期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 5, 页码 2538-2546出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00118
关键词
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资金
- National Natural Science Foundation of China [21172260, 30901859, 91229204, 81230076]
- Chen Guang project - Shanghai Municipal Education Commission [12CG42]
- Chen Guang project - Shanghai Education Development Foundation [12CG42]
- Hi-Tech Research and Development Program of China [2012AA020302]
A potent combretastatin A-4 (CA-4) like tubulin polymerization inhibitor 22b was found with strong antitumor activity previously. However, it easily undergoes cis-trans isomerization under natural light, and the resulting decrease in activity limits its further applications. In this study, we used quantum chemistry calculations to explore the molecular basis of its instability. Aided by the calculations, two rounds of structural optimization of 22b were conducted. Accelerated quantitative light stability testing confirmed that the stability of these designed compounds was significantly improved as predicted. Among them, compounds 1 and 3b displayed more potent inhibitory activity on tumor cell growth than 22b. In addition, the potent in vivo antitumor activity of compound 1 was confirmed. Quantum chemistry calculations were used in the optimization of stilbene-like molecules, providing new insight into stilbenoid optimization and important implications for the future development of novel CA-4-like tubulin polymerization inhibitors.
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