These three authors equally contribute to this paper.
Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives
Article first published online: 26 DEC 2013
© 2013 John Wiley & Sons A/S.
Chemical Biology & Drug Design
Volume 83, Issue 3, pages 334–343, March 2014
How to Cite
Wang, X.-M., Lin, H.-Y., Kong, W.-Y., Guo, J., Shi, J., Huang, S.-C., Qi, J.-L., Yang, R.-W., Gu, H.-W. and Yang, Y.-H. (2014), Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives. Chemical Biology & Drug Design, 83: 334–343. doi: 10.1111/cbdd.12247
- Issue published online: 25 FEB 2014
- Article first published online: 26 DEC 2013
- Accepted manuscript online: 12 OCT 2013 11:12AM EST
- Manuscript Accepted: 4 OCT 2013
- Manuscript Revised: 2 SEP 2013
- Manuscript Received: 2 JUN 2013
- National Natural Science Foundation . Grant Numbers: 30701041, 31171161
- Research Team in University . Grant Number: IRT1020
- Fundamental Research Funds for the Central Universities. Grant Numbers: 1106020824, 1082020803
- Natural Science Foundations of the Jiangsu. Grant Number: BK2010053
- shikonin derivatives;
- thiophene carboxylic acids;
- indol carboxylic acids
A series of shikonin derivatives (1–13) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-(1H-indol-3-yl)propanoate) and compound 8 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(thiophen-3-yl)acetate) exhibited good antiproliferative activity of A875 (IC50 = 0.005 ± 0.001 μm, 0.009 ± 0.002 μm) and HeLa (IC50 = 11.84 ± 0.64 μm, 4.62 ± 0.31 μm) cancer cell lines in vitro, respectively. Shikonin (IC50 = 0.46 ± 0.002 μm, 4.80 ± 0.48 μm) and colchicine (IC50 = 0.75 ± 0.05 μm, 17.79 ± 0.76 μm) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC50 of 3.96 ± 0.13 μm and 3.05 ± 0.30 μm, respectively), which were compared with shikonin (IC50 = 15.20 ± 0.25 μm) and colchicine (IC50 = 3.50 ± 0.35 μm). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.