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

The South African willow tree Combretum caffrum has yielded a number of potent cancer cell growth inhibitors. The present SAR studies of the antineoplastic agent combretastatin A-4 (1c) were focused mainly on the olefinic bridge to determine the effects on cancer cell growth and, potentially, to better define the combretastatin A-4 binding site on tubulin. The geometric trans-isomer 3a of combretastatin A-4 was converted to the (1S,2S)- and (1R, 2R)-vicinal diols 4c and 4d, respectively, under Sharpless' asymmetric dihydroxylation 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) = 22μM, versus 1.2 μM for combretastatin A-4), while 4d was inactive (IC₅₀ > 40 μM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.