BRD4小分子抑制剂的设计、合成以及初步活性研究

发布时间：2018-05-21 06:46

  本文选题：BRD + 二氢喹喔啉-(H)-酮　； 参考：《药学学报》2017年10期

【摘要】：含溴结构域的蛋白(bromodomain-containing proteins,BCPs)可以特异性识别组蛋白的乙酰化赖氨酸(KAc)。近年来的研究表明一些激酶抑制剂也可以结合于溴结构域,如PLK1抑制剂BI-2536和JAK2抑制剂TG101209。为了获得新颖结构类型的溴结构域BRD4抑制剂,本研究基于抑制剂BI-2536的结合特点,采用二氢喹喔啉-2(1H)-酮代替BI-2536中的7,8-二氢蝶啶-6(5H)-酮。通过探索新的二氢喹喔啉-2(1H)-酮骨架的构效关系,最终获得一类结构新颖的具有苯基侧链的BRD4抑制剂。在该系列化合物中,获得的一些活性较好的BRD4抑制剂如化合物16、22、28和29,它们在荧光各向异性方法 (fluorescence anisotropy,FA)的分子结合测试中IC50均小于100 nmol·L~(-1),值得进一步深入研究。
[Abstract]:Bromodomain-containing protein (BCPs) can specifically recognize acetyllysine of histone. Recent studies have shown that some kinase inhibitors can also bind to bromine domains, such as PLK1 inhibitor BI-2536 and JAK2 inhibitor TG101209. In order to obtain a novel type of bromine domain BRD4 inhibitor, based on the binding characteristics of the inhibitor BI-2536, dihydroquinoxaline (DHQ) -2N (1H) -one was used to replace 7 / 8-dihydropteridine (DHP) -6H (5H) -one in BI-2536. A novel BRD4 inhibitor with phenyl side chain was obtained by exploring the structure-activity relationship of a new framework of dihydroquinoxaline-2H _ (1) H _ (1) H _ (1) H _ (2) O _ (1). In this series of compounds, some BRD4 inhibitors with good activity, such as compounds 1622, 28 and 29, have been obtained. Their molecular binding tests for fluorescence anisotropyfas are all less than 100 nmol / L ~ (-1), which are worthy of further study.
【作者单位】： 中国科学院上海药物研究所药物化学国家重点实验室药物化学系;中国科学院大学;
【分类号】：R914;R96
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本文编号：1918172