N-Benzyl arylamide derivatives as novel and potent tubulin polymerization inhibitors against gastric cancers: Design, structure–activity relationships and biological evaluations

In this work, we employed a ring-opening strategy to develop a series of novel N-benzyl arylamide derivatives as tubulin polymerization inhibitors. Notably, 13n (MY-1388) exhibited remarkable antiproliferative potency on fifteen human cancer cell lines, with half maximal inhibitory concentration (IC50) values ranging from 8 nmol/L to 48 nmol/L. Furthermore, 13n effectively suppressed tubulin polymerization by targeting the colchicine-binding site (IC50 = 0.62 μmol/L). 13n also exhibited significant inhibition of cell colony formation, as well as displayed potent effects on inducing G2/M phase cell cycle arrest and promoting apoptosis. Importantly, 13n exhibited enhanced and adequate liver microsomal stability in human and rat liver microsomes, and also exhibited a moderate half-life (T1/2 = 0.938 h) in vivo. Meanwhile, 13n demonstrated effective antitumor effects in vivo in suppressing tumor growth in the MGC-803 xenograft model (tumor growth inhibition (TGI) value was 76.4% at the dosage of 30 mg kg−1 day−1) with a good safety profile. Collectively, these results revealed that 13n represents a promising tubulin polymerization inhibitor that deserves further investigation for its efficacy in treating gastric cancers.