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

Apcin is one of the
few compounds that have been previously reported
as a 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 assays. It is possible that another mechanism of
action might exist. Further evidence demonstrated that compound 9f also inhibited tubulin polymerization, disorganized the
microtubule network, and blocked the cell cycle at the M phase with
changes in the expression of cyclins. Thus, it 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 provide guidance for developing the current
series as potential new anticancer therapeutics.