| Autor: |
Hart BP; Department of Chemistry, University of Michigan, Ann Arbor 48109-1055, USA., Haile WH, Licato NJ, Bolanowska WE, McGuire JJ, Coward JK |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1996 Jan 05; Vol. 39 (1), pp. 56-65. |
| DOI: |
10.1021/jm950515e |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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