Design and Synthesis of 3, 5-Diphenylpyrazole derivatives as Selective Estrogen Receptor Modulators
This exploratory work encompasses synthetic chemistry to develop novel 3, 5- diphenylethanone derivatives compounds based on the medicinally relevant scaffold of pyrazole as that of standard SERM i.e. Tamoxifen and Raloxifene. Specific strategies for the synthesis of novel analogues were used and were subjected to modeling and docking studies for analyzing the ER subtype selectivity. The in-silico studies were conducted in order to attain a better insight into the interactions of these molecules with their target receptor in order to study their subtype selectivity and preferential binding site. The various orientations taken by ligands while binding the estrogen receptor-α were studied over 1ERR (PDB) using Schrodinger Maestro environments. The anti-cancer potential of these derivatives were evaluated in estrogen receptor-positive cell lines in an in vitro assay, exploring MCF-7 and Zr-75-1 cell lines. Amongst all, the derivatives that displaced promising anticancer activity (4-chloro substituted, compound 4b) were selectively screened for in vivo anti-cancer activity subjected to NMU administration mammary carcinoma in female Sprague- Dawley rat. As hormone estrogen has been largely implemented in the metastasis of breast cancer, it has become imperative to measure levels of the hormone in tumor-affected animals. The percentage of incidences, tumor latency, tumor burden, and tumor volume was measured after sacrificing the experimental animals.
Keywords:Breast cancer, Docking, MCF-7, Pyrazole, SERM
American Cancer Society. Cancer Facts & Figures. Atlanta: American Cancer Society, pages 3–4, 2019.
L Liu, Z Tang, C Wu, X Li, A Huang, X Lu, Q You, and H Xiang. Synthesis and Biological evaluation of 4,6-diaryl-2-pyrimidinamine derivatives as anti-breast cancer agents. Bioorg. Med. Chem. Lett, 28(6):1138–1142, 2018.
F Bray, J Ferlay, I Soerjomataram, R L Siegel, L A Torre, and A Jemal. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin, 68(6):394–424, 2018.
I Ahmad Shagufta. Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives. Eur. J. Med. Chem, 143:515–531, 2018.
J M Gross and D Yee. How does the estrogen receptor work? Breast Cancer Res, 4(2):62–64, 2002.
M Jia, K D Wright, and J A Gustafsson. Estrogen receptor alpha and beta in health and disease. Best Practice & Research. Clinical Endocrinology & Metabolism, 29(4):557–568, 2015.
P N Dube, Y B Thombare, and V A Chatpalliwar. Design and Synthesis of Novel Chalcone-Phenylpyranone Derivatives as Estrogen Receptor Modulators. Proceedings MDPI, 9(1):1–7, 2019.
S Fustero, M S Rosello, P Barrio, and A S Fuentes. From 2000 to Mid-2010: A Fruitful Decade for the Synthesis of Pyrazoles. Chem. Rev, 111(11):6984–7034, 2011.
C Zhuang, W Zhang, C Sheng, W Zhang, C Xing, and Z Miao. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem. Rev, 117(12):7762–7810, 2017.
E A Ariazi, G M Clark, and J E Mertz. Estrogen related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer. Cancer Res, 62(22):6510–6518, 2002.
S Mandal and J R Davie. An integrated analysis of genes and pathways exhibiting metabolic differences between estrogen receptorpositive breast cancer cells. BMC Cancer, 7:181–181, 2007.
P N Dube, M N Waghmare, and S N Mokale. Synthesis, In-vitro & In-vivo biological evaluation and Molecular Docking Analysis of Novel 3-(3-oxo-substituted phenyl-3-)4-(2-(piperidinyl)ethoxy)phenyl)propyl)-2Hchromen-2-one Derivatives as Anti- breast Cancer Agents. Chem. Biol. Drug Des, 87(4):608–617, 2016.
P N Dube and S N Mokale. Design and Synthesis of Some Novel Estrogen Receptor Modulators as Anti-Breast Cancer Agents: In Vitro & In Vivo Screening, Docking Analysis. Anti-cancer Agents Med. Chem, 16(11):1461–1467, 2016.
P Skehan, R Storeng, D Scudiero, A Monks, J Mcmohan, D Vistica, T W Jonathan, J T Warren, H Bokesch, S Kenny, and M R Boyd. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst, 82(13):1107–1112, 1990.
P N Dube, N S Sakle, S A Dhawale, S A More, and S N Mokale. Synthesis, Biological Investigation and Docking Study of Novel Chromen Derivatives as Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry, 19(9):1150– 1160, 2019.
S N Mokale, A Begum, N S Sakle, V R Shelke, and S A Bhavale. Design, synthesis and anti- cancer screening of 3-(3-(substituted phenyl) acryloyl)-2H-chromen-2-ones as selective anti-breast cancer agent. Biomedicine & Pharmacotherapy, 89:966–972, 2017.
S R Teplitzky, T L Kiefer, Q Cheng, P D Dwivedi, K Moroz, L Myers, M B Anderson, A Collins, J Dai, L Yuan, L L Spriggs, D E Blask, and S M Hill. Chemoprevention of NMU-induced rat mammary carcinoma with the combination of melatonin and 9-cis-retinoic acid. Cancer Lett, 168(2):155–163, 2001.
Schrödinger Release. Schrödinger Release 2019-1: Glide, Schrödinger, LLC, New York, 2019.
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