The addition of a variety of
thiols to the alpha,beta-unsaturated
lactone 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 regenerate
brefeldin A. The
sulfoxides were more active than the
sulfides as
cytotoxic agents in a variety of human
cancer cell cultures with the activities of the
sulfoxides approaching that of
brefeldin A itself. The cytotoxicities of the
sulfoxides may be due to their conversion back to
brefeldin A. The kinetics of
sulfoxide elimination to form
brefeldin A were studied in four cases, and the results indicate that substantial 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
sulfides derived from
brefeldin A can be considered as potential
brefeldin A prodrugs. Several of the
sulfide derivatives were determined to have enhanced 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
cancer cell cultures. Some of the more active
brefeldin A derivatives were tested in an in vivo animal model in which hollow fibers containing
cancer cell cultures were implanted subcutaneously (SC) and intraperitoneally (IP), and the compounds were administered IP. Greater cytotoxic activity was observed at the SC site than at the IP site for the majority of these compounds, an observation which is consistent with the hypothesis that they are acting as
brefeldin A prodrugs in vivo.