Synthesis and biological evaluation of boronic acid containing cis-stilbenes as apoptotic tubulin polymerization inhibitors.
A series of boronic acid containing cis-stilbenes as potent inhibitors of tubulin polymerization was synthesized by the introduction of boronic acid as an acceptor-type functional group into the aromatic ring B of the combretastatin framework. High cell-growth inhibition was observed with boron compounds 13 c and 13 d, in which a hydroxy group on the aromatic ring B of combretastatin A-4 was replaced with boronic acid; IC50 values toward B-16 and 1-87 cell lines are 0.48-2.1 microM. Compounds 13 c and 13 d exhibited significant inhibitory activity toward tubulin polymerization (IC50=21-22 microM). The carboxylic acid derivative 17, which can be considered as a mimic of boronic acid 13 c, did not show significant inhibition of cell growth or tubulin polymerization. According to the FACScan analysis using Jurkat cells, apoptosis was induced after incubation for 8 h with 13 c at a concentration of >10(-8) M. Growth inhibitory experiments against a panel of 39 human cancer cell lines revealed 13 c to inhibit growth differently than combretastatin A-4; the correlation coefficient (r) between the two compounds was 0.553 in the COMPARE analysis.
Nakamura
Hiroyuki
H
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan. hiroyuki.nakamura@gakushuin.ac.jp
Kuroda
Hirokazu
H
Saito
Hiroyuki
H
Suzuki
Ryo
R
Yamori
Takao
T
Maruyama
Kazuo
K
Haga
Tatsuya
T
D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D013267:Stilbenes / Q000737:chemistry; D014404:Tubulin / Q000187:drug effects*; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D001897:Boronic Acids; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators