Abstract
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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Folic Acid / analogs & derivatives*
-
Folic Acid / chemical synthesis
-
Folic Acid / chemistry
-
Folic Acid / pharmacology
-
Folic Acid Antagonists / chemical synthesis
-
Folic Acid Antagonists / pharmacology
-
Glutamates / chemical synthesis*
-
Glutamates / pharmacology
-
Humans
-
Kinetics
-
Magnetic Resonance Spectroscopy
-
Methotrexate / analogs & derivatives*
-
Methotrexate / chemical synthesis
-
Methotrexate / chemistry
-
Methotrexate / pharmacology
-
Molecular Structure
-
Peptide Synthases / metabolism
-
Pteroylpolyglutamic Acids / antagonists & inhibitors
-
Pteroylpolyglutamic Acids / metabolism
-
Rats
-
Stereoisomerism
-
Tetrahydrofolate Dehydrogenase / metabolism
-
Tumor Cells, Cultured
Substances
-
Folic Acid Antagonists
-
Glutamates
-
Pteroylpolyglutamic Acids
-
beta,beta-difluorofolic acid
-
fluoresceinated methotrexate
-
gamma-fluorofolic acid
-
Folic Acid
-
Tetrahydrofolate Dehydrogenase
-
Peptide Synthases
-
folylpolyglutamate synthetase
-
Methotrexate