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论文类型：期刊论文

发表时间：2011-09-01

发表刊物：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录刊物：Scopus、SCIE、PubMed

卷号：46

期号：9

页面范围：3909-3916

ISSN号：0223-5234

关键字：Apoptosis; Mcl-1; Bcl-2; p2 pocket; Dual inhibitor

摘要：Based on our previous discovery of a dual inhibitor of Mcl-1 and Bcl-2, 3-thiomorpholin-8-oxo-8H-acenaphthol[,2-b]pyrrole-9-carbonitrile (1, S1), and guided by structure insight of 1 complex with Mcl-1 and Bcl-2, we exploited the spatial orientation of BH3 groove of the two proteins by a series of analogues of 1. These analogues contain substitutes with various steric hindrance designed to explore the width and length of the p2 pocket. The structure-activity relationships (SARs) studies together with docking studies and cell-based assays proved that the p2 pocket of Mcl-1 is relatively wider and shorter than that of Bcl-2. A novel dual inhibitor 6 was obtained based on these new findings that it exhibited nanomalar affinities toward Mcl-1 and Bcl-2, as well as nanomalar cytotoxicity activity against multiple cancer cell lines. (C) 2011 Elsevier Masson SAS. All rights reserved.