Iron-hydroxypyridone redox chemistry: Kinetic and thermodynamic limitations to Fenton activity

The oral iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one (CP20) is undergoing widespread clinical trials but discrepant reports of its toxicity have stimulated debate on its suitability and on its role in preventing metal-dependent oxygen radical formation. We therefore investigated the electrochemical basis for the iron-catalyzed Fenton reaction by studying rotating disk electrode and cyclic voltammetry of iron complexes with CP20 and with its diethyl analog CP94. Reduction of Fe(III)-hydroxypyridone complexes at the glassy carbon electrode occurs through one-electron quasi-reversible reduction of Fe3+ after dissociation of the complex. Complex dissociation is fast and does not limit the current of the forward reaction. The physiologically relevant formal potentials (i.e. at neutral pH) of the bis- and tris-complexes were then determined. The formal potential of Fe(CP20)(3) (-828 mV versus NHE) is well below the range of physiological reducing agents and reduction in vivo is thermodynamically unfavorable. In contrast, E(o)' of the (H2O)(2)Fe(CP2O)(2)(+) complex (-454 mV versus NHE) is within this range and reduction is feasible. However, reoxidation of Fe2+ in the presence of the hydroxypyridones is limited by the kinetics of a slow tautomeric equilibrium of the ligands. Thus the rate of chemical reoxidation of Fe2+, e.g. by hydrogen peroxide, places a Limitation on the rate at which iron can be expected to redox cycle in the presence of hydroxypyridone.