Design, synthesis and biological evaluation of millepachine derivatives as a new class of tubulin polymerization inhibitors.

A series of novel tubulin polymerization inhibitors (9a-9p) have been synthesized and evaluated for their in vitro and in vivo biological activities. Among these compounds, 9e displayed strong antiproliferative activity against several tumor cell lines (IC50=0.15-0.62μM). Compound 9e was also shown to arrest cells in the G2/M phase of the cell cycle and inhibit the polymerization of tubulin. Molecular docking studies suggested that 9e binds into the colchicine binding site of tubulin. In xenograft experiments, 9e exerted more potent anticancer effect than anticancer drug taxol against the H460 Human lung carcinoma in BALB/c nude mice. In summary, these findings suggest that 9e is a promising new antimitotic compound for the potential treatment of cancer.