title: Fenton chemistry and iron chelation under physiologically relevant conditions: Electrochemistry and kinetics.
abstract: The goal of iron-chelation therapy is to reduce the levels of labile plasma iron, and intravenously administered desferrioxamine is the gold standard of therapeutic agents. Hydroxypyridinones, e.g., CP20 (3-hydroxy-1,2-dimethylpyridin-4(1H)-one), are used or are under investigation as orally administered iron chelators. We determined electrode potentials of CP20, the related hydoxypyridones CP361, CP363, and CP502, and ICL670 (4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid) under physiologically relevant conditions to address the question of whether iron in the presence of these chelating agents can carry out Fenton chemistry in vivo. We found that iron(III) but not iron(II) binds tightly to both CP20 and ICL670 at pH 7 and higher, compared to nearly complete binding of 1 microM iron(II) to 10 microM desferrioxamine at pH 7.4 The electrode potentials of the hydroxypyridinones shift to more negative values with decreasing pK(a) values at lower concentrations of iron(III) (0.02 mM) and ligand (0.1 mM). The electrode potential of the iron-CP20 system decreases as a function of increasing pH, with a minimum near pH 10.5. We estimate an electrode potential for the ascorbyl radical/ascorbate couple under physiological conditions of +105 mV, which is higher than the electrode potential of the iron(III) complex of CP20 at all concentrations of iron. The rate of oxidation of iron(II) in the presence of CP20 by hydrogen peroxide increases with the concentrations of both ligand and peroxide. Although iron(II) is oxidized by hydrogen peroxide, the thus-formed Fe(III)(CP20)(3) complex cannot be reduced by ascorbate. Therefore, the tight binding of iron(III) by this class of chelators prevents redox cycling.
authors.affiliation: Laboratorium für Anorganische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, CH-8093 Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Merkofer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kissner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Brunk
authors.forename: Willem H
authors.initials: WH
authors.lastname: Koppenol
mesh_terms: D001205:Ascorbic Acid / Q000737:chemistry; D000077543:Deferiprone; D004563:Electrochemistry; D004566:Electrodes; D006861:Hydrogen Peroxide / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation; D007501:Iron / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000737:chemistry*; D007700:Kinetics; D015394:Molecular Structure; D011728:Pyridones / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: C045076:Fenton's reagent; D007502:Iron Chelating Agents; D011728:Pyridones; D014867:Water; D000077543:Deferiprone; D006861:Hydrogen Peroxide; D007501:Iron; D001205:Ascorbic Acid