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个人信息Personal Information
讲师
性别：男
毕业院校：大连理工大学
学位：博士
所在单位：化学学院
电子邮箱：wuzhiyong@dlut.edu.cn
3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-x(L) and Mcl-1
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论文类型：期刊论文
发表时间：2013-01-01
发表刊物：BIOORGANIC & MEDICINAL CHEMISTRY
收录刊物：PubMed、SCIE、Scopus
卷号：21
期号：1
页面范围：11-20
ISSN号：0968-0896
关键字：Pan-Bcl-2 inhibitor; Bcl-2; Mcl-1; p4 Pocket; Apoptosis
摘要：Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC50 = 10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives. (C) 2012 Elsevier Ltd. All rights reserved.
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