Isolation, Structure, Synthesis, and Antimitotic Properties of Combretastatins B-3 and B-4 from Combretum caffrum

Abstract

Further investigation of a CH2Cl2 fraction prepared from the South African tree Combretum caffrum for substances inhibitory to the murine P-388 lymphocytic leukemia (PS system) cell line has led to the isolation of two new bibenzyls, designated combretastatins B-3 [3] and B-4 [4], accompanied by the previously known bibenzyls 7, 8 and 9. The structure of each substance was ascertained by results of mass and nmr spectral analyses and confirmed by crystal structure determination (for 7) or synthesis. Combretastatins B-3 and B-4 gave PS ED50 values of 0.4 and 1.7 ug/ml, respectively, and bibenzyls 7, 8, and 9 were comparably cell growth inhibitory against the PS cell line with ED50 results of 1.7, 2.5 and 0.25 .mu.g/ml, respectively. All the bibenzyls caused leukemia cells to accumulate in mitosis at cytotoxic drug concentrations; however, a wide range of in vitro activity against the protein tubulin (the major component of the mitotic spindle) was observed.