Discovery of chiral 1,4-diarylazetidin-2-one-based hydroxamic acid derivatives as novel tubulin polymerization inhibitors with histone deacetylase inhibitory activity.

Tubulin and histone deacetylase have been clinically proven as promising targets for cancer therapy. Herein, we describe the design and synthesis of chiral 1,4-diarylazetidin-2-one-based hydroxamic acids as novel tubulin/HDAC dual inhibitors. Among them, compound 12a was validated to effectively disrupt tubulin polymerization, and exhibited potent HDAC1/8 inhibitory activities. Meanwhile, 12a showed good antiproliferative activities against four tumor cell lines. Further studies showed 12a works through blocking cellular cycle, inducing apoptosis and inhibiting colony formation. In addition, 12a has suitable physicochemical properties and high liver microsomal metabolic stability. Importantly, compound 12a was found to exhibit significant antitumor efficacy in vivo, thus warranting it as a promising tubulin/HDAC dual inhibitor for further development.