1620824-79-4Relevant academic research and scientific papers
Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors
Li, Rongshi,Cheng, Chunwei,Balasis, Maria E.,Liu, Yan,Garner, Thomas P.,Daniel, Kenyon G.,Li, Jerry,Qin, Yong,Gavathiotis, Evripidis,Sebti, Said M.
, p. 315 - 331 (2015)
Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogs and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors. The most selective Mcl-1 antagonists were 34, 36 and 37 with 16-, 13-and 9-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding, respectively. Among the most potent dual inhibitors is 42 which inhibited Mcl-1/Bim and Bcl-xL/Bim binding 15-fold (IC50 = 600 nM) and 33-fold (500 nM) more potently than (±)-marinopyrrole A (1), respectively. Fluorescence quenching, NMR analysis and molecular docking indicated binding of marinopyrroles to the BH3 binding site of Mcl-1. Several marinopyrroles potently decreased Mcl-1 cellular levels and induced caspase 3 activation in human breast cancer cells. Our studies provide novel lead marinopyrroles for further optimization as selective Mcl-1 inhibitors and dual Mcl-1 and Bcl-xL inhibitors.
MARINOPYRROLE DERIVATIVES AND METHODS OF MAKING AND USING SAME
-
, (2015/09/23)
Marinopyrrole derivatives and methods for their synthesis and use are described herein. Novel cyclic and symmetric marinopyrroles with triazole substituents having antibacterial activity against resistant bacterial strains, such as MRSA are introduced. Al
