N-[4-[[(3,4-dihydro-4-oxo-1,2,3-benzotriazin-6- yl)methyl]amino]benzoyl]-L-glutamic Acid, a Novel A-ring Analogue of 2-desamino-5,8-dideazafolic Acid

J Med Chem. 1992 Jul 10;35(14):2626-30. doi: 10.1021/jm00092a013.

Abstract

N-[4-[[(3,4-Dihydro-4-oxo-1,2,3-benzotriazin-6- yl)methyl]amino]benzoyl]-L-glutamic acid ("2-aza-2-desamino-5,8- dideazafolic acid", ADDF) was synthesized from 2-amino-5-methylbenzamide via a four-step sequence consisting of diazotization, benzylic bromination, condensation with dimethyl N-(4-aminobenzoyl)-L-glutamate, and ester hydrolysis. ADDF was an inhibitor of recombinant mouse thymidylate synthase; inhibition was competitive with 5,10-methylenetetrahydrofolate as variable substrate (Ki = 2.3 microM). It was a substrate for murine folylpolyglutamate synthetase with kinetic characteristics (Km = 28 microM) comparable to those of aminopterin, and it inhibited the growth of L1210 cells in culture (IC50 = 0.52 microM). The structural modification of the A-ring embodied in ADDF appears to offer a novel, heretofore unexplored approach to the design of TS inhibitors.

Publication types

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

MeSH terms

  • Acyltransferases / metabolism
  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemistry
  • Folic Acid / pharmacology
  • Hydroxymethyl and Formyl Transferases*
  • Leukemia L1210 / drug therapy
  • Liver / enzymology
  • Mice
  • Peptide Synthases / metabolism
  • Phosphoribosylglycinamide Formyltransferase
  • Recombinant Proteins / antagonists & inhibitors
  • Thymidylate Synthase / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Recombinant Proteins
  • 2-desamino-5,8-dideazafolic acid
  • 2-aza-2-desamino-5,8-dideazafolic acid
  • Folic Acid
  • Thymidylate Synthase
  • Hydroxymethyl and Formyl Transferases
  • Phosphoribosylglycinamide Formyltransferase
  • Acyltransferases
  • Peptide Synthases
  • folylpolyglutamate synthetase