Structure-based Design, Synthesis, And Evaluation of a New Bcl-2/Mcl-1 Inhibitor

Based on our previously reported Bcl-2/Mcl-1 dual inhibitor S1, we designed a new Bcl-2/Mcl-1 inhibitor through a structure-based scaffold-hopping approach, replacing the 6-thiomorpholine of S1 by piperazine group for P2 occupation. Compound S1-11 was synthesized readily by nucleophilic substitution reaction between 1-oxo-1H-phenalene-2,3-dicarbonitrile (OPD) with piperazine, and exhibited potent binding capability to both Bcl-2 (Ki=0.82 ± 0.06 μM) and Mcl-1 (Ki=0.43 ± 0.01 μM). Furthermore, S1-11 exhibited potent lethality on MCF-7 cells.