1xqc › Citations

Selective estrogen receptor modulators with conformationally restricted side chains. Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands.

Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P
J Med Chem 48 364-79 (2005)
Cited: 38 times
EuropePMC logo PMID: 15658851

Abstract

We disclose herein the discovery of estrogen receptor alpha (ERalpha) selective estrogen receptor modulators (SERMs) of the tetrahydroisoquinoline series that incorporate novel conformationally restricted side chains as replacement of the aminoethoxy residue typical of SERMs. Molecular modeling studies used in conjunction with the X-ray crystal structure of the ERalpha ligand binding domain (LBD) with raloxifene (7) suggested a diazadecaline moiety as a viable mimic of the SERM side chain. On the basis of this knowledge, the piperidinylethoxy moiety of our lead compound 60 was replaced by a diazadecaline subunit, providing the novel tetrahydroisoquinoline 29. In addition to exhibiting a binding affinity to ERalpha and antagonistic properties in the estrogen response element and MCF-7 assays similar to those of the parent compound 60, ligand 29 showed a reduced agonist behavior in the MCF-7 assay in the absence of 17beta-estradiol. These data point toward the fact that 29 may have a potential for breast cancer prevention/treatment in vivo, a feature which is particularly attractive in the quest for safe alternatives to hormone replacement therapy. In a pharmacokinetic experiment carried out in rats, 29 displayed an interesting profile, with a bioavailability of 49%. We also disclose the X-ray crystal structure of 29 in complex with ERalpha-LBD, which reveals the preferred configurations of 29 at the two chiral centers and the details of its interactions with the receptor. Finally, our structure-activity relationship studies show that other analogues bearing constrained side chains retain potency and antagonist activity and that a 3-OH substituted phenyl D-ring increases the selectivity of a set of piperazinyl-containing ligands in favor of ERalpha over ERbeta.

Reviews - 1xqc mentioned but not cited (2)

  1. Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands. Ng HW, Perkins R, Tong W, Hong H. Int J Environ Res Public Health 11 8709-8742 (2014)
  2. Estrogen Receptor-α Targeting: PROTACs, SNIPERs, Peptide-PROTACs, Antibody Conjugated PROTACs and SNIPERs. Negi A, Kesari KK, Voisin-Chiret AS. Pharmaceutics 14 2523 (2022)

Articles - 1xqc mentioned but not cited (7)

  1. Improved docking, screening and selectivity prediction for small molecule nuclear receptor modulators using conformational ensembles. Park SJ, Kufareva I, Abagyan R. J Comput Aided Mol Des 24 459-471 (2010)
  2. The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene. Vajdos FF, Hoth LR, Geoghegan KF, Simons SP, LeMotte PK, Danley DE, Ammirati MJ, Pandit J. Protein Sci 16 897-905 (2007)
  3. Training a scoring function for the alignment of small molecules. Chan SL, Labute P. J Chem Inf Model 50 1724-1735 (2010)
  4. Characterization of ligand type of estrogen receptor by MD simulation and mm-PBSA free energy analysis. Liu JY, Mooney SD. Int J Biochem Mol Biol 2 190-198 (2011)
  5. Structural dynamic studies on identification of EGCG analogues for the inhibition of Human Papillomavirus E7. Aarthy M, Panwar U, Singh SK. Sci Rep 10 8661 (2020)
  6. PTS: a pharmaceutical target seeker. Ding P, Yan X, Liu Z, Du J, Du Y, Lu Y, Wu D, Xu Y, Zhou H, Gu Q, Xu J. Database (Oxford) 2017 bax095 (2017)
  7. Human Estrogen Receptor Alpha Antagonists, Part 3: 3-D Pharmacophore and 3-D QSAR Guided Brefeldin A Hit-to-Lead Optimization toward New Breast Cancer Suppressants. Kurtanović N, Tomašević N, Matić S, Proia E, Sabatino M, Antonini L, Mladenović M, Ragno R. Molecules 27 2823 (2022)


Reviews citing this publication (8)

  1. Estrogen receptors: how do they signal and what are their targets. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Ström A, Treuter E, Warner M, Gustafsson JA. Physiol Rev 87 905-931 (2007)
  2. Biaryl phosphane ligands in palladium-catalyzed amination. Surry DS, Buchwald SL. Angew Chem Int Ed Engl 47 6338-6361 (2008)
  3. Structure-function relationship of estrogen receptor alpha and beta: impact on human health. Ascenzi P, Bocedi A, Marino M. Mol Aspects Med 27 299-402 (2006)
  4. Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics. Huang P, Chandra V, Rastinejad F. Annu Rev Physiol 72 247-272 (2010)
  5. Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects. di Masi A, De Marinis E, Ascenzi P, Marino M. Mol Aspects Med 30 297-343 (2009)
  6. Tamoxifen: catalyst for the change to targeted therapy. Jordan VC. Eur J Cancer 44 30-38 (2008)
  7. Lessons learnt from structural studies of the oestrogen receptor. Pike AC. Best Pract Res Clin Endocrinol Metab 20 1-14 (2006)
  8. Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer. Shagufta, Ahmad I, Mathew S, Rahman S. RSC Med Chem 11 438-454 (2020)

Articles citing this publication (21)

