2. Academic Validation
  3. Synthesis and biological evaluation of novel millepachine derivatives as a new class of tubulin polymerization inhibitors

Synthesis and biological evaluation of novel millepachine derivatives as a new class of tubulin polymerization inhibitors

  • J Med Chem. 2014 Oct 9;57(19):7977-89. doi: 10.1021/jm500849z.
Zhuang Yang 1,  Wenshuang Wu,  Jingjing Wang,  Li Liu,  Luyuan Li,  Jianhong Yang,  Guangcheng Wang,  Dong Cao,  Ronghong Zhang,  Minghai Tang,  Jiaolin Wen,  Jun Zhu,  Wei Xiang,  Fang Wang,  Liang Ma,  Mingli Xiang,  Jingsong You,  Lijuan Chen
Affiliations

Affiliation

  • 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, China.
PMID: 25208345 DOI: 10.1021/jm500849z
Abstract

Twenty-one novel derivatives of millepachine were synthesized and evaluated for their in vitro antiproliferative 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·HCl) significantly improved the bioavailability up to 47% while retaining the antiproliferative activity. Importantly, 8·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.

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