From a series of gossypol derivatives studied, we conclude that the carbonyl groups of gossypol are needed for inhibition of erythrocyte anion transport and the hydroxy groups affect but are not essential to that inhibition. In an in vitro mouse erythroleukemia cytocidal assay, the most active compounds were gossypol and apogossypol. The latter was not active in the inhibition of erythrocyte anion transport or in a spermicidal assay. Of the more simple structures related to gossypol, those that were active in the cytocidal and spermicidal assays were bi-aromatic, linked by a 1- and not a 4-carbon chain and had free phenolic hydroxyl groups. These results are included in a discussion of the specificity and mechanism of action of gossypol.
PIP: The analysis of multiple biological assays of gossypol and its derivatives suggests that the carbonyl groups of gossypol are required for inhibition of erythrocyte anion transport and the hydroxy groups affect but are not essential to that inhibition. In an in vitro mouse erythroleukemia cytocidal assay, the most active compounds were gossypol and apogossypol. The latter was not active in the inhibition of erythrocyte anion transport or in a spermicidal assay. Of the more simple structures related to gossypol, those that were active in the cytocidal and spermicidal assays were biaromatic, linked by a 1- and not a 4-carbon chain, and had free phenolic hydroxyl groups. When gossypol inhibits the anion transporter, the carbonyl group does not seem to form a Schiff base. Gossypol is a unique compound since it alone, but not any of its derivatives, has in vivo as well as in vitro antifertility activity. It remains unknown, however, whether similar mechanisms are involved in gossypol's in vivo and in vitro effects. In whatever manner gossypol exerts its toxic effects, the selectivity for testicular tissue must be explained.