Synthesis and antifolate properties of 5,10-methylenetetrahydro-8,10-dideazaminopterin.

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DeGraw JI, Colwell WT, Kisliuk RL, Gaumont Y, Sirotnak FM

Synthesis and antifolate properties of 5,10-methylenetetrahydro-8,10-dideazaminopterin.

J Med Chem. 1986 Sep;29(9):1786-9.

PubMed ID

3091834 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Methotrexate	Thymidylate synthase	IC 50 (nM)	100000	N/A	N/A	Details