Synthesis and Biological Evaluation of N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine

J Med Chem. 1992 May 29;35(11):2002-6. doi: 10.1021/jm00089a009.

Abstract

A novel folic acid analogue, N alpha-(5-deaza-5,6,7,8-tetrahydropteroyl)-L-ornithine, 3, was prepared via a multistep synthetic sequence. The key steps involved the conversion of 5-deazapteroic acid to its N10-formyl derivative followed by catalytic hydrogenation of the pyridine ring and subsequent heating in dilute sodium hydroxide to afford the new 5-deaza-5,6,7,8-tetrahydropteroic acid. After trifluoroacetylation, this compound was coupled to N delta-(tert-butyl-oxycarbonyl)-L-ornithine using conventional peptide bond forming conditions. Deprotection first in base and then in acid gave the title compound. Compound 3 was an effective inhibitor of hog liver folylpolyglutamate synthetase (Kis, estimated = 64 nM), and was shown to retard the formation of polyglutamates of a structurally related folic acid analogue in HCT-8 cells in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Animals
  • Breast Neoplasms / metabolism
  • Cell Survival / drug effects
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemical synthesis
  • Folic Acid / metabolism
  • Folic Acid / pharmacology
  • Folic Acid Antagonists
  • Humans
  • Liver / enzymology
  • Peptide Synthases / antagonists & inhibitors*
  • Polyglutamic Acid / metabolism
  • Swine
  • Tumor Cells, Cultured

Substances

  • Folic Acid Antagonists
  • N(alpha)-(5-deaza-5,6,7,8-tetrahydropteroyl)ornithine
  • Polyglutamic Acid
  • Folic Acid
  • Peptide Synthases
  • folylpolyglutamate synthetase