IsoCombretaQuinazolines: Potent Cytotoxic Agents with Antitubulin Activity
Résumé
A series of novel isocombretaquinazolines (isoCoQ) 4 was quickly prepared using the coupling of N-tosylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which could be regarded as isoCA-4 analogues devoid of the 3,4,5-trimethoxyphenyl ring, displayed a nanomolar level of cytotoxicity against various human cancer cells and inhibited tubulin polymerization effectively. IsoCoQ 4b, 4c and 4d having the greatest ressemblance to isoCA-4, isoFCA-4 and isoNH2CA-4, respectively, led to the arrest of HCT116 cancer cell lines in the G2/M phase of the cell cycle at a very low concentration. Preliminary in vitro antivascular results showed that 4d has disrupted a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All of these results clearly demonstrated that the replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 by a quinazoline nucleus is possible and leads to new highly promising derivatives of potential for further development as antitubulin agents.
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