The mechanism underlying nitroxyl and nitric oxide formation from hydroxamic acids.

BACKGROUND

The 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.

METHODS

Acetohydroxamic and glycine-hydroxamic acids were oxidized at pH 7.0 by a continuous flux of radiolytically generated (·)OH or by metmyoglobin and H(2)O(2) reactions system. Gas chromatography and spectroscopic methods were used to monitor the accumulation of N(2)O, N(2), nitrite and hydroxylamine.

RESULTS

Oxidation of HXs by (·)OH under anoxia yields N(2)O, but not nitrite, N(2) or hydroxylamine. Upon the addition of H(2)O(2) to solutions containing HX and metmyoglobin, which is instantaneously and continuously converted into compound II, nitrite and, to a lesser extent, N(2)O are accumulated under both anoxia and normoxia.

CONCLUSIONS

Oxidation 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/H(2)O(2) 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 SIGNIFICANCE: HXs 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.