5,10-Methylenetetrahydro-5-deazafolic Acid and Analogues: Synthesis and Biological Activities

J Med Chem. 1992 Oct 2;35(20):3678-85. doi: 10.1021/jm00098a013.

Abstract

The synthesis of 5,10-methylene-5-deazatetrahydrofolic acid (2), a stable, rigid analogue of 5,10-methylenetetrahydrofolate (1), is reported as a potential inhibitor of thymidylate synthase. The target compound was obtained by a Fisher-indole type cyclization of the hydrazone 16 from 2-amino-6-hydrazino-4-oxopyrimidine (10) and diethyl N-[4-(3-formyl-1-pyrrolyl)benzoyl]-L-glutamate (15) followed by catalytic reduction of the product 17. Similarly, modification of the Fisher-indole type cyclization of the appropriate hydrazone precursors 11 and 12 afforded the nonclassical analogues 3-amino-7,8,9-trimethyl-2H-pyrrolo[3',4':4,5]pyrido[2,3-d]pyrimidin-1- one (4) and 3-amino-8-benzyl-7,9-dimethyl-2H-pyrrolo[3',4':4,5]pyrido [2,3-d]pyrimidin-1-one (5), respectively. The target compound 2, its aromatic precursor 18, and the nonclassical analogue 4 were evaluated as inhibitors of the growth of Manca human lymphoma cells and also as inhibitors of human dihydrofolate reductase, human thymidylate synthase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase. Compound 18 showed weak inhibition of lymphoma cell growth (IC50 = 42 microM) and of AICAR formylTF (IC50 = 17 microM). Compounds 2 and 4 did not inhibit lymphoma cell growth or thymidylate synthase. The inactivity of 2 was attributed to its lack of flexibility leading to its inability to bind to thymidylate synthase.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemical synthesis
  • Folic Acid / pharmacology
  • Humans
  • Pyrroles / chemical synthesis
  • Tetrahydrofolates / chemical synthesis*
  • Tetrahydrofolates / pharmacology
  • Thymidylate Synthase / antagonists & inhibitors
  • Tumor Cells, Cultured / drug effects

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Pyrroles
  • Tetrahydrofolates
  • 5,10-methylenetetrahydro-5-deazafolic acid
  • Folic Acid
  • Thymidylate Synthase