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Synthesis and antifolate properties of 5,10-methylenetetrahydro-8,10-dideazaminopterin.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 1986 Sep; Vol. 29 (9), pp. 1786-9. - Publication Year :
- 1986
-
Abstract
- The synthesis of the 5,10-methylene analogue of 5,6,7,8-tetrahydro-8,10-dideazaminopterin, a potential dual inhibitor of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzymes, is described. The dimethyl ester of 10-carboxy-4-amino-4-deoxy-8,10-dideazapteroic acid was converted to the tetrahydro derivative by hydrogenation. Thermally induced cyclization of the 10-carbomethoxy and the 5-NH groups afforded the 5,10-carbonyl analogue. Reduction of the lactam with borane readily yielded the key 5,10-methylene-4-amino-4-deoxy-8,10-dideazatetrahydropteroic acid methyl ester. Saponification of the benzoate ester and coupling with L-glutamate concluded the synthesis. The title compound was a modest inhibitor of growth in folate-dependent bacteria. Streptococcus faecium and Lactobacillus casei, but inhibition of DHFR or TS derived from L. casei was poor. The compound was also a weak inhibitor of DHFR derived from L1210 murine leukemia and was a weak inhibitor of L1210 growth in culture.
- Subjects :
- Aminopterin chemical synthesis
Aminopterin pharmacology
Animals
Cell Division drug effects
Chemical Phenomena
Chemistry
Lacticaseibacillus casei drug effects
Lacticaseibacillus casei growth & development
Leukemia L1210 enzymology
Leukemia L1210 pathology
Methotrexate pharmacology
Mice
Streptococcus drug effects
Streptococcus growth & development
Thymidylate Synthase antagonists & inhibitors
Aminopterin analogs & derivatives
Folic Acid Antagonists pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 29
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 3091834
- Full Text :
- https://doi.org/10.1021/jm00159a039