Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC50 values ranging from 12 to 27 nM against several cancer cell lines, possessed good plasma stability satisfactory physicochemical properties. Mechanism studies demonstrated that bound the colchicine binding site displayed potent anti-vascular activity. Notably, corresponding disodium phosphate 20b-P an excellent safety profile LD50 value 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth decreased microvessel density in liver H22 allograft mouse model without obvious toxicity. Collectively, are promising anti-tubulin agents more druggable properties deserve be further investigated for therapy.