ANTINEOPLASTIC AGENTS .291. ISOLATION AND SYNTHESIS OF COMBRETASTATINS A-4, A-5, AND A-6

The antineoplastic constituents of Combretum caffrum (Eckl. and Zeyh) Kuntze (Combretaceae family), a species indigenous to South Africa, ha ve been investigated. Subsequently we isolated a series of closely rel ated bibenzyls, stilbenes, and phenanthrenes from C. caffrum. Some of the stilbenes proved to be potent antimitotic agents which inhibited b oth tubulin polymerization and the binding of colchicine to tubulin. C ombretastatin A-4 has been shown to be the most potent cancer cell gro wth inhibitor of the series. Presently this cis-stilbene is the most e ffective inhibitor of colchicine binding to tubulin and the simplest n atural product yet described with such potent antitubulin effects. Com bretastatin A-4, A-5, and A-6 were also found to inhibit growth of Nei sseria gonorrhoeae. Details of the isolation and syntheses of combreta statins A-4 (2a), A-5 (2c), and A-6 (3a) have been described.