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(E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and cancer chemopreventive agent
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2017-11-06 , DOI: 10.1016/j.bmcl.2017.11.009
Neill J. Horley , Kenneth J.M. Beresford , Supriya Kaduskar , Prashant Joshi , Glen J.P. McCann , Ketan C. Ruparelia , Ibidapo S. Williams , Linda Gatchie , Vinay R. Sonawane , Sandip B. Bharate , Bhabatosh Chaudhuri

The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in Sacchrosomes™ and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent.



中文翻译:

E)-3-(3,4,5-三甲氧基苯基)-1-(吡啶-4-基)丙-2-烯-1-酮,杂环查尔酮是一种有效且选择性的CYP1A1抑制剂和癌症化学预防剂

CYP1酶家族的过表达据报道与人类癌症的发展有关。众所周知,CYP1A1特异性抑制剂可防止癌变。本文合成了13个吡啶-4-基系列查耳酮,并筛选了Sacchrosomes™和活人HEK293细胞中CYP1亚型1A1、1B1和1A2的抑制作用。结构-活性关系分析表明,在非杂环上带有三烷氧基的查耳酮(8a8k)表现出对CYP1A1酶的选择性抑制作用,IC 50值分别为58和65 nM。3,4,5-三甲氧基取代的衍生物8a相对于CYP1亚家族的其他酶,对CYP1A1的选择性> 10倍,对CYP2和CYP3酶的选择性> 100倍。高效,选择性的CYP1A1抑制剂8a对酵母细胞中B [ a ] P介导的芳香烃受体(AhR)的活化具有拮抗作用,并且还保护人细胞免受CYP1A1介导的人细胞中B [ a ] P毒性的影响。这种有效且选择性的CYP1A1酶抑制剂具有发展为癌症化学预防剂的潜力。

更新日期:2017-11-06
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