Development of a new benzophenone-diketopiperazine-type potent antimicrotubule agent possessing a 2-pyridine structure

ACS Med Chem Lett. 2014 Jul 23;5(10):1094-8. doi: 10.1021/ml5001883. eCollection 2014 Oct 9.


A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.

Keywords: Cyclic dipeptide; anticancer; antimicrotubule agent; diketopiperazine.