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引用本文:刘瑶,李珊,裘旎,胡永洲,曹戟,盛荣.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[J].中国现代应用药学,2022,39(5):573-583.
LIU Yao,LI Shan,QIU Ni,HU Yongzhou,CAO Ji,SHENG Rong.Design, Synthesis and Structure-activity Relationship Study of 3-Aryl-5-triazolyl-oxadiazole Derivatives as Hypoxia-inducible Factor-1 Inhibitors[J].Chin J Mod Appl Pharm(中国现代应用药学),2022,39(5):573-583.
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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
刘瑶, 李珊, 裘旎, 胡永洲, 曹戟, 盛荣
浙江大学药学院, 杭州 310058
摘要:
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,IC50值为0.59 μmol·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。
关键词:  缺氧诱导因子-1  抑制剂  3-芳基-5-三氮唑基-噁二唑衍生物  构效关系  肿瘤转移
DOI:10.13748/j.cnki.issn1007-7693.2022.05.001
分类号:R914.4
基金项目:国家自然科学基金项目(21672187);浙江省自然科学基金项目(LZ17H300002)
Design, Synthesis and Structure-activity Relationship Study of 3-Aryl-5-triazolyl-oxadiazole Derivatives as Hypoxia-inducible Factor-1 Inhibitors
LIU Yao, LI Shan, QIU Ni, HU Yongzhou, CAO Ji, SHENG Rong
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract:
OBJECTIVE To design and synthesize a series of 3-aryl-5-triazolyl-oxadiazole derivatives as hypoxia- inducible 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 10n was the most potent inhibitor with IC50 value of 0.59 μmol·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.
Key words:  HIF-1  inhibitor  3-aryl-5-triazolyl-oxadiazoles derivatives  structure-activity relationship  tumor metastasis
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