小分子p53-MDM2抑制剂先导化合物苄普地尔的研究
投稿时间:2020-09-15  修订日期:2021-03-07  点此下载全文
引用本文:罗川,李锦,张万年,缪震元.小分子p53-MDM2抑制剂先导化合物苄普地尔的研究[J].药学实践杂志,2021,39(2):126~129
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作者单位E-mail
罗川 安徽华润金蟾药业股份有限公司安徽 淮北 235000  
李锦 海军军医大学药学院上海 200433  
张万年 海军军医大学药学院上海 200433  
缪震元 海军军医大学药学院上海 200433 miaozhenyuan@hotmail.com 
基金项目:国家自然科学基金(81373331)
中文摘要:目的 采用老药新用药物设计方法,探寻p53-MDM2蛋白结合小分子抑制剂的先导化合物。方法 通过荧光偏振(FP)法和蛋白印迹试验法,分别测定化合物的p53-MDM2蛋白结合抑制活性和相关蛋白的表达变化,采用四甲基偶氮唑盐微量酶反应比色法(MTT法)测试其体外抗肿瘤活性,并且测定人肝微粒体中代谢产物。结果 发现苄普地尔具有优秀的体外抗肿瘤活性和较强的p53-MDM2蛋白结合抑制活性,能显著降低MDM2蛋白的表达,而且呈剂量依赖性。在人肝微粒体中的代谢产物主要为苯环羟基单氧化代谢产物。结论 苄普地尔可作为p53-MDM2蛋白结合小分子抑制剂先导化合物,用于后续的结构优化设计研究。
中文关键词:老药新用  药物设计  苄普地尔  p53-MDM2蛋白结合抑制剂
 
Discovery of bepridil as a valuable lead compound with potent p53-MDM2 inhibitory activity
Abstract:Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy.Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting. MTT method was used to determine the in-vitro antitumor activities. The metabolites in human liver microsomes were tested.Results Bepridil showed excellent in-vitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity, which can significantly reduce the expression of MDM2 protein in a dose-dependent manner. The metabolites in human liver microsomes are mainly benzene ring hydroxyl mono-oxidation metabolites.Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.
keywords:new uses of old drugs strategy  drug design  bepridil  p53-MDM2 inhibitor
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