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

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 IC50 value against Mcl-1 (5 nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over 3.