  1. Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User's Guide. Surry DS, Buchwald SL. Chem Sci 2 27-50 (2011)
  2. Photoredox Activation and Anion Binding Catalysis in the Dual Catalytic Enantioselective Synthesis of β-Amino Esters. Bergonzini G, Schindler CS, Wallentin CJ, Jacobsen EN, Stephenson CR. Chem Sci 5 (2014)
  3. Identification of xenoestrogens in food additives by an integrated in silico and in vitro approach. Amadasi A, Mozzarelli A, Meda C, Maggi A, Cozzini P. Chem Res Toxicol 22 52-63 (2009)
  4. The ubiquitin ligase RNF181 stabilizes ERα and modulates breast cancer progression. Zhu J, Li X, Su P, Xue M, Zang Y, Ding Y. Oncogene 39 6776-6788 (2020)
  5. Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat. Scott JS, Bailey A, Davies RD, Degorce SL, MacFaul PA, Gingell H, Moss T, Norman RA, Pink JH, Rabow AA, Roberts B, Smith PD. ACS Med Chem Lett 7 94-99 (2016)
  6. Practical demethylation of aryl methyl ethers using an odorless thiol reagent. Chae J. Arch Pharm Res 31 305-309 (2008)
  7. Synthesis and evaluation of 11β-(4-substituted phenyl) estradiol analogs: transition from estrogen receptor agonists to antagonists. Hanson RN, Hua E, Hendricks JA, Labaree D, Hochberg RB. Bioorg Med Chem 20 3768-3780 (2012)
  8. Identification of a series of tetrahydroisoquinoline derivatives as potential therapeutic agents for breast cancer. Lin HR, Safo MK, Abraham DJ. Bioorg Med Chem Lett 17 2581-2589 (2007)
  9. Estrogen receptor ligands. Part 14: application of novel antagonist side chains to existing platforms. Blizzard TA, Morgan JD, Chan W, Birzin ET, Pai LY, Hayes EC, DaSilva CA, Mosley RT, Yang YT, Rohrer SP, Dininno F, Hammond ML. Bioorg Med Chem Lett 15 5124-5128 (2005)
  10. In-vitro Antiproliferative Activity of New Tetrahydroisoquinolines (THIQs) on Ishikawa Cells and their 3D Pharmacophore Models. Eyunni SK, Gangapuram M, Redda KK. Lett Drug Des Discov 11 428-436 (2014)
  11. Synthesis and preliminary biological evaluation of new carbon-11 labeled tetrahydroisoquinoline derivatives as SERM radioligands for PET imaging of ER expression in breast cancer. Gao M, Wang M, Miller KD, Sledge GW, Zheng QH. Eur J Med Chem 43 2211-2219 (2008)
  12. Application of 4D-QSAR studies to a series of raloxifene analogs and design of potential selective estrogen receptor modulators. Sodero AC, Romeiro NC, da Cunha EF, de Oliveira Magalhaães U, de Alencastro RB, Rodrigues CR, Cabral LM, Castro HC, Albuquerque MG. Molecules 17 7415-7439 (2012)
  13. Ethers of 3-hydroxyphenylacetic acid as selective gamma-hydroxybutyric acid receptor ligands. Chen W, Wu H, Hernandez RJ, Mehta AK, Ticku MK, France CP, Coop A. Bioorg Med Chem Lett 15 3201-3202 (2005)
  14. Synthesis and Pharmacological Evolution of Tetrahydroisoquinolines as Anti Breast Cancer Agents. Gangapuram M, Eyunni S, Redda KK. J Cancer Sci Ther 6 161-169 (2014)
  15. Cleaved thioredoxin fusion protein enables the crystallization of poorly soluble ERalpha in complex with synthetic ligands. Cura V, Gangloff M, Eiler S, Moras D, Ruff M. Acta Crystallogr Sect F Struct Biol Cryst Commun 64 54-57 (2008)
  16. Preparation of novel (Z)-4-ylidenebenzo[b]furo[3,2-d][1,3]oxazines and their biological activity. Tabuchi Y, Ando Y, Kanemura H, Kawasaki I, Ohishi T, Koida M, Fukuyama R, Nakamuta H, Ohta S, Nishide K, Ohishi Y. Bioorg Med Chem 17 3959-3967 (2009)
  17. Relationships between the structure of 6-substituted 6,8-diazabicyclo[3.2.2]nonan-2-ones and their sigma receptor affinity and cytotoxic activity. Holl R, Schepmann D, Bednarski PJ, Grünert R, Wünsch B. Bioorg Med Chem 17 1445-1455 (2009)
  18. Synthesis and Biological Evaluations of Ring Substituted Tetrahydroisoquinolines (THIQs) as Anti-Breast Cancer Agents. Eyunni SV, Gangapuram M, Mochona B, Mateeva N, Redda KK. J Cancer Sci Ther 9 528-540 (2017)
  19. Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor. Wang Z, Yang Y, Zheng X, Zhang T, Huang W, Yan D, Zhang W, Wang X, Shen Z. J Pharm Pharmacol 70 910-918 (2018)
  20. TRIM3 facilitates estrogen signaling and modulates breast cancer cell progression. Zhuang T, Wang B, Tan X, Wu L, Li X, Li Z, Cai Y, Fan R, Yang X, Zhang C, Xia Y, Niu Z, Liu B, Cao Q, Ding Y, Zhou Z, Huang Q, Yang H. Cell Commun Signal 20 45 (2022)
  21. Beta-lactam type molecular scaffolds for antiproliferative activity: synthesis and cytotoxic effects in breast cancer cells. Meegan MJ, Carr M, Knox AJ, Zisterer DM, Lloyd DG. J Enzyme Inhib Med Chem 23 668-685 (2008)


Quick links