Complex Formation of ICL670 and Related Ligands with Fe^III and Fe^II

Abstract

Complex formation of 4‐[3,5‐bis(2‐hydroxyphenyl)‐1,2,4‐triazol‐1‐yl]benzoic acid (ICL670, H3Lx), 4‐[3,5‐bis(2‐hydroxyphenyl)‐1,2,4‐triazol‐1‐yl]benzosulfonic acid (H3Ly), and 3,5‐bis(2‐hydroxyphenyl)‐1‐phenyl‐1,2,4‐triazole (H2Lz) with Fe3+ and Fe2+ was investigated in H2O and in H2O/DMSO mixtures by potentiometry, spectrophotometry and cyclic voltammetry. ICL670 has previously been considered as a promising drug for an oral treatment of iron overload. In this paper, the stability and redox properties of the various FeII and FeIII complexes were elucidated with a particular focus on their potential involvement in the generation of oxidative stress. The overall stability constants of [FeIII(Lx)] and [FeIII(Lx)2]3− (25 °C, 0.1 M KCl in H2O) are log β1 = 22.0 and log β2 = 36.9, respectively. The affinity of these ligands for Fe2+ is remarkably poor. In particular, the 1:2 complexes [FeII(Lx)2]4− and [FeII(Ly)2]4− were found to be less stable. As a consequence, the redox chemistry of the [FeIII(Lx)]/[FeII(Lx)]− and the [FeIII(Lx)2]3−/[FeII(Lx)2]4− couples differs significantly. [FeIII(Lx)2]3− is a very weak oxidizing agent (E1/2 is approximately −0.6 V versus NHE) and reduction of [FeIII(Lx)2]3− is not anticipated under physiological conditions. The reduction potential of the [FeIII(Lx)]/[FeII(Lx)]− couple is considerably less negative and was estimated to be +0.1 V (versus NHE). The possible roles of the various Fe complexes as catalysts for the Fenton reaction in biological media are discussed. The crystal structures of H3Lx, Na[Fe(Lz)2]·4EtOH, Na[Al(Lz)2]· 4EtOH, and [Cu(Lz)(pyridine)]2 were investigated by single‐crystal X‐ray diffraction, and the possible influence of the particular steric requirements of these ligands on the stability of the metal complexes has been analyzed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Chelation versus Binucleation: Metal Complex Formation with the Hexadentate all‐cis‐N1,N2‐Bis(2,4,6‐trihydroxy‐3,5‐diaminocyclohexyl)ethane‐1,2‐diamine

“…[48] For the determination of the pK a values of H 6 (L e ) 6 + , several alkalimetric titrations were carried out with analytically pure samples of L e ·6 HCl·2.5 H 2 O (total L e = 1.0 mm), using KCl (0.1 or 1.0 m) or KNO 3 (1.0 m) as inert electrolyte. The formation constants of metal complexes were determined using solutions that contained L e ·6 HCl·2.5 H 2 O and the metal salt in 2:1, 1:1 or 1:2 molar ratios (total L e and total M varied between 0.5 and 2 mm) at an ionic strength of 0.1 m (KCl).…”

“…A PC was used to trigger the recording of a spectrum just prior to the addition of each new aliquot of base. [48] Calculations of equilibrium constants: Equilibrium constants were generally calculated as concentration quotients (pH = Àlog [H + ]) by using the computer programs Hyperquad2000 and Specfit. [49,50] The total concentrations of the reactants and the pK w (13.78 for m = 0.1 m, 13.77 for m = 1.0 m) were not refined.…”

The Coordination Chemistry of 1,4‐Diazepan‐6‐amine

“…[41] Simple potentiometric titrations were carried out with total M/total daza ratios of 1:1 and 1:2 in 0.1 m KCl or 0.1 m KNO 3 ( Figure 5). Titration experiments, which were followed by potentiometric and spectrophotometric methods, were performed in 1 m KCl.…”

IN VITRO BLOOD DISTRIBUTION AND PLASMA PROTEIN BINDING OF THE IRON CHELATOR DEFERASIROX (ICL670) AND ITS IRON COMPLEX FE-[ICL670]2 FOR RAT, MARMOSET, RABBIT, MOUSE, DOG, AND HUMAN

“…Two molecules of deferasirox can form a complex with ferric iron 2 ) ( Fig. 1) (Steinhauser et al, 2004); solubilized, chelated iron is then excreted.…”