3-芳基-5-三氮唑基-噁二唑衍生物HIF-1抑制剂的设计、合成与构效关系研究

Design,Synthesis and Structure-activity Relationship Study of 3-Aryl-5-triazolyl-oxadiazole Derivatives as Hypoxia-inducible Factor-1 Inhibitors

目的设计、合成3-芳基-5-三氮唑基-噁二唑类缺氧诱导因子-1(hypoxia-inducible factor 1,HIF-1)抑制剂。方法以化合物8为先导,将吡唑基替换为1,2,3-三氮唑基,并对噁二唑和苯环取代基等进行改造,获得全新的3-芳基-5-三氮唑基-噁二唑衍生物。结果所合成的大部分化合物均显示出较优的HIF-1抑制活性,化合物10n活性最强,IC_(50)值为0.59μmol·L^(-1),其作用机制是抑制HIF-1α蛋白表达,且能显著抑制SKOV3细胞的侵袭和迁移。结论设计、合成的3-芳基-5-三氮唑基-噁二唑类衍生物是全新的HIF-1抑制剂,显示出抑制肿瘤迁移的效应。

OBJECTIVE To design and synthesize a series of 3-aryl-5-triazolyl-oxadiazole derivatives as hypoxiainducible factor 1(HIF-1)inhibitors.METHODS Taking compound 8 as the guide,the pyrazolyl group was replaced with 1,2,3-triazole group,and the oxadiazole and benzene ring substituents were modified to obtain a novel series of 3-aryl-5-triazole group oxadiazole derivatives.RESULTS Most of these newly designed compounds showed good HIF-1 inhibitory activities and compound 10 n was the most potent inhibitor with IC_(50) value of 0.59μmol·L^(-1).Its mechanism of action was to inhibit the expression of HIF-1α protein,and could significantly inhibit the invasion and migration of SKOV3 cells.CONCLUSION The series of 3-aryl-5-triazolyl-oxadiazole derivatives are new HIF-1 inhibitors,showing the effect of inhibiting tumor migration.