Synthesis of N-[N-(4-deoxy-4-amino-10-methylpteroyl)-4-fluoroglutamyl]-.gamma.-glutamate, an unusual substrate for folylpoly-.gamma.-glutamate synthetase and .gamma.-glutamyl hydrolase

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Abstract
N-[N-(4-Deoxy-4-amino-10-methylpteroyl)-4-fluoroglutamyl]-.gamma.-glutamate has been synthesized and its ability to serve as a substrate for folylpolyglutamate synthetase and .gamma.-glutamyl hydrolase has been investigated. It was anticipated that this compound would be a substrate for both of these enzymes. Although the title compound proved to be a good substrate for folylpolyglutamate synthetase, hydrolysis catalyzed by .gamma.-glutamyl hydrolase was unexpectedly slow. These results suggest the use of fluoroglutamate-containing peptides as hydrolase-resistant folates or antifols in a variety of chemotherapeutic regimens.