{"documents": [{"abstract": "Tripterine and closely related triterpenoid derivatives as IL-1 beta release inhibitors are discussed.", "authors": "Huang FC, Chan WK, Moriarty KJ, Zhang DC, Chang MN, He W, Yu KT, Zilberstein A.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1130892", "doi": "10.1016/s0960-894x(98)00331-x", "doi_chembl": null, "first_page": "1883", "issue": "14", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "1886", "patent_id": null, "pubmed_id": 9873452, "score": 15.0, "src_id": 1, "title": "Novel cytokine release inhibitors. Part I: Triterpenes.", "volume": "8", "year": 1998}, {"abstract": "Steroidal derivatives as IL-1 beta release inhibitors are discussed.", "authors": "He W, Huang FC, Morytko M, Jariwala N, Yu KT.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1130623", "doi": "10.1016/s0960-894x(98)00521-6", "doi_chembl": null, "first_page": "2825", "issue": "20", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "2828", "patent_id": null, "pubmed_id": 9873630, "score": 15.0, "src_id": 1, "title": "Novel cytokine release inhibitors. Part II: Steroids.", "volume": "8", "year": 1998}, {"abstract": "We describe herein the synthesis and biological activity of two indoloazepines that are structurally related to the marine sponge metabolite hymenialdisine. The natural product hymenialdisine was found to be a potent inhibitor of interleukin-2 (IC(50) = 2.4 microM) and tumor necrosis factor alpha (IC(50) = 1.4 microM) production. One of the hymenialdisine derived indoloazepines was found to also inhibit interleukin-2 (IC(50) = 3.5 microM) and tumor necrosis factor alpha (IC(50) = 8.2 microM) production.", "authors": "Sharma V, Lansdell TA, Jin G, Tepe JJ.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1148362", "doi": "10.1021/jm040013d", "doi_chembl": null, "first_page": "3700", "issue": "14", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "3703", "patent_id": null, "pubmed_id": 15214798, "score": 15.0, "src_id": 1, "title": "Inhibition of cytokine production by hymenialdisine derivatives.", "volume": "47", "year": 2004}, {"abstract": "A series of pyrrolo[2,3-d]pyrimidone nucleosides were synthesized and evaluated for their ability to enhance Type 2 cytokines and to suppress Type 1 cytokines in human T cells activated in vitro. Compounds 16b, 16c, 16d, 18c, and 19b induced substantial enhancement of IL-4 (a Type 2 cytokine) levels while three compounds (16b, 16c, and 16f) showed significant suppression of IFNgamma (a Type 1 cytokine) levels. The results revealed a strict structural requirement for the nucleoside-mediated enhancement of IL-4. Modifications of the ribofuranose moiety of the nucleosides either abolished or dramatically reduced the activity. Both the 5'-hydroxy and 5-carboxamidine are crucial for the activity. Of the few nucleoside analogues that demonstrated enhancement on Type 2 cytokine production, 7-(beta-D-ribofuranosyl)pyrrolo[2, 3-d]-4-pyrimidone-5-carboxamidine (16c) showed a dramatic enhancement (>200%) of IL-4 levels and a significant enhancement (36%) of IL-5 levels. Moreover, this compound showed substantial suppression of the Type 1 cytokines, IFNgamma (42%), IL-2 (54%), and TNFalpha (55%). Similarly, compound 16b showed a substantial enhancement of IL-4 (46%) and suppression of IL-2 (35%), IFNgamma (30%), and TNFalpha (26%). To our knowledge, these are the first nucleoside analogues that induce a Type 2 cytokine bias in T cells. The cytokine modulation property of 16c and 16b merits the therapeutic evaluation of these compounds in treating diseases in which immunopathology is associated with polarized Type 1 cytokine responses.", "authors": "Wang G, Tam RC, Gunic E, Du J, Bard J, Pai B.