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

Nathaniel I Martin; Joshua J Woodward; Michael B Winter; Michael A Marletta

doi:10.1016/j.bmcl.2009.01.076

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.

Authors

Nathaniel I Martin¹, Joshua J Woodward, Michael B Winter, Michael A Marletta

Affiliation

¹ Department of Medicinal Chemistry and Chemical Biology, University of Utrecht, 3584 CA, The Netherlands.

PMID: 19230661
DOI: 10.1016/j.bmcl.2009.01.076

Abstract

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

Substances

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