Novel Mcl-1/Bcl-2 dual inhibitors created by the structure-based hybridization of drug-divided building blocks and a fragment deconstructed from a known two-face BH3 mimetic.

We have previously reported a small-molecule two-face Bim BH3 mimetic, 2,3-dihydroxy-6-(4-isopropylphenylthio)anthracene-9,10-dione (1). Herein, we linked a polyphenol fragment, which was deconstructed from compound 1, with a drug-derived building block gained from computer-aided molecular design. 2-Phenyl-1H-benzo[d]imidazole as a new scaffold for two-face Bim mimetics was developed; based on this, a series of Mcl-1/Bcl-2 dual inhibitors were obtained. The most potent compound 6d binds to Mcl-1 and Bcl-2 with Ki values of 127 and 607 nM, respectively, and effectively induces apoptosis in a dose-dependent, mechanism-based manner in multiple cancer cell lines.