4,4-Difluorinated analogues of l-arginine and N(G)-hydroxy-l-arginine as mechanistic probes for nitric oxide synthase

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1758-62. doi: 10.1016/j.bmcl.2009.01.076. Epub 2009 Feb 18.


4,4-Difluoro-l-arginine and 4,4-difluoro-N(G)-hydroxy-l-arginine were synthesized and shown to be substrates for the inducible isoform of nitric oxide synthase (iNOS). Binding of both fluorinated analogues to the NOS active site was also investigated using a spectral binding assay employing a heme domain construct of the inducible NOS isoform (iNOS(heme)). 4,4-Difluoro-N(G)-hydroxy-arginine was found to bind at the NOS active site in a unique manner consistent with a model involving ligation of the Fe(III) heme center by the oxygen atom of the N(G)-hydroxy moiety.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / analogs & derivatives*
  • Arginine / chemistry
  • Catalysis
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Fluorine / chemistry
  • Heme / chemistry
  • Models, Chemical
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase / chemistry
  • Oxygen / chemistry
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Substrate Specificity


  • Protein Isoforms
  • Fluorine
  • Heme
  • N(omega)-hydroxyarginine
  • Arginine
  • Nitric Oxide Synthase
  • Oxygen