Synthesis, biological evaluation of 1,1-diarylethylenes as a novel class of antimitotic agents.
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.
Université Paris-Sud, CNRS, BioCIS-UMR, Châtenay-Malabry, France.
Abdallah
A
Hamze
Anne
A
Giraud
Samir
S
Messaoudi
Olivier
O
Provot
Jean-François
JF
Peyrat
Jérôme
J
Bignon
Jian-Miao
JM
Liu
Joanna
J
Wdzieczak-Bakala
Sylviane
S
Thoret
Joëlle
J
Dubois
Jean-Daniel
JD
Brion
Mouad
M
Alami
D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001577:Benzophenones / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D003078:Colchicine / Q000494:pharmacology; D016195:G2 Phase; D006801:Humans; D010755:Organophosphates / Q000494:pharmacology; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
D050256:Antimitotic Agents; D001577:Benzophenones; D010755:Organophosphates; D013267:Stilbenes; D050257:Tubulin Modulators; C112107:phenstatin phosphate; C058728:fosbretabulin; D003078:Colchicine