Abstract
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)