Synthesis and Biological Evaluation of Novel Millepachine Derivatives As a New Class of Tubulin Polymerization Inhibitors

Twenty-one novel derivatives of millepachine were synthesized and evaluated for their in vitro antiprolifer-active activity. Among them, 8 exhibited the most potent activity, with IC50 values of 8-27 nM against panel of cancer cell lines and retained full activity in multidrug resistant cancer cells. Treated cells were arrested in G2/M phase and resulted in cellular apoptosis. Microtubule dynamics confirmed 8 was a novel tubulin. polymerization inhibitor by binding at the colchicine site 8 also exhibited antivascular activity because it concentration dependently reduced the cell migration and disrupted capillary like tube formation in HUVEC cells. Furthermore the hydrochloride salt of 8 (8 center dot HCl) significantly improved the bioavailability up to 47% while retaining the antiproliferative activity. Importantly, 8 center dot HCl significantly inhibited tumor growths in four xenograft models including resistance tumor-cell bearing mice models without causing significant loss of body weight, suggesting that 8 is a promising new orally anticancer agent to be developed.