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Synthesis, Biological Evaluation of 1,1‐Diarylethylenes as a Novel Class of Antimitotic Agents

2009; Wiley; Volume: 4; Issue: 11 Linguagem: Inglês

10.1002/cmdc.200900290

1860-7187

Abdallah Hamzé, Anne Giraud, Samir Messaoudi, Olivier Provot, Jean‐François Peyrat, Jérôme Bignon, Jianmiao Liu, Joanna Wdzieczak‐Bakala, Sylviane Thoret, Joëlle Dubois, Jean‐Daniel Brion, Mouâd Alami,

Synthesis and Reactions of Organic Compounds

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B-ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA-4 (2 e), isoCA-4 (2 k) and isoNH(2)CA-4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC(50) values of 4, 2 and 1.5 microM, respectively. These derivatives were found to be 10-fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G(2)/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel-like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.