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

J Med Chem. 1986 Sep;29(9):1786-9. doi: 10.1021/jm00159a039.

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aminopterin / analogs & derivatives*
  • Aminopterin / chemical synthesis
  • Aminopterin / pharmacology
  • Animals
  • Cell Division / drug effects
  • Chemical Phenomena
  • Chemistry
  • Folic Acid Antagonists / pharmacology*
  • 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

Substances

  • Folic Acid Antagonists
  • 5,10-methylene-5,6,7,8-tetrahydro-8,10-dideazaminopterin
  • Thymidylate Synthase
  • Aminopterin
  • Methotrexate