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 anti-proliferative activities with IC50 values ranging from 12 to 27 nM against several cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD50 value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for cancer therapy. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

Novel N-benzylbenzamide derivatives 20b and its corresponding disodium phosphate 20b-P show significant anti-cancer activity with excellent safety profile, making them promising anti-tubulin agents for further investigation in cancer therapy.