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1133764", "doi": "10.1021/jm000035+", "doi_chembl": null, "first_page": "2566", "issue": "13", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "2574", "patent_id": null, "pubmed_id": 10891116, "score": 14.0, "src_id": 1, "title": "Synthesis and cytokine modulation properties of pyrrolo[2, 3-d]-4-pyrimidone nucleosides.", "volume": "43", "year": 2000}, {"abstract": "A series of 1,2,4-triazole L-nucleosides were synthesized and evaluated for their ability to stimulate type 1 cytokine production by activated human T cells in direct comparison to the known active agent ribavirin. Among the compounds prepared, 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamide (5, ICN 17261) was found to be the most uniformly potent compound. Conversion of the 3-carboxamide group of 5 to a carboxamidine functionality resulted in 1-beta-L-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (10), which induced cytokine levels comparable to 5 for two of the three type 1 cytokines examined. Modification of the carbohydrate moiety of 5 provided compounds of reduced activity. Significantly, ICN 17261 offers interesting immunomodulatory potential for the treatment of diseases where type 1 cytokines play an important role.", "authors": "Ramasamy KS, Tam RC, Bard J, Averett DR.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1133712", "doi": "10.1021/jm9905514", "doi_chembl": null, "first_page": "1019", "issue": "5", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "1028", "patent_id": null, "pubmed_id": 10715165, "score": 14.0, "src_id": 1, "title": "Monocyclic L-nucleosides with type 1 cytokine-inducing activity.", "volume": "43", "year": 2000}, {"abstract": "On the basis of model imidazole inhibitors of cytokine release, a series of novel pyridinyl pyrimidine derivatives was prepared and tested on their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells (PBMC) and human whole blood. In the pyrimidine series, structure-activity relationships (SARs) similar to those of the imidazole series were found, although generally pyrimidine compounds were less potent. Modification of the substituent at the 2 position of the pyrimidine led to the most active compound 14 which inhibited release of TNF-alpha (IC(50) = 3.2 microM) and IL-1beta (IC(50) = 2.3 microM) from PBMC as effectively as the model imidazole inhibitor ML 3163 (TNF-alpha, IC(50) = 3.7 microM; IL-1beta, IC(50) = 0.9 microM). Screening in an isolated enzyme assay revealed both imidazole and pyrimidine compounds as inhibitors of p38 MAP (mitogen-activated protein) kinase.", "authors": "Laufer SA, Wagner GK.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1135478", "doi": "10.1021/jm011098a", "doi_chembl": null, "first_page": "2733", "issue": "13", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "2740", "patent_id": null, "pubmed_id": 12061876, "score": 14.0, "src_id": 1, "title": "From imidazoles to pyrimidines: new inhibitors of cytokine release.", "volume": "45", "year": 2002}, {"abstract": "4-Aryl-5-pyrimidyl based cytokine synthesis inhibitors that contain a novel monocyclic, pyrazolone heterocyclic core are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production. One of the compounds (6e) was found to be efficacious in the rat iodoacetate (RIA) in vivo model of osteoarthritis. The X-ray crystal structure of a pyrazolone inhibitor cocrystallized with mutated p38 (mp38) is presented.", "authors": "Golebiowski A, Townes JA, Laufersweiler MJ, Brugel TA, Clark MP, Clark CM, Djung JF, Laughlin SK, Sabat MP, Bookland RG, VanRens JC, De B, Hsieh LC, Janusz MJ, Walter RL, Webster ME, Mekel MJ.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1144379", "doi": "10.1016/j.bmcl.2005.03.007", "doi_chembl": null, "first_page": "2285", "issue": "9", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "2289", "patent_id": null, "pubmed_id": 15837310, "score": 14.0, "src_id": 1, "title": "The development of monocyclic pyrazolone based cytokine synthesis inhibitors.", "volume": "15", "year": 2005}, {"abstract": "Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy-α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.", "authors": "Jervis PJ, Graham LM, Foster EL, Cox LR, Porcelli SA, Besra