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Redox cycling by iron bound to bidentate and tridentate orally active chelating agents

Redox cycling of iron is considered important for its toxicity. Reduction of a low molecular weight Fe(III)-complex followed by oxidation of the Fe(II)-complex by H2O2 may yield the reactive OH" radical (Fenton reaction). Complexation of iron that shifts the one-electron reduction potential to either far below that of reductants, such as monohydroascorbate or to far above that of peroxides, is essential to limit Fenton reactivity.

The bidentate ligand Deferiprone, or CP20, and its derivatives, CP502, CP509, supplied by Prof. R. C. Hider, and the tridentate ligand ICL670 are effective oral chelating agents for the removal of iron. The standard electrode potentials of the iron complexes, measured by cyclic voltammetry are -620 mV, -535 mV, -535 mV and -600 mV, respectively. However, at micromolar concentrations of iron and excess ligand, these values are significantly higher, and under these conditions Fe(II) should not be fully complexed.

By pulse radiolysis, we showed that after diffusion-controlled (6.4 × 10'10 M-1s-1) reduction of Fe(III)(CP20)3 by e-aq, ligand dissociation occurs with a rate constant of (8 +/- 1) x 10'3 s-1. This finding illustrates that, indeed, at dilute conditions iron(II) is not fully complexed by CP20 and could therefore be oxidised by dioxygen to produce superoxide.

Reported by

SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZUERICH
Hoenggerberg, HCI
8093 ZURICH
Switzerland
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