Synthesis and biological evaluation of (3,4,5-trimethoxyphenyl)indol-3-ylmethane derivatives as potential antivascular agents.
Combretastatin A-4 (CSA-4), a stilbene derivative, is a potent vascular disrupting agent (VDA) with the structural requirement of a cis-configuration to maintain a molecular geometry and a correct orientation of both phenyl groups. A series of indolic analogues of CSA-4 was synthesized by means of an efficient strategy. Six compounds (20b, 25b-27b, 32b, and 35b) were identified as potent inhibitors of tubulin polymerization and also displayed cytotoxic activities on B16 melanoma cells at a nanomolar level. Both activities were well correlated with the ability to induce morphological changes of EA.hy 926 endothelial cells. In conclusion, the cis-stilbene skeleton of CSA-4 could conveniently be replaced by the 3-aroylindolic moiety, thus avoiding any isomerization leading to inactive trans compounds.
Dupeyre
Grégory
G
Université Paris 5, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8638 CNRS, Laboratoire de Pharmacognosie, France.
Chabot
Guy G
GG
Thoret
Sylviane
S
Cachet
Xavier
X
Seguin
Johanne
J
Guénard
Daniel
D
Tillequin
François
F
Scherman
Daniel
D
Koch
Michel
M
Michel
Sylvie
S
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects*; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D013267:Stilbenes / Q000737:chemistry*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin