Design and synthesis of cell permeable phosphinic acid inibitors of folylpolyglutamate synthetase

Cross, Michael E., Elyse L. McKenna, and David M. Bartley

Folylpolyglutamate synthetase (FPGS) catalyzes the synthesis of poly-glutamyl metabolites of folates and antifolates.  The design and synthesis of inhibitors of FPGS is important for studying the significance of poly-glutamyl metabolite synthesis and degradation in cellular regulation and could be an important lead in increasing the efficiency of the antifolates in use as anti-tumor agents.  Extremely potent phosphinic acid containing pseudopeptide inhibotors of FPGS have previously been synthesized but they are unable to penetrate the cellular membrane.  Previous experiments have suggested that these inhibitors are unable to utilize the folate transport system because they contain negatively charged carboxylate moieties.  These negative charges also prevent the compounds from passively diffusing through the cell membrane.  Progress toward the synthesis of cell permeable FPGS inhibitors will be presented.