Discovery of a Dual Tubulin Polymerization and Cell Division Cycle 20 Homologue Inhibitor via Structural Modification on Apcin

Abstract

Few compounds but apcin have previously been reported as Cdc20 specific inhibitor, although Cdc20 is a very promising drug target. We reported here the design, synthesis, and biological evaluations of 2,2,2-trichloro-1-aryl carbamate derivatives as Cdc20 inhibitors. Among these derivatives, compound 9f was much more efficient than the positive compound apcin in inhibiting cancer cell growth, but it had approximately the same binding affinity with apcin in SPR assay, the assumption that other mechanisms of action might exist was feasible. Consistently, further evidences demonstrated that compound 9f also inhibited tubulin polymerization and disorganized microtubule, blocked cell cycle arrest in M phase with the alteration in the expression of cyclins, thus induced apoptosis through the activation of caspase-3 and PARP. In addition, compound 9f inhibited cell migration and invasion in a concentration-dependent manner. These results supported further guidance for developing the current series as potential new anticancer therapeutics.