Antineoplastic agents. 410. Asymmetric hydroxylation of trans-combretastatin A-4

The South African willow tree Combretum caffrum has yielded a number of pot ent cancer cell growth inhibitors. The present SAR studies of the antineopl astic agent combretastatin A-4 (1c) were focused mainly on the olefinic bri dge to determine the effects on cancer cell growth and, potentially, to bet ter define the combretastatin A-4 binding site on tubulin. The geometric tr ans-isomer 3a of combretastatin A-4 was converted to the (1S,2S)- and (1R,2 R)-vicinal diols 4c and 4d, respectively, under Sharpless' asymmetric dihyd roxylation conditions. Cancer cell line testing showed the (1S,2S)-diol 4c to be more potent than its enantiomer 4d. Diol 4c weakly inhibited tubulin polymerization (IC50 = 22 mu M, versus 1.2 mu M for combretastatin A-4), wh ile 4d was inactive (IC50 > 40 mu M). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitor y activity.