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

Complex formation of 4‐[3,5‐bis(2‐hydroxyphenyl)‐1,2,4‐triazol‐1‐ y l]benzoic acid (ICL670, H 3 L x ), 4‐[3,5‐bis(2‐hydroxyphenyl)‐1,2,4‐triazol‐1‐yl]benzosulfonic acid (H 3 L y ), and 3,5‐bis(2‐hydroxyphenyl)‐1‐phenyl‐1,2,4‐triazole (H 2 L z ) with Fe 3+ and Fe 2+ was investigated in H 2 O and in H 2 O/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 Fe II 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 °C, 0.1 M KCl in H 2 O) are log β 1 = 22.0 and log β 2 = 36.9, respectively. The affinity of these ligands for Fe 2+ 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 H 3 L x , 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. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)