Complex formation of ICL670 and related ligands with FeIII and FeII

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 (H3L(y)), and 3,5-bis(2-hydroxyphenyl)-1-phenyl-1,2,4-triazole (H2Lx) 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 Fell and Fe-III complexes were elucidated with a particular focus on their potential involvement in the generation of oxidative stress. The overall stability constants of [Fe-III(L-x)] and [Fe-III(L-x)(2)](3-) (25 degreesC, 0.1 M KCl in H2O) are log beta(1) = 22.0 and log beta(2) = 36.9, respectively. The affinity of these ligands for Fe2+ is remarkably poor. In particular, the 1:2 complexes [Fe-II(L-x)(2)](4-) and [Fe-II(L-y)(2)](4-) were found to be less stable. As a consequence, the redox chemistry of the [Fe-III(L-x)]/[Fe-II(L-x)](-) and the [Fe-III(L-x)(2)](3-)/[Fe-II(L-x)(2)](4-) couples differs significantly. [Fe-III(L-x)(2)](3-) is a very weak oxidizing agent (E-1/2 is approximately -0.6 V versus NHE) and reduction of [Fe-III(L-x)(2)](3-) is not anticipated under physiological conditions. The reduction potential of the [Fe-III(L-x)]/[Fe-II(L-x)](-) 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(L-z)(2)](.)4EtOH, Na[Al(L-z)2](.)4EtOH, and [Cu(L-z)(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. (C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.