Isolation, structure, and synthesis of combretastatins A-1 and B-1, potent new inhibitors of microtubule assembly, derived from Combretum caffrum.
The principal antineoplastic constituent of the South African tree Combretum caffrum has been isolated and designated combretastatin A-1. The structure of this new cis-stilbene was unequivocally established by X-ray crystal structure determination and total synthesis. A Wittig reaction sequence in THF comprised the synthetic key step (92.5% yield) and provided a very favorable 9:1 ratio of the cis:trans [1c:2c, geometrical isomers]. Selective hydrogenation of combretastatin A-1 afforded combretastatin B-1, a companion cell growth inhibitory constituent of C. caffrum. Combretastatin A-1 provided 26-29% life extension at 2.75-11 mg/kg dose levels with ED50 0.99 microgram/ml against the murine P-388 lymphocytic leukemia in vivo and in vitro systems. Both combretastatin A-1 and combretastatin B-1 are potent inhibitors of microtubule assembly in vitro and among the most potent inhibitors of the binding of colchicine to tubulin yet described. The structural simplicity and ready synthesis of combretastatin A-1 and combretastatin B-1 suggest that these new biosynthetic products will become useful in a variety of biological endeavors.
D000107:Acetylation; D000818:Animals; D000840:Anisoles / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification* / Q000494:pharmacology; D001632:Bibenzyls; D003078:Colchicine / Q000378:metabolism; D003460:Crystallization; D007941:Leukemia P388 / Q000188:drug therapy; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D010946:Plants, Medicinal / Q000032:analysis*; D011485:Protein Binding / Q000187:drug effects; D013267:Stilbenes; D014404:Tubulin / Q000096:biosynthesis
D000840:Anisoles; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D013267:Stilbenes; D014404:Tubulin; C040105:combretastatin; D003078:Colchicine