GS.", "chembl_release": {"chembl_release": "CHEMBL_15", "creation_date": "2013-01-23"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL2057201", "doi": "10.1016/j.bmcl.2012.05.009", "doi_chembl": null, "first_page": "4348", "issue": "13", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "4352", "patent_id": null, "pubmed_id": 22652050, "score": 14.0, "src_id": 1, "title": "New CD1d agonists: synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides.", "volume": "22", "year": 2012}, {"abstract": "Polycomb Repressive Complex 2 (PRC2) is an epigenetic regulator induced in many cancers. It is thought to drive tumorigenesis by repressing division, stemness, and/or developmental regulators. Cancers evade immune detection, and diverse immune regulators are perturbed in different tumors. It is unclear how such cell-specific effects are coordinated. Here, we show a profound and cancer-selective role for PRC2 in repressing multiple cytokine pathways. We find that PRC2 represses hundreds of IFNγ stimulated genes (ISGs), cytokines and cytokine receptors. This target repertoire is significantly broadened in cancer vs non-cancer cells, and is distinct in different cancer types. PRC2 is therefore a higher order regulator of the immune program in cancer cells. Inhibiting PRC2 with either RNAi or EZH2 inhibitors activates cytokine/cytokine receptor promoters marked with bivalent H3K27me3/H3K4me3 chromatin, and augments responsiveness to diverse immune signals. PRC2 inhibition rescues immune gene induction even in the absence of SWI/SNF, a tumor suppressor defective in ~20% of human cancers. This novel PRC2 function in tumor cells could profoundly impact the mechanism of action and efficacy of EZH2 inhibitors in cancer treatment.", "authors": "Abou El Hassan M, Huang K, Eswara MB, Zhao M, Song L, Yu T, Liu Y, Liu JC, McCurdy S, Ma A, Wither J, Jin J, Zacksenhaus E, Wrana JL, Bremner R.", "chembl_release": {"chembl_release": "CHEMBL_36", "creation_date": "2025-07-28"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL5674868", "doi": "10.1371/journal.pone.0126466", "doi_chembl": null, "first_page": "126466", "issue": "6", "journal": "PLoS One", "journal_full_title": null, "last_page": "126466", "patent_id": null, "pubmed_id": 26030458, "score": 14.0, "src_id": 72, "title": "Cancer Cells Hijack PRC2 to Modify Multiple Cytokine Pathways.", "volume": "10", "year": 2015}, {"abstract": "", "authors": "Ting PC, Lee JF, Solomon DM, Smith SR, Terminelli CA, Jakway JP, Zambas DN", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1128081", "doi": "10.1016/0960-894X(95)00466-7", "doi_chembl": null, "first_page": "2749", "issue": "22", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "2754", "patent_id": null, "pubmed_id": null, "score": 13.0, "src_id": 1, "title": "Synthesis of dibenzo[a,d]cycloheptanes as cytokine biosynthesis inhibitors", "volume": "5", "year": 1995}, {"abstract": "Truncated analogs of tripterine as cytokine (IL-1 alpha, IL-1 beta, TNF-alpha, IL-6, and IL-8) release inhibitors are discussed.", "authors": "He W, Huang FC, Gavai A, Chan WK, Amato G, Yu KT, Zilberstein A.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1130726", "doi": "10.1016/s0960-894x(98)00671-4", "doi_chembl": null, "first_page": "3659", "issue": "24", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "3664", "patent_id": null, "pubmed_id": 9934491, "score": 13.0, "src_id": 1, "title": "Novel cytokine release inhibitors. Part III: Truncated analogs of tripterine.", "volume": "8", "year": 1998}, {"abstract": "Podocarpic acid derivatives as cytokine (IL-1beta) release inhibitors are discussed.", "authors": "He W, Gavai A, Huang FC, Regan J, Hanney B, Poli G, Bruno J, Chan WK, Djuric SW, Yu KT, Zilberstein A.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1131935", "doi": "10.1016/s0960-894x(99)00023-2", "doi_chembl": null, "first_page": "469", "issue": "3", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "474", "patent_id": null, "pubmed_id": 10091704, "score": 13.0, "src_id": 1, "title": "Novel cytokine release inhibitors. Part IV: analogs of podocarpic acid.", "volume": "9", "year": 1999}, {"abstract": "Novel 2,4,5-trisubstituted imidazole derivatives were prepared as potential anticytokine agents. Thirty-seven compounds were tested on their ability to inhibit the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) from peripheral blood mononuclear cells (PBMC) or human whole blood. SARs (structure activity relationships) for substituents at the 4 and 5 position of the imidazole core were similar to those described for other inhibitors of cytokine release and p38 MAP (mitogen-activated protein) kinase. Starting from benzylsulfanyl imidazole 2b (IC(50) p38, 4.0 microM; TNF-alpha, 1.1 microM; IL-1beta, 0.38 microM), the contribution of substituents at the 2 position to enzyme inhibitory and cellular activity of test compounds was investigated. This strategy led to the identification of compound 2q (IC(50) p38, 0.63 microM; TNF-alpha, 0.90 microM; IL-1beta, 0.04 microM), which was 6-10 times more potent than the initial lead 2b with respect to inhibition of p38 and IL-1beta release and equipotently inhibited TNF-alpha release.", "authors": "Laufer SA, Striegel HG, Wagner GK.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1135626", "doi": "10.1021/jm020873z", "doi_chembl": null, "first_page": "4695", "issue": "21", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "4705", "patent_id": null, "pubmed_id": 12361396, "score": 13.0, "src_id": 1, "title": "Imidazole inhibitors of cytokine release: probing substituents in the 2 position.", "volume": "45", "year": 2002}, {"abstract": "4-Aryl-5-pyrimidyl-based cytokine synthesis inhibitors of TNF-alpha production, which contain a novel bicyclic pyrazole heterocyclic core, are described. Many of these inhibitors showed low nanomolar activity against LPS-induced TNF-alpha production in a THP-1 cell-based assay and against human p38 alpha MAP kinase in an isolated enzyme assay. The X-ray crystal structure of a bicyclic pyrazole inhibitor co-crystallized with mutated p38 (mp38) is presented.", "authors": "Townes JA, Golebiowski A, Clark MP, Laufersweiler MJ, Brugel TA, Sabat M, Bookland RG, Laughlin SK, VanRens JC, De B, Hsieh LC, Xu SC, Janusz MJ, Walter RL.", "chembl_release": {"chembl_release": "CHEMBL_1", "creation_date": "2009-09-03"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1137879", "doi": "10.1016/j.bmcl.2004.07.024", "doi_chembl": null, "first_page": "4945", "issue": "19", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "4948", "patent_id": null, "pubmed_id": 15341957, "score": 13.0, "src_id": 1, "title": "The development of new bicyclic pyrazole-based cytokine synthesis inhibitors.", "volume": "14", "year": 2004}, {"abstract": "Derangement of cellular immunity is central in the pathophysiology of multiple sclerosis (MS) and is often manifested by abnormal cytokine production. We investigated cytokine secretion in peripheral blood mononuclear cells (PBMC) of 18 MS patients and 15 controls and correlated cytokine polarization with the nature of antigenic stimulus. We synthesized two novel citrullinated peptides, linear [Cit(91), Ala(96), Cit(97)]MBP(87-99) and cyclo(87-99)[Cit(91), Ala(96), Cit(97)]MBP(87-99) that resulted from citrullination of 91,97 Arg residues in antagonists, linear [Arg(91), Ala(96)]MBP(87-99) and cyclo(87-99)[Arg(91), Ala(96)]MBP(87-99) peptides. PBMC from MS patients and controls were cultured with citrullinated peptides, and both peptides caused a Th1 polarization in all MS patients studied. In contrast, culture with noncitrullinated MBP peptides resulted in heterogeneous cytokine secretion that differed between individual patients. Thus, citrullination of self-antigens may potentially trigger disease in susceptible individuals. This finding may open new avenues in drug design of new substances that inhibit citrullination and arrest epitope spreading and worsening of MS.", "authors": "Deraos G, Chatzantoni