期刊
CHEMMEDCHEM
卷 10, 期 8, 页码 1392-1402出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201500069
关键词
cancer; combretastatins; cytotoxicity; isoCA-4; quinazolines; tubulin
资金
- Centre National de la Recherche Scientifique (CNRS)
- la Ligue contre le Cancer through an Equipe labellisee
- Agence Nationale de la Recherche [ANR-10-LABX-33]
A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N-toluenesulfonylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatinA-4 (isoCA-4) analogues that lack the 3,4,5-trimethoxyphenyl ring, displayed nanomolar-level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol (4b), 4-[1-(3-fluoro-4-methoxyphenyl)vinyl]-2-methylquinazoline (4c), and 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline (4d), which respectively bear the greatest resemblance to isoCA-4, isoFCA-4, and isoNH(2)CA-4, are able to arrest HCT116 cancer cells in the G(2)/M cell-cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4d is able to disrupt a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.
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