DESIGN AND SYNTHESIS OF BREFELDIN-A SULFIDE DERIVATIVES AS PRODRUG CANDIDATES WITH ENHANCED AQUEOUS SOLUBILITIES

The addition of a variety of thiols to the alpha,beta-unsaturated lact one functionality present in brefeldin A has been carried out, and the resulting sulfides have been oxidized to the corresponding sulfoxides . These sulfoxides have the potential to undergo syn elimination to re generate brefeldin A. The sulfoxides were more active than the sulfide s as cytotoxic agents in a variety of human cancer cell cultures with the activities of the sulfoxides approaching that of brefeldin A itsel f. The cytotoxicities of the sulfoxides may be due to their conversion back to brefeldin A. The kinetics of sulfoxide elimination to form br efeldin A were studied in four cases, and the results indicate that su bstantial amounts of brefeldin A are likely to be generated during the cytotoxicity assays of the sulfoxide derivatives. Since the oxidation of sulfides to sulfoxides is a common metabolic reaction, the sulfide s derived from brefeldin A can be considered as potential brefeldin A prodrugs. Several of the sulfide derivatives were determined to have e nhanced aqueous solubilities relative to brefeldin A itself, A number of brefeldin A succinates, glutarates, oxidation products, and sulfone derivatives were also prepared and evaluated for cytotoxicity in danc er cell cultures. Some of the more active brefeldin A derivatives were tested in an in vivo animal model in which hollow fibers containing c ancer cell cultures were implanted subcutaneously (SC) and intraperito neally (IF), and the compounds were administered IP. Greater cytotoxic activity was observed at the SC site than at the IP site for the majo rity of these compounds, an observation which is consistent with the h ypothesis that they are acting as brefeldin A prodrugs in vivo.