Pyrazole and pyrimidine phenylacylsulfonamides as dual Bcl-2/Bcl-xL antagonists

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• 作者：Gretchen M. Schroeder^a ; ^&dagger ; ; ^{gretchen.schroeder@bms.com} ; Donna Wei^a ; ^&dagger ; ; Patrizia Banfi^b ; Zhen-Wei Cai^a ; ^&Dagger ; ; Jonathan Lippy^a ; Maria Menichincheri^b ; Michele Modugno^b ; Joseph Naglich^a ; Becky Penhallow^a ; Heidi L. Perez^a ; John Sack^a ; Robert J. Schmidt^a ; Andrew Tebben^a ; Chunhong Yan^a ; Liping Zhang^a ; Arturo Galvani^b ; Louis J. Lombardo^a ; ^§ ; ; Robert M. Borzilleri^a
• 关键词：Bcl-2 ; Bcl-xL ; Isolated mitochondria ; Protein&ndash ; protein interaction ; Cytochrome c
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 June, 2012
• 卷：22
• 期：12
• 页码：3951-3956
• 文件大小：2368 K

摘要

5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.