Methotrexate analogs. 16. Importance of the side-chain amide carbonyl group as a structural determinant of biological activity
- 1 December 1982
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 25 (12) , 1454-1459
- https://doi.org/10.1021/jm00354a013
Abstract
N-[[[(2,4-diaminopteridin-6-yl)methyl]amino]benzyl]-L-glutamic acid (deoxaminopterin, 1), a new aminopterin analog containing a CH2 group in the side chain in place of the amide C.dbd.O, was synthesized by condensation of 2,4-diamino-6-(bromomethyl)pteridine with diethyl N-(p-aminobenzyl)-L-glutamate, followed by saponification with a stoichiometric amount of barium hydroxide in 50% ethanol. The apparent importance of the amide C.dbd.O group as a structural determinant of biological activity was indicated by the finding that 1 has 10- to 20-fold lower affinity for bacterial dihydrofolate reductase than aminopterin, is not toxic to L1210 murine leukemia cells in culture at a concentration of up to 1.0 .mu.M and shows no antitumor effect in L1210 leukemic mice at doses as high as 240 mg/kg.This publication has 12 references indexed in Scilit:
- Methotrexate analogs. 14. Synthesis of new .gamma.-substituted derivatives as dihydrofolate reductase inhibitors and potential anticancer agentsJournal of Medicinal Chemistry, 1981
- Affinity labeling of chicken liver dihydrofolate reductase by a substituted 4,6-diaminodihydrotriazine bearing a terminal sulfonyl fluoride.Journal of Biological Chemistry, 1981
- Methotrexate analogs. 13. Chemical and pharmacological studies on amide, hydrazide, and hydroxamic acid derivatives of the glutamate side chainJournal of Medicinal Chemistry, 1981
- Methotrexate analogs. 11. Unambiguous chemical synthesis and in vitro biological evaluation of .alpha.- and .gamma.-monoesters as potential prodrugsJournal of Medicinal Chemistry, 1978
- Methotrexate analogs. 10. Direct coupling of methotrexate and diethyl L-glutamate in the presence of peptide bond-forming reagentsJournal of Medicinal Chemistry, 1978
- Methotrexate analogs. 8. Synthesis and biological evaluation of bisamide derivatives as potential prodrugsJournal of Medicinal Chemistry, 1977
- Acidic dissociation constants of folic acid, dihydrofolic acid, and methotrexate.Journal of Biological Chemistry, 1977
- Methotrexate analogs. 7. Synthesis of two higher homologs and a positional isomer of methotrexate diethyl ester as potential antitumor agentsJournal of Heterocyclic Chemistry, 1976
- On the nature of permeability of sarcoma-180 cells to amethopterin in vitroBiochimica et Biophysica Acta (BBA) - Biophysics including Photosynthesis, 1965
- The pharmacological and biochemical activity of 4-amino-4-deoxy-10-methyl-pteroylaspartic acidBiochemical Pharmacology, 1965