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  • Title: Antineoplastic agents. 410. Asymmetric hydroxylation of trans-combretastatin A-4.
    Author: Pettit GR, Toki BE, Herald DL, Boyd MR, Hamel E, Pettit RK, Chapuis JC.
    Journal: J Med Chem; 1999 Apr 22; 42(8):1459-65. PubMed ID: 10212132.
    Abstract:
    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 = 22 microM, versus 1.2 microM for combretastatin A-4), while 4d was inactive (IC50 > 40 microM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.
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