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 = 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.
Pettit
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GR
Cancer Research Institute and Department of Chemistry, Arizona State University, P.O. Box 872404, Tempe, Arizona 85287-2404, USA.
Toki
B E
BE
Herald
D L
DL
Boyd
M R
MR
Hamel
E
E
Pettit
R K
RK
Chapuis
J C
JC
D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001704:Biopolymers; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005658:Fungi / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D051379:Mice; D008958:Models, Molecular; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D001704:Biopolymers; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin