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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。
Bromodomain-containing proteins (BCPs) can specifically recognize histone acetylated lysine (KAc). Recent studies show that some kinase inhibitors can also bind to bromodomain, such as PLK1 inhibitor BI-2536 and JAK2 inhibitor TG101209. In order to obtain bromodomain BRD4 inhibitors of novel structure type, dihydroquinoxalin-2 (1H) -one was used in place of 7,8-dihydrogen bromide in BI-2536 based on the binding characteristics of inhibitor BI-2536 Pteridin-6 (5H) -one. By exploring the structure-activity relationship of the novel dihydroquinoxalin-2 (1H) -one skeleton, a novel class of BRD4 inhibitors with phenyl side chains were finally obtained. Some of the more active BRD4 inhibitors obtained in this series of compounds, such as compounds 16, 22, 28 and 29, have IC50 values of less than 100 nmol in molecular binding assays for fluorescence anisotropy (FA) L ~ (-1), it is worth further study.