Synthesis and biological evaluation of boronic acid containing cis-stilbenes as apoptotic tubulin polymerzation 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 13c and 13d, 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 mu M. Compounds 13 c and 13d exhibited significant inhibitory activity toward tubulin Polymerization (IC50=21-22 mu M). The carboxylic acid derivative 17, which con be considered as a mimic of boronic acid 13c, 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 73 c at a concentration of >10(-8) M. Growth inhibitory experiments against a panel of 39 human cancer cell lines revealed 13c to inhibit growth differently than combretastatin A-4; the correlation coefficient (r) between the two compounds was 0.553 in the COMPARE analysis.