Structure-activity studies on gossypol in tumor cell lines

Gossypol [(2,2'-binaphthalene)-8,8'-dicarboxaldehyde-1,1 ',6,6',7,7'-hexahy droxy-5,5'-diisopropyl-3,3'-dimethyl] 1a is a naturally occurring compound extracted from the cotton plant and has been extensively studied as an oral male contraceptive. Its favorable toxicity profile, and the more recent de monstration of anti-tumor activity in animals and humans, prompted us to in vestigate the role of the aldehyde groups in a structure-activity study in cultured tumor cells. Four racemic compounds were evaluated: gossypol la, g ossypolone 2, the bis Schiff's base of L-phenylalanine methyl ester with go ssypol (bis Schiff's base). Ic and apogossypol 1b. The former two compounds both retain the aldehyde functional groups at positions 8 and 8' of the mo lecule whilst in the latter two compounds the aldehydes are blocked or abse nt, respectively. In addition, the i- and d-isomers of gossypol 1a, the bis Schiff's base 1c and the half Schiff's base 1d (one aldehyde blocked) were tested. The cell lines studied included melanoma (SK-mel-19), cervix (Siha s), small cell lung (H69) and myelogenous leukemia (K562). Cytotoxicity was measured using the MTT and flow cytometric viability assays. Racemic gossy pol la and gossypolone 2 induced similar dose-dependent decreases in cell v iability in all the cell lines with IC50 Values of 23-46 and 28- 50 mu M, r espectively. In contrast, the racemic bis Schiff's base derivative of gossy pol 1c and apogossypol 1b showed minimal activity in any cell line up to 50 mu M. The I-enantiomer of gossypol 1a was significantly more active than t he d-enantiomer (IC50 Of 20 Versus >50 mu M, respectively). When one aldehy de of either enantiomer was blocked 1d cytoxicity was comparable to the l-e nantiomer of gossypol. The data suggest that only one aldehyde group is req uired for the cytotoxicity of gossypol 1a, irrespective of the stereoconfig uration [(C) 2000 Lippincott Williams & Wilkins.].