Inhibition of Hog Liver Folylpolyglutamate Synthetase by 5-substituted 5,8-dideaza Analogues of Folic Acid Bearing a Terminal L-ornithine Residue

J Med Chem. 1992 Oct 30;35(22):4078-85. doi: 10.1021/jm00100a013.

Abstract

Five new N alpha-(5,8-dideazapteroyl)-L-ornithines have been prepared using multistep synthetic sequences. These include N alpha-[5-(trifluoromethyl)-5,8-dideazapteroyl]-L-ornithine, 3, as well as N alpha-[5-(trifluoromethyl)-5,8-dideazaisopteroyl]-L-ornithine, 4, and its 5-fluoro and 5-chloro analogues. Both of the compounds containing a 5-(trifluoromethyl) group (3 and 4) were found to be excellent inhibitors of homogeneous hog liver folylpolyglutamate synthetase, having Ki values in the same range as N alpha-(5-chloro-5,8-dideazapteroyl)-L-ornithine, 2, (approximately 10 nM). However, the bridge-reversed isomer of 2 was 60-fold less inhibitory than 2.

Publication types

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

MeSH terms

  • Animals
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemical synthesis
  • Folic Acid / pharmacology
  • Kinetics
  • Liver / enzymology*
  • Ornithine / analogs & derivatives*
  • Ornithine / chemical synthesis
  • Ornithine / pharmacology
  • Peptide Synthases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Swine

Substances

  • Folic Acid
  • Ornithine
  • Peptide Synthases
  • folylpolyglutamate synthetase