Redox Properties of the Iron Complexes of Orally Active Iron Chelators CP20, CP502, CP509 , and ICL670

Redox cycling of iron is a critical aspect of iron toxicity. Reduction of a low‐molecular‐weight iron(III)‐complex followed by oxidation of the iron(II)‐complex by hydrogen peroxide may yield the reactive hydroxyl radical (OH . ) or an oxoiron(IV) species (the Fenton reaction). Complexation of iron by a ligand that shifts the electrode potential of the complex to either to far below −350 mV (dioxygen/superoxide, pH=7) or to far above +320 mV (H 2 O 2 /HO . , H 2 O pH=7) is essential for limitting Fenton reactivity. The oral chelating agents CP20, CP502, CP509 , and ICL670 effectively remove iron from patients suffering from iron overload. We measured the electrode potentials of the iron(III) complexes of these drugs by cyclic voltammetry with a mercury electrode and determined the dependence on concentration, pH, and stoichiometry. The standard electrode potentials measured are −620 mV, −600 mV, −535 mV, and −535 mV with iron bound to CP20, ICL670, CP502 , and CP509 , respectively, but, at lower chelator concentrations, electrode potentials are significantly higher.