本文選題：BRD + 二氫喹喔啉-(H)-酮��； 參考：《藥學(xué)學(xué)報》2017年10期

【摘要】：含溴結(jié)構(gòu)域的蛋白(bromodomain-containing proteins,BCPs)可以特異性識別組蛋白的乙�；嚢彼�(KAc)。近年來的研究表明一些激酶抑制劑也可以結(jié)合于溴結(jié)構(gòu)域,如PLK1抑制劑BI-2536和JAK2抑制劑TG101209。為了獲得新穎結(jié)構(gòu)類型的溴結(jié)構(gòu)域BRD4抑制劑,本研究基于抑制劑BI-2536的結(jié)合特點,采用二氫喹喔啉-2(1H)-酮代替BI-2536中的7,8-二氫蝶啶-6(5H)-酮。通過探索新的二氫喹喔啉-2(1H)-酮骨架的構(gòu)效關(guān)系,最終獲得一類結(jié)構(gòu)新穎的具有苯基側(cè)鏈的BRD4抑制劑。在該系列化合物中,獲得的一些活性較好的BRD4抑制劑如化合物16、22、28和29,它們在熒光各向異性方法 (fluorescence anisotropy,FA)的分子結(jié)合測試中IC50均小于100 nmol·L~(-1),值得進(jìn)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.
【作者單位】： 中國科學(xué)院上海藥物研究所藥物化學(xué)國家重點實驗室藥物化學(xué)系;中國科學(xué)院大學(xué);
【分類號】：R914;R96
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本文編號：1918172