Design, synthesis and antitumor evaluation of novel chiral diaryl substituted azetidin-2-one derivatives as tubulin polymerization inhibitors

A novel class of diaryl substituted azetidin-2-one derivatives were designed, asymmetrically synthesized, and evaluated for antiproliferative activities. The in vitro antitumor assay revealed that among the 4-aryl-substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones (B series), most possessed moderate to strong activities, with compound B7c that bears a 2-naphthyl substituent being the most potent one (IC50 0.16-0.40 mu M) against a panel of human cancer cell lines. In contrast, none of the 3-(arylmethylene)-substituted 1-(3,4,5-trimethoxyphenyl)azetidin-2-ones (L series) showed significant activities in the assay. Further studies indicated that B7c inhibited tubulin polymerization, disrupted in vitro vascularization, blocked cell cycle progression at G2/M phase, induced cell apoptosis, decreased mitochondrial membrane potential, and increased the intracellular reactive oxygen species level in a dose-dependent way. Compound B7c also inhibited significantly tumor growth in a xenograft mice model with no obvious drop in the mice body weights. Collectively, these results suggested that B7c and its analogues should merit further investigation as new promising antitumor agents.

Automated summary

A novel class of diaryl substituted azetidin-2-one derivatives were designed, synthesized, and evaluated for antiproliferative activities, with compound B7c showing potent anticancer effects through multiple mechanisms. These results suggest that B7c and its analogues may serve as promising new antitumor agents.