期刊
CHEMMEDCHEM
卷 12, 期 5, 页码 399-406出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700001
关键词
antitumor agents; docking studies; shikonin; tubulin polymerization
资金
- Program for Changjiang Scholars and Innovative Research Team in University [IRT_14R27]
- fund for University PhD Program from the Ministry of Education of China [20120091110037]
- National Natural Science Foundation of China (NSFC) [31470384, 31171161]
The biological importance of microtubules in mitosis makes them an interesting target for the development of anticancer agents. In this study, a series of novel chalcone-containing shikonin derivatives was designed, synthesized, and evaluated for biological activities. Among them, derivative PMMB-259 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl (E)-2-(4-(3-oxo-3-(3-(trifluoromethoxy)phenyl)prop-1-en-1-yl)phenoxy)acetate] was identified as a potent inhibitor of tubulin polymerization. Further investigation confirmed that PMMB-259 can induce MCF-7 cell apoptosis, reduce the mitochondrial transmembrane potential, and arrest the cell cycle at the G(2)/M phase. Moreover, the morphological variation of treated cells was visualized by confocal microscopy. The results, along with docking simulations, further indicated that PMMB-259 can bind well to tubulin at the colchicine site. Overall, these studies may provide a new molecular scaffold for the further development of antitumor agents that target tubulin.
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