Nitroxide metabolites from alkylhydroxylamines and N-hydroxyurea derivatives resulting from reductive inhibition of soybean lipoxygenase.
One proposed mechanism of the inactivation of lipoxygenase by inhibitors is the reduction of the catalytically active ferric form of the enzyme to its ferrous form. Recent studies have shown that compounds containing the hydroxamate moiety are potent inhibitors of lipoxygenase. The hydroxamate portion of the inhibitor is thought to bind to iron at the catalytic site of the enzyme. We now report evidence that the NOH of the hydroxamate group of N-(4-chlorophenyl)-N-hydroxy-N'-(3-chlorophenyl)urea, N-[(E)-3-(3-phenoxyphenyl)prop-2-enyl]acetohydroxamic acid (BW A4C), and N-(1-benzo(b)thien-2-ylethyl)-N-hydroxyurea (Zileuton) is oxidized by lipoxygenase to form their corresponding nitroxides, which are directly detected by electron paramagnetic resonance spectroscopy. It is consistently found that the selected NOH-containing compounds, e.g. alkylhydroxylamines or N-hydroxyureas, are also oxidized by lipoxygenase to form their corresponding nitroxides.
Chamulitrat
W
W
National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
Mason
R P
RP
Riendeau
D
D
D044482:Benzeneacetamides; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006877:Hydroxamic Acids / Q000494:pharmacology; D006898:Hydroxylamines / Q000378:metabolism* / Q000494:pharmacology; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000378:metabolism*; D010084:Oxidation-Reduction; D013025:Glycine max / Q000201:enzymology*; D013329:Structure-Activity Relationship
D044482:Benzeneacetamides; D005609:Free Radicals; D006877:Hydroxamic Acids; D006898:Hydroxylamines; D016859:Lipoxygenase Inhibitors; D009589:Nitrogen Oxides; C056614:N-(3-phenoxycinnamyl)acetohydroxamic acid; C039900:nitroxyl; C063449:zileuton; D006918:Hydroxyurea