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.
N-[N-(4-Deoxy-4-amino-10-methylpteroyl)-4-fluoroglutamyl]-ga mma-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.
Licato
N J
NJ
Department of Medicinal Chemistry, University of Michigan, Ann Arbor 48109.
Coward
J K
JK
Nimec
Z
Z
Galivan
J
J
Bolanowska
W E
WE
McGuire
J J
JJ
D000818:Animals; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004151:Dipeptides / Q000378:metabolism; D005492:Folic Acid / Q000031:analogs & derivatives*; D006868:Hydrolysis; D008727:Methotrexate / Q000378:metabolism; D010453:Peptide Synthases / Q000502:physiology*; D011624:Pteroylpolyglutamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013552:Swine; D011623:gamma-Glutamyl Hydrolase / Q000502:physiology*
D004151:Dipeptides; D011624:Pteroylpolyglutamic Acids; C063276:N-(N-(4-deoxy-4-amino-10-methylpteroyl)-4-fluoroglutamyl)-gamma-glutamate; D005492:Folic Acid; D011623:gamma-Glutamyl Hydrolase; D003546:Cysteine Endopeptidases; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate