Isocombretastatins A: 1,1-diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds.
Isocombretastatins A are 1,1-diarylethene isomers of combretastatins A. We have synthesized the isomers of combretastatin A-4, deoxycombretastatin A-4, 3-amino-deoxycombretastatin A-4 (AVE-8063), naphthylcombretastatin and the N-methyl- and N-ethyl-5-indolyl analogues of combretastatin A-4. Analogues with a 2,3,4-trimethoxyphenyl ring instead of the 3,4,5-trimethoxyphenyl ring have also been prepared. The isocombretastatins A strongly inhibit tubulin polymerization and are potent cytotoxic compounds, some of them with IC(50)s in the nanomolar range. This new family of tubulin inhibitors shows higher or comparable potency when compared to phenstatin or combretastatin analogues. These results suggest that one carbon bridges with a geminal diaryl substitution can successfully replace the two carbon bridge of combretastatins and that the carbonyl group of phenstatins is not essential for high potency.
Alvarez
Raquel
R
Departamento de Química Farmacéutica, Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno s/n, Salamanca E-37007, Spain.
Alvarez
Concepción
C
Mollinedo
Faustino
F
Sierra
Beatriz G
BG
Medarde
Manuel
M
Peláez
Rafael
R
D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D007536:Isomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
D001632:Bibenzyls; D014404:Tubulin; D050257:Tubulin Modulators; C040105:combretastatin