K, Matsoukas MT, Tselios T, Deraos S, Katsara M, Papathanasopoulos P, Vynios D, Apostolopoulos V, Mouzaki A, Matsoukas J.", "chembl_release": {"chembl_release": "CHEMBL_2", "creation_date": "2009-11-30"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1151727", "doi": "10.1021/jm800891n", "doi_chembl": null, "first_page": "7834", "issue": "24", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "7842", "patent_id": null, "pubmed_id": 19053745, "score": 13.0, "src_id": 1, "title": "Citrullination of linear and cyclic altered peptide ligands from myelin basic protein (MBP(87-99)) epitope elicits a Th1 polarized response by T cells isolated from multiple sclerosis patients: implications in triggering disease.", "volume": "51", "year": 2008}, {"abstract": "The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.", "authors": "Kahlon DK, Lansdell TA, Fisk JS, Hupp CD, Friebe TL, Hovde S, Jones AD, Dyer RD, Henry RW, Tepe JJ.", "chembl_release": {"chembl_release": "CHEMBL_2", "creation_date": "2009-11-30"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1140925", "doi": "10.1021/jm8013162", "doi_chembl": null, "first_page": "1302", "issue": "5", "journal": "J Med Chem", "journal_full_title": "Journal of medicinal chemistry.", "last_page": "1309", "patent_id": null, "pubmed_id": 19220017, "score": 13.0, "src_id": 1, "title": "Nuclear factor-kappaB mediated inhibition of cytokine production by imidazoline scaffolds.", "volume": "52", "year": 2009}, {"abstract": "Quercetin (1) is known to have both antioxidant and antinociceptive effects. However, the mechanism involved in its antinociceptive effect is not fully elucidated. Cytokines and reactive oxygen species have been implicated in the cascade of events resulting in inflammatory pain. Therefore, we evaluated the antinociceptive mechanism of 1 focusing on the role of cytokines and oxidative stress. Intraperitoneal and oral treatments with 1 dose-dependently inhibited inflammatory nociception induced by acetic acid and phenyl-p-benzoquinone and also the second phase of formalin- and carrageenin-induced mechanical hypernociception. Compound 1 also inhibited the hypernociception induced by cytokines (e.g., TNFalpha and CXCL1), but not by inflammatory mediators that directly sensitize the nociceptor such as PGE2 and dopamine. On the other hand, 1 reduced carrageenin-induced IL-1beta production as well as carrageenin-induced decrease of reduced glutathione (GSH) levels. These results suggest that 1 exerts its analgesic effect by inhibiting pro-nociceptive cytokine production and the oxidative imbalance mediation of inflammatory pain.", "authors": "Valério DA, Georgetti SR, Magro DA, Casagrande R, Cunha TM, Vicentini FT, Vieira SM, Fonseca MJ, Ferreira SH, Cunha FQ, Verri WA.", "chembl_release": {"chembl_release": "CHEMBL_6", "creation_date": "2010-08-27"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1153728", "doi": "10.1021/np900259y", "doi_chembl": null, "first_page": "1975", "issue": "11", "journal": "J Nat Prod", "journal_full_title": "Journal of natural products.", "last_page": "1979", "patent_id": null, "pubmed_id": 19899776, "score": 13.0, "src_id": 1, "title": "Quercetin reduces inflammatory pain: inhibition of oxidative stress and cytokine production.", "volume": "72", "year": 2009}, {"abstract": "Stimulation of iNKT cells by α-galactosyl ceramide (α-GalCer), also known as KRN7000, and its truncated analogue OCH induces both Th1- and Th2-cytokines, with OCH inducing a Th2-cytokine bias. Skewing of the iNKT cells' response towards either a Th1- or Th2-cytokine profile offers potential therapeutic benefits. The length of both the acyl and the sphingosine chains in α-galactosyl ceramides is known to influence the cytokine release profile. We have synthesized analogues of α-GalCer with truncated sphingosine chains for biological evaluation, with particular emphasis on the Th1/Th2 distribution. Starting from a common precursor, d-lyxose, the sphingosine derivatives were synthesised via a straightforward Wittig condensation.", "authors": "Veerapen N, Reddington F, Salio M, Cerundolo V, Besra GS.", "chembl_release": {"chembl_release": "CHEMBL_11", "creation_date": "2011-08-01"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL1641364", "doi": "10.1016/j.bmc.2010.11.032", "doi_chembl": null, "first_page": "221", "issue": "1", "journal": "Bioorg Med Chem", "journal_full_title": "Bioorganic & medicinal chemistry.", "last_page": "228", "patent_id": null, "pubmed_id": 21145749, "score": 13.0, "src_id": 1, "title": "Synthesis of truncated analogues of the iNKT cell agonist, α-galactosyl ceramide (KRN7000), and their biological evaluation.", "volume": "19", "year": 2011}, {"abstract": "Toll-like receptors (TLRs) are key targets in the design of immunomodulating agents for use as vaccine adjuvants and anticancer treatments. The imidazoquinolines, imiquimod and resiquimod, have been shown to activate TLR-7 and -8 which in turn induce cytokine production as part of the innate immune response. Herein, we report the synthesis and discovery of a C7-methoxycarbonyl derivative of imiquimod that stimulates cytokine production but is devoid of TLR-7/8 activity. Data is presented that shows this analog not only induces IL-12p40 and TNF production, similar to that of imiquimod and resiquimod, but greatly enhances the production of IL-1β, a key cytokine involved in activation of CD4 T cells. It is further demonstrated that TLR-7/8 activation can be recovered by the addition of a C2-alkyl substituent to this newly discovered analog. The results support the existence of an alternative mechanism of action by which imidazoquinolines can stimulate cytokine production.", "authors": "Shi C, Xiong Z, Chittepu P, Aldrich CC, Ohlfest JR, Ferguson DM.", "chembl_release": {"chembl_release": "CHEMBL_16", "creation_date": "2013-05-07"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL2216754", "doi": "10.1021/ml300079e", "doi_chembl": null, "first_page": "501", "issue": "6", "journal": "ACS Med Chem Lett", "journal_full_title": "ACS medicinal chemistry letters.", "last_page": "504", "patent_id": null, "pubmed_id": 22837811, "score": 13.0, "src_id": 1, "title": "Discovery of Imidazoquinolines with Toll-Like Receptor 7/8 Independent Cytokine Induction.", "volume": "3", "year": 2012}, {"abstract": "Apoptotic cell death is the cause of the loss of insulin-producing β-cells in all forms of diabetes mellitus. The identification of small molecules capable of protecting cytokine-induced apoptosis could form the basis of useful therapeutic interventions. Here in, we present the discovery and synthesis of new benzimidazole derivatives, capable of rescuing pancreatic β-cells from cytokine-induced apoptosis. Three hydrazone derivatives of benzimidazole significantly increased the cellular ATP levels, reduced caspase-3 activity, reduced nitrite production and increased glucose-stimulated insulin secretion in the presence of proinflammatory cytokines. These findings suggest that these compounds may protect β-cells from the harmful effects of cytokines and may serve as candidates for therapeutic intervention for diabetes.", "authors": "Zawawi NK, Rajput SA, Taha M, Ahmat N, Ismail NH, Abdullah N, Khan KM, Choudhary MI.", "chembl_release": {"chembl_release": "CHEMBL_22", "creation_date": "2016-11-08"}, "contact": null, "doc_type": "PUBLICATION", "document_chembl_id": "CHEMBL3616384", "doi": "10.1016/j.bmcl.2015.08.022", "doi_chembl": null, "first_page": "4672", "issue": "20", "journal": "Bioorg Med Chem Lett", "journal_full_title": "Bioorganic & medicinal chemistry letters.", "last_page": "4676", "patent_id": null, "pubmed_id": 26330080, "score": 13.0, "src_id": 1, "title": "Benzimidazole derivatives protect against cytokine-induced apoptosis in pancreatic β-Cells.", "volume": "25", "year": 2015}], "page_meta": {"limit": 20, "next": "/chembl/api/data/document/search.json?limit=20&offset=20&q=cytokine", "offset": 0, "previous": null, "total_count": 934}}