Synthesis and biological activity of folic acid and methotrexate analogues containing L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid.
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.
Hart
B P
BP
Department of Chemistry, University of Michigan, Ann Arbor 48109-1055, USA.
Haile
W H
WH
Licato
N J
NJ
Bolanowska
W E
WE
McGuire
J J
JJ
Coward
J K
JK
D000818:Animals; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D005971:Glutamates / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010453:Peptide Synthases / Q000378:metabolism; D011624:Pteroylpolyglutamic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D005493:Folic Acid Antagonists; D005971:Glutamates; D011624:Pteroylpolyglutamic Acids; C097768:beta,beta-difluorofolic acid; C036539:fluoresceinated methotrexate; C097767:gamma-fluorofolic acid; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate