The mechanism underlying nitroxyl and nitric oxide formation from hydroxamic acids

Abstract

BackgroundThe pharmacological effects of hydroxamic acids (RC(O)NHOH, HX) are partially attributed to their ability to serve as HNO and/or NO donors under oxidative stress. Given the development and use of HXs as therapeutic agents, elucidation of the oxidation mechanism is needed for more educated selection of HX-based drugs. MethodsAcetohydroxamic and glycine-hydroxamic acids were oxidized at pH 7.0 by a continuous flux of radiolytically generated ·OH or by metmyoglobin and H2O2 reactions system. Gas chromatography and spectroscopic methods were used to monitor the accumulation of N2O, N2, nitrite and hydroxylamine. ResultsOxidation of HXs by ·OH under anoxia yields N2O, but not nitrite, N2 or hydroxylamine. Upon the addition of H2O2 to solutions containing HX and metmyoglobin, which is instantaneously and continuously converted into compound II, nitrite and, to a lesser extent, N2O are accumulated under both anoxia and normoxia. ConclusionsOxidation of HXs under anoxia by a continuous flux of ·OH, which solely oxidizes the hydroxamate moiety to RC(O)NHO·, forms HNO. This observation implies that bimolecular decomposition of RC(O)NHO· competes efficiently with unimolecular decomposition processes such as internal disproportionation, hydrolysis or homolysis. Oxidation by metmyoglobin/H2O2 involves relatively mild oxidants (compounds I and II). Compound I reacts with HX forming RC(O)NHO· and compound II, which oxidizes HX, RC(O)NHO·, HNO and NO. The latter reaction is the main source of nitrite. General significanceHXs under oxidative stress release HNO, but can be considered as NO-donors provided that HNO oxidation is more efficient than its reaction with other biological targets.