| Autor: |
Hart, B. P., Haile, W. H., Licato, N. J., Bolanowska, W. E., McGuire, J. J., Coward, J. K. |
| Zdroj: |
Journal of Medicinal Chemistry; January 5, 1996, Vol. 39 Issue: 1 p56-65, 10p |
| Abstrakt: |
The stereospecific syntheses of l-threo-γ-fluoromethotrexate (1t) and l-threo-γ-fluorofolic acid (3t) are reported. Compounds 1t and 3t have no substrate activity with folylpoly-γ-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-β,β-difluorofolic acid (4) are also reported. Compound 4 acts as a better substrate for human CCRF-CEM folylpoly-γ-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: |
Supplemental Index |
| Externí odkaz: |
|
