RESUMEN
The stereospecific syntheses of L-threo-gamma-fluoromethotrexate (1t) and L-threo-gamma-fluorofolic acid (3t) are reported. Compounds 1t and 3t have no substrate activity with folylpoly-gamma-glutamate synthetase isolated from CCRF-CEM human leukemia cells, and compound 1t inhibits human dihydrofolate reductase at similar levels as methotrexate. The synthesis of DL-3,3-difluoroglutamic acid (6) and its incorporation into DL-beta,beta-difluorofolic acid (4) are also reported. Compound 4 acts as a better substrate for human CCRF-CEM folylpoly-gamma-glutamate synthetase than folic acid (V/K = ca. 7-fold greater). Thus, replacement of the glutamate moiety of methotrexate and folic acid with 4-fluoroglutamic acid and 3,3-difluoroglutamic acid results in folates and antifolates with altered polyglutamylation activity.
Asunto(s)
Ácido Fólico/análogos & derivados , Glutamatos/síntesis química , Metotrexato/análogos & derivados , Animales , Ácido Fólico/síntesis química , Ácido Fólico/química , Ácido Fólico/farmacología , Antagonistas del Ácido Fólico/síntesis química , Antagonistas del Ácido Fólico/farmacología , Glutamatos/farmacología , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Metotrexato/síntesis química , Metotrexato/química , Metotrexato/farmacología , Estructura Molecular , Péptido Sintasas/metabolismo , Ácidos Pteroilpoliglutámicos/antagonistas & inhibidores , Ácidos Pteroilpoliglutámicos/metabolismo , Ratas , Estereoisomerismo , Tetrahidrofolato Deshidrogenasa/metabolismo , Células Tumorales CultivadasRESUMEN
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.