1. Synthesis and Biological Evaluationof Novel MillepachineDerivatives As a New Class of Tubulin Polymerization Inhibitors.
- Author
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Yang, Zhuang, Wu, Wenshuang, Wang, Jingjing, Liu, Li, Li, Luyuan, Yang, Jianhong, Wang, Guangcheng, Cao, Dong, Zhang, Ronghong, Tang, Minghai, Wen, Jiaolin, Zhu, Jun, Xiang, Wei, Wang, Fang, Ma, Liang, Xiang, Mingli, You, Jingsong, and Chen, Lijuan
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BIOSYNTHESIS , *TUBULINS , *POLYMERIZATION , *CHALCONES , *MULTIDRUG resistance , *APOPTOSIS , *CANCER cells , *MICROTUBULES - Abstract
Twenty-one novel derivatives of millepachinewere synthesized andevaluated for their in vitro antiproliferative activity. Among them, 8exhibited the most potent activity, with IC50values of 8–27 nM against panel of cancer cell lines andretained full activity in multidrug resistant cancer cells. Treatedcells were arrested in G2/M phase and resulted in cellular apoptosis.Microtubule dynamics confirmed 8was a novel tubulinpolymerization inhibitor by binding at the colchicine site. 8also exhibited antivascular activity because it concentrationdependently reduced the cell migration and disrupted capillary liketube formation in HUVEC cells. Furthermore, the hydrochloride saltof 8(8·HCl) significantlyimproved the bioavailability up to 47% while retaining the antiproliferativeactivity. Importantly, 8·HClsignificantlyinhibited tumor growths in four xenograft models including resistancetumor-cell-bearing mice models without causing significant loss ofbody weight, suggesting that 8is a promising new orallyanticancer agent to be developed. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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