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J Med Chem. 2011 Feb 24;54(4):1101-5. doi: 10.1021/jm101181u. Epub 2011 Jan 14.

3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) based molecules as potent, dual inhibitors of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1): structure-based design and structure-activity relationship studies.

Author information

  • 1School of Chemistry, Dalian University of Technology, Dalian 116012, People's Republic of China. zczhang@dlut.edu.cn

Erratum in

  • J Med Chem. 2013 Nov 27;56(22):9366-7.

Abstract

We recently described the discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure-activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-1, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (6h) was obtained, which showed significant enhanced IC(50) value against Mcl-1 (5 nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over 3.

PMID:
21235240
[PubMed - indexed for MEDLINE]
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