Evaluation of 1,2-dimethyl-3-hydroxy-4-pyridinecarboxylic acid and of other 3-hydroxy-4-pyridinecarboxylic acid derivatives for a possible application in iron and aluminium chelation therapy

Four new possible chelating agents for iron and aluminium, 1,2-dimethyl-3-hydroxy-4-pyridinecarboxylic acid (DT712), 3-hydroxy-1,2,6-trimethyl-4-pyridinecarboxylic acid, 2,6-dimethyl-3-hydroxy-4-pyridinecarboxylic acid, and 2-ethyl-3-hydroxy-1-methyl-4-pyridinecarboxylic acid, were synthesized, and their complex formation with Fe(III) and Al(III) was studied by means of potentiometry, UV/Vis, NMR, and electrospray mass spectrometry. Number, stoichiometry, and stability constants of metal-ligand complexes were obtained at 25 °C in aqueous (Na)Cl 0.6 m. DT712 is the most promising hydroxypyridinecarboