Synthesis of Ester Prodrugs for Folypolyglutamate Synthetase Inhibition

Bandaranayake, Prabash, Jacqueline Nortman, Bhavisha Patel, Andrew Mastay, and David Bartley

Folylpolyglutamate synthetase (FPGS) catalyzes the synthesis of poly(γ-glutamyl) metabolites (“conjugates”) of folates and antifolates. The design and synthesis of inhibitors of FPGS is important for studying the significance of poly(γ-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 inhibitors 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. Research in our laboratory focuses on synthesizing prodrug esters of these inhibitors. Progress toward a cell permeable FPGS inhibitor will be presented.