期刊
CHEMICAL BIOLOGY & DRUG DESIGN
卷 84, 期 5, 页码 603-615出版社
WILEY
DOI: 10.1111/cbdd.12353
关键词
apoptosis; confocal microscopy; molecular docking; shikonin derivatives; tubulin
资金
- National Natural Science Foundation of China (NSFC) [31071082, 31170275, 31171161, 81301896]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT1020]
- Project of New Century Excellent Talents in University [NCET-11-0234]
- Natural Science Foundations of the Jiangsu [BK2010053, BK2011414]
- Foundations of Huaian High-Tech Research Institute of Nanjing University [2011Z2]
- Natural Science Foundation of the Colleges and Universities in Jiangsu Province [13KJB320011]
In this study, we report the identification of a new shikonin-phenoxyacetic acid derivative, as an inhibitor of tubulin. A series of compounds were prepared; among them, compound 16 [(R) -1 - (5, 8- dihydroxy-1, 4- dioxo-1, 4- dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2- (4- phenoxyphenyl) acetate] potently inhibited the function of microtubules, inducing cell growth inhibition, apoptosis of cancer cell lines in a concentration and time-dependent manner. Molecular docking involving 16 at the vinblastine binding site of tubulin indicated that a phenoxy moiety interacted with tubulin via hydrogen bonding with asparaginate (Asn) and tyrosine (Tyr). Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density. Cell cycle assay further proved that HepG2 cells were blocked in G2/M phase. Our study provides a new, promising compound for the development of tubulin inhibitors by proposing a new target for the anticancer activity of shikonin.
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