of these being our Entity of the Month chlorophyll a (CHEBI:18230). Thus, even though chlorophyll is usually thought of as a "cofactor", the sheer bulk of chlorophylls in PSI makes us (ChEBIsts) look at it differently. One can say that PSI is mostly chlorophyll with some proteins wrapped around! [Amunts, A., Drory, O., Nelson, N. (2007) The structure of a plant photosystem I supercomplex at 3.4 Å resolution. Nature 447, 58–63].


25 April 2007, brussalexin A

Phytoalexins are antimicrobial compounds synthesised by plants when stressed which help the weakened plant to defend itself against infection. Soledade Pedras and her research team at the University of Saskatchewan have been using UV irradiation to stress Brussels sprouts (Brassica oleracea var. gemmifera) in order to discover new molecules and have now isolated from their experiments a remarkable new phytoalexin which they name brussalexin A (CHEBI:38130). The compound contains an allyl thiocarbamate group, a structure not previously seen in phytoalexins and whose formation cannot be explained using currently known pathways. Brussalexin A proves to be toxic towards several species of fungus, in particular Sclerotina sclerotiorum, which causes stem rot in many plant families. Pedras' group will now investigate how fungal pathogens break down brussalexin A, with their principal aim being to treat crops with compounds that inhibit these detoxification routes, thus allowing the plants' natural defence mechanisms to work for longer [Pedras, M.S.C., Zheng, Q.-A. and Sarwar, M.G. (2007) Efficient synthesis of brussalexin A, a remarkable phytoalexin from Brussels sprouts. Org. Biomol. Chem. 5, 1167–1169; see also the article "Stressed sprouts hit back" in Chemical Biology 2007, vol. 5.].


28 March 2007, cimicifoetiside A

Cimicifuga foetida is a herbaceous perennial plant native to China where it is used as an antipyretic and analgesic agent in traditional Chinese medicines. Alcoholic extracts from its rhizomes are now being imported into Western markets in order to meet an ever-increasing demand for its North American relative C. racemosa (known commonly as black cohosh, black bugbane or black snakeroot) which is widely used in the United States and Europe as a herbal dietary supplement for the relief of symptoms related to menopause. A collaboration between workers in Kunming, China, and Washington University in the US investigating the constituents of C. foetida has recently resulted in the isolation of a novel cycloartane-type triterpene glycoside which they have named cimicifoetiside A (CHEBI:37779), together with its 25-O-acetyl derivative, named cimicifoetiside B (CHEBI:37780). The compounds are interesting both structurally, in that they possess a relatively uncommon 2-O-acetyl α-L-arabinosyl unit, and physiologically, as they exhibit potent cytotoxicity against human breast cancer cells, suggesting the potential for further examination of these and other cycloartane triterpene glycosides from Cimicifuga spp. for the prevention or treatment of human breast cancers [Sun et al. (2007) Beilstein Journal of Organic Chemistry 3,3].


28 February 2007, beauvericin

Beauvericin (CHEBI:3000) is a cyclodepsipeptide of alternating L-N-methylphenylalanyl and D-α-hydroxyvaleryl residues. Well known as a mycotoxin affecting wheat and other cereal crops, it is produced by several Fusarium species and has also been isolated from the entomopathogenic fungus Beauvaria bassiana . Beauvericin is capable of complexing both alkaline-earth metals and alkali-metal ions and transporting them through membranes in biological systems. New reports of its properties and usage constantly emerge, as exemplified by a very recent publication from two groups in Arizona in which inhibition by beauvericin of metastatic prostate cancer and breast cancer cells, as well as antiangiogenic activity, is demonstrated [Zhan et al. (2007) J. Nat. Prod. 70,227–232 ].


31 January 2007, (–)-epigallocatechin 3-gallate

Catechins (CHEBI:23053) are a group of polyphenolic plant metabolites found extensively in extracts of green, unfermented, tea (Camellia sinensis ). The various health benefits attributed to green tea have until recently been thought to be linked to the antioxidant properties of its constituent catechins. However the use of green tea extract in oral hygiene for several centuries suggests that green tea may also have antibacterial activity. Roman Jerala and his colleagues at the National Institute of Chemistry in Ljubljana, Slovenia, have now, using heteronuclear 2D NMR and fluorescence spectroscopy, studied the properties of (–)-epigallocatechin 3-gallate (EGCG) (CHEBI:4806), the major catechin found in green tea. Their results show that ECGC inhibits the bacterial enzyme DNA gyrase by binding to the ATP binding site of one of its two subunits, known as gyrase B. This subunit catalyses ATP hydrolysis, providing the driving force for supercoiling of DNA, and has been previously investigated as a target for antibacterial drugs. Jerala believes that his findings with EGCG should allow pharmaceutical companies to design novel analogues which improve on EGCG's antibacterial activity without prohibitive side effects emerging [Gradišar, H., Pristovšek, P., Plaper, A. and Jerala, R. (2007) Green tea catechins inhibit bacterial DNA gyrase by interaction with its ATP binding site. J. Med. Chem. 50, 264–271 ; see also: Bradley, D. Tea for who? SpectroscopyNOW.com, January 15, 2007 ].




2006

20 December 2006, tangeretin

The tradition of putting a tangerine (Citrus nobilis var. Tangeriana) into the toe of a Christmas stocking is thought by some to represent the landing within stockings hung up to dry of dowry money which St Nicholas ('Santa Claus') tossed down a chimney in order to rescue several poor maidens from being sold into slavery. In more recent years, however, a more scientific importance of tangerines has emerged, namely that a valuable constituent of their peel (and that of some other citrus fruits) is tangeretin (CHEBI:9400), a polymethoxylated flavone which exhibits a wide range of pharmacological activity. In vitro studies have demonstrated antimutagenic, antiinvasive and antiproliferative effects, while animal research has suggested its potential as both a cholesterol-lowering agent and a protector against Parkinson's disease. More significantly perhaps is the potential of tangeretin as an anti-cancer agent, demonstrated by its inhibition of leukaemic HL-60 cell growth through induction of apoptosis [Hirano et al. (1995) Br. J. Cancer 72, 1380-1388 ], although it must be noted that in the presence of dietary tangeretin a neutralization of the tumour-inhibitory effect of the anti-cancer drug tamoxifen (CHEBI:9396) is observed [Bracke et al. (1999) J. Natl. Cancer Inst. 91, 354-359 ]. A very recent report [Takano et al. (2007) Am. J. Physiol. Cell Physiol. 292, C353–C361 ] highlights the ability of tangeretin and similar polymethoxyflavones to protect cells against endoplasmic reticulum (ER) stress.


1 November 2006, (R)-amygdalin

(R)-Amygdalin (CHEBI:17019; commonly known merely as 'amygdalin' or as 'Vitamin B17') is a by-product of the fruit industry. A naturally occurring cyanogenic glycoside, it is found in many food plants such as the kernels of apricots, almonds and apples and is used as a main constituent in commercial preparations of laetrile, a purported therapeutic agent. George John and Praveen Kumar Vemula from the City College of the City University of New York have now used an enzyme catalysis route to make amygdalin-based amphiphiles (molecules with parts which engage separately in hydrophilic and hydrophobic interactions) which showed unprecedented gelation properties in a wide range of solvents. Using further enzyme catalysis, the supramolecularly organised hydrogels thus formed were then employed as a successful drug-delivery vehicle for curcumin, a well known drug with anti-inflammatory and anti-cancer properties. The project is part of John's ongoing work on the design and development of new soft nanomaterials derived from plant/crop-based renewable feedstocks [John, G. and Vemula, P.K. (2006) Design and development of soft nanomaterials from biobased amphiphiles. Soft Matter 2, 909-914].


27 September 2006, ciguatoxin

The huge ladder-like polycyclic ether ciguatoxin (CHEBI:36467) is a marine toxin found in tropical fish. It is produced by an epiphytic dinoflagellate, Gambierdiscus toxicus, and transferred to herbiverous and carnivorous fish through the aquatic food chain. Ciguatoxin and its congeners are the principal causative agents of ciguatera poisoning, the symptoms of which include gastrointestinal, cardiovascular and neurological disorders which can last for many years. Ciguatoxin is one of the most lethal natural products known with a toxicity almost 300 times that of tetrodotoxin, the infamous compound found in pufferfish. Until now, detailed biological studies, as well as the development of therapeutic methods for ciguatera, have been hampered by the very limited supply of the natural product (the yield from 4000 kg of moray eels is only 0.35 mg). Professor Masayuki Inoue and his colleagues in the Hirama Resarch Group at Tohoku University, Sendai, have now published the first total synthesis of ciguatoxin and one of its hydroxylated derivatives, an achievement that will undoubtedly lead to the development of strategies to contol ciguatera food poisoning [M. Inoue et al. (2006) Total Synthesis of Ciguatoxin and 51-HydroxyCTX3C. J. Am. Chem. Soc. 1280, 9352-9354].


30 August 2006, 19-norandrosterone

19-Norandrosterone (CHEBI:36412) is a naturally produced steroid and a metabolite of the anabolic steroid nandrolone, which is still used illegally by some athletes to boost muscle mass. Evidence for nandrolone abuse is normally provided from analysis of urine samples for 19-norandrosterone, although current tests are unable to distinguish whether the norandrosterone is of synthetic or physiological origin (it is produced naturally in the adrenal glands, gonads and placenta). Researchers at the German Sport University Cologne and the Montreal Anti-doping Laboratory at the INRS-Institut Armand-Frappier have recently developed a technique called gas chromatography combustion isotope ratio mass spectrometry, which can distinguish between the two by analysing the ratio of 13C to 12C in the urine samples. The method can detect concentrations of 19-norandrosterone as low as 2 ng per ml of urine (the level currently allowed by the World Anti-Doping Agency) and may help to resolve cases where athletes have elevated levels of 19-norandrosterone in their urine but insist that they have never taken steroids [Hebestreit et al. (2006) Analyst 131, 1021-1026].


24 July 2006, ozone

Ozone (O3; CHEBI:25812), one of the most toxic inorganic compounds known, is present in low concentrations throughout the Earth's atmosphere. Ground-level ozone, formed by reaction of hydrocarbons and nitrogen oxides with sunlight, is an air pollutant with harmful effects on lung function. A current prolonged period of hot sunny weather across the UK, with daytime temperatures over 30 degrees Celsius, combined with a flow of air from continental Europe containing ozone precursor particulates, led during July of this year to the UK government department Defra issuing a Smog Warning. Levels of ozone across the UK are monitored by the Air Quality Archive, which also offers health advice to those who may be particularly sensitive to air pollution.


27 June 2006, C60 fullerene

C60 fullerene (CHEBI:33128; known also as buckminsterfullerene, footballene and soccerballene) was discovered in 1985 by Sir Harold Kroto in the UK and Richard E. Smalley and Robert F. Curl, Jr. in the USA. These three researchers shared The 1996 Nobel Prize in Chemistry for their discovery. C60 fullerene's atoms are bonded together into a highly symmetrical, hollow polygon structure with the same geometry as that of a football (soccerball). Named after the architect Richard Buckminster "Bucky" Fuller whose geodesic dome design is similar to the molecular structure of C60, these unique structures, also known as buckyballs, have led to an entirely new branch of chemistry. A recent review lists several interesting biological and pharmacological properties of C60 fullerene and derivatives, such as nitric oxide synthase inhibition, nitric oxide-scavenging activity, reactive oxygen species-generating activity, superoxide dismutase mimic properties, and HIV reverse transcriptase and RNA polymerase inhibition [Satoh, M. and Takayanagi, I. (2006) Pharmacological studies on fullerene (C60), a novel carbon allotrope, and its derivatives. J. Pharmacol. Sci. 100, 513–518]. The ChEBI team find it fitting that this 10th anniversary of the Fullerene Nobel Prize should coincide with the staging of the 2006 Football World Cup!


31 May 2006, porphyra-334

The mycosporine-like amino acid porphyra-334 (CHEBI:35671) was first isolated in 1979 from the red alga Porphyra tenera Kjelman. Morris Srebnik and his team at The Hebrew University of Jerusalem have now also isolated porphyra-334 from the aquatic bacterium Aphanizimenon flos-aquae and compared its UVA absorption with that of some commercial sun-care products. Their results show that porphyra-334 provides an equivalent of sun protection factor (SPF) 4 against UVA rays. Furthermore, it dissipates UV energy without creating any reactive species which might cause a phototoxic effect on living organisms, suggesting its possible further development as a commercial sunscreen [Torres, A., Enk, C.D., Hochberg, M. and Srebnik, M. (2006) Porphyra-334, a potential natural source for UVA protective sunscreens. Photochem. Photobiol. Sci. 5, 432–435].


26 April 2006, adenosine 5'-monophosphate 1-oxide

Royal jelly is a sticky, creamy white secretion produced by honey bees to feed the larvae of the colony until they develop to the desired rank. The larvae to develop into the queen will receive only royal jelly as their food source. Royal jelly has been claimed to have various beneficial effects on human health. It is a mixture of vitamins, amino acids, proteins, sugars and lipids, as well as the hero of this month, adenosine 5'-monophosphate 1-oxide (CHEBI:35483), or AMP 1-oxide. AMP 1-oxide was previously shown to inhibit the growth of tumor cells in culture as well as vaccinia virus replication by the blockade of translation of virus mRNAs. However, there have been no reports showing the distribution of adenosine 1-oxide derivatives in natural products, or the activity on the nervous system. Recently, Hattori and co-authors have shown that AMP 1-oxide is an active component of royal jelly that induces neuronal differentiation of pheochromocytoma PC12 cells. AMP 1-oxide induced neurite (process)-formation, inhibited cell growth, and facilitated neurofilament M expression, which suggests that AMP 1-oxide stimulates neuronal differentiation of PC12 cells similarly to nerve growth factor (NGF). [Hattori, N., Nomoto, H., Mishima, S., Inagaki, S., Goto, M., Sako, M. and Furukawa, S. (2006) Identification of AMP N1-oxide in royal jelly as a component neurotrophic toward cultured rat pheochromocytoma PC12 cells. Biosci. Biotechnol. Biochem. 70, 897–906].


22 March 2006, (25R)-5β-spirostan-1β,3α-diol

(25R)-5β-spirostan-1β,3α-diol (CHEBI:35370) is a previously unknown naturally occurring steroidal sapogenin which has been recently isolated from the bulbs of a southern African grassland lily, Ornithogalum tenuifolium. The steroid monomers stack to form one-dimensional chains that interlock with neighbouring polymers, with the overall structure of the natural product almost perfectly mimicking a man-made zip-fastener. It is the first-known zip-like structure to be composed of individual steroid molecules rather than the more usual coupled polymer chains such as those found in DNA [Munro et al. (2006) New J. Chem. 30, 197–207].


22 February 2006, apratoxin A

Apratoxins are marine cyanobacterial cyclodepsipeptides containing discrete polypeptide and polyketide domains. Apratoxin A (CHEBI:35212) demonstrates potent cytotoxicity against tumor cell lines through an unknown mechanism. In a recent communication, Luesch and co-authors used a functional genomics approach, including mRNA expression analysis and genome-wide arrayed cDNA overexpression, to elucidate the molecular basis for this activity. The authors conclude that apratoxin A mediates tumor cytotoxicity through the induction of cell cycle arrest and of apoptosis, which is at least partially initiated through antagonism of fibroblast growth factor (FGF) signalling [Luesch, H., Chanda, S.K., Raya, R.M., Dejesus, P.D., Orth, A.P., Walker, J.R., Izpisúa Belmonte, J.C. and Schultz, P.G. (2006) A functional genomics approach to the mode of action of apratoxin A. Nature Chemical Biology 2, 158–167].


25 January 2006, cis-bis(μ-acetato)[tetrakis(acetonitrile)]diaquadirhodium(RhRh)(2+)

The dinuclear rhodium complex cis-bis(μ-acetato)[hexakis(acetonitrile)]dirhodium(RhRh)(2+) (CHEBI:33863) exchanges its two axial acetonitrile ligands for solvent molecules in water to yield a diaqua complex, cis-bis(μ-acetato)[tetrakis(acetonitrile)]diaquadirhodium(RhRh)(2+) (CHEBI:33894). It has recently been shown that upon irradiation with visible light, the diaqua complex exchanges two further acetonitrile ligands to yield a tetraaqua complex cis-bis(μ-acetato)[bis(acetonitrile)]tetraaquadirhodium(RhRh)(2+) (CHEBI:33895), which is able to bind covalently to double-stranded DNA. The low cytotoxicity in the dark makes the diaqua complex a promising potential agent for photodynamic therapy [Lutterman, D.A., Fu, P.K.-L. and Turro, C. (2006) J. Am. Chem. Soc. 128, 738–739].




2005

7 December 2005, S-adenosyl-L-methionine

S-adenosyl-L-methionine (AdoMet; SAM; CHEBI:15414) is an important sulfonium intermediate in one-carbon metabolism, the 'active methyl' of the methionine being donated to an acceptor molecule by transmethylation with production of S-adenosyl-L-homocysteine. A recent communication reports the synthesis of analogues withextended allylic and propargylic chains replacing the methyl group and shows their suitability as cofactors for DNA methyltransferases, providing a new method for sequence-specific covalent derivatization of DNA.


26 October 2005, quinacrine

The human prion protein in its normal form, PrPc, plays an important role in maintaining several cell functions. The pathogenic form, PrPSc, has an essentially identical primary structure but is folded differently and displays different physiological interactions giving rise to prion diseases such as variant CJD. Quinacrine (CHEBI:8711), an acridine derivative formerly widely used as an antimalarial, is known to bind to PrPc prions and is currently undergoing human clinical trials through the British Medical Research Council to investigate its efficacy in combating such prion diseases.


22 September 2005, tomatine

The glycoalkaloid tomatine (CHEBI:9630) is a steroidalsaponin that occurs in the leaves of wild tomato plants where it inhibits the growth of various fungi and bacteria. Researchers at the University of East Anglia in the UK have recently published a one-pot synthetic route to the tetrasaccharide part of tomatine which should facilitate studies into understanding the ecological relationships between plants and fungi [Jones, N.A., Nepogodiev, S.A. and Field, R.A. (2005) Organic & Biomolecular Chemistry 3, 3201–3206).


31 August 2005, rofecoxib

Rofecoxib (CHEBI:8887), a cyclooxygenase (COX) inhibitor, was formerly marketed by Merck and Co. under the trade name VIOXX. Its specificity for only one form of the enzyme, COX-2, allowed it to reduce inflammation and pain while minimizing undesired gastrointestinal adverse effects, common with other nonsteroidal anti-inflammatory drugs. On August 19 2005 a US jury found Merck negligent in the death of a man who used it and awarded his widow $253.4m. Merck is to appeal against the decision. A view of the moleculeand some further reading are available here.


27 July 2005, ATTA-Eu3+

A dioxygen molecule in an excited singlet state, known as singlet molecular oxygen (1O2), reacts withmany kinds of biomolecules, such as DNA, proteins and lipids. Researchers at the Chinese Academy of Sciences have recently reported the synthesis and characterization of ATTA-Eu3+ (CHEBI:33025), the first europium(3+) chelate-based phosphorescence probe specific for time-resolved luminescence detection of 1O2. The structure of ATTA-Eu3+ is shown in the abstract of this report [Song, B., Wang, G. and Yuan, J. Chem. Commun., 2005, 3553–3555].


29 June 2005, pelargonidin 3-glucoside

The predominant pigment in strawberries (Fragaria sp.) is pelargonidin 3-glucoside (CHEBI:31967). One of three anthocyanins which contribute to the red colour inripe fruit, it is present at a concentration of around 900 μmol/kg and metabolised in humans principally viaformation of various pelargonidin monoglucuronic acid conjugates. A view of the molecule is shownhere.


25 May 2005, ellagic acid

Ellagic acid [CHEBI:4775] is a fused four-ring polyphenol found abundantly in various fruits, nuts and vegetables. It is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and oesophagus of rodents, and TPA-induced tumour promotion in mouse. Studies suggest that the mechanisms of mutagenesis and carcinogenesis involve adduct formation with DNA, thus masking binding sites to be occupied by the mutagen or carcinogen. A representation of the molecule is available here.


27 April 2005, vancomycin

Vancomycin [CHEBI:28001], a glycopeptide isolated from Streptomyces orientalis, inhibits a specific step in the synthesis of the peptidoglycan layer in Staphylococcus aureusand Clostridium difficile. For over 40 years it has been used to kill bacteria when no other drug works and has become known as the "antibiotic of last resort". However, in recent years vancomycin-resistant enterococci (VRE) have emerged,prompting restrictions in the drug's use. A 3-D representation of the molecule is available here.


16 March 2005, cisplatin

Cisplatin [CHEBI:27899], the structure of which is incorporated into the ChEBI logo, is a square planar platinum complex widely used for the treatment of a variety of tumours. Its mode of action involves loss of its Cl ligands and binding mainly to the N-7 atoms of a pair of guanine bases on either the same or adjacent strands of DNA, thus causing distortion of the DNA structure and inhibition of cell repair. A diagram showing such linking occurring between adjacent DNA strands is available here.


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