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

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

Bioorganic & medicinal chemistry letters 2009 Mar 15

filter terms:

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.

Citation

Nathaniel I Martin, Joshua J Woodward, Michael B Winter, Michael A Marletta. 4,4-Difluorinated analogues of l-arginine and N(G)-hydroxy-l-arginine as mechanistic probes for nitric oxide synthase. Bioorganic & medicinal chemistry letters. 2009 Mar 15;19(6):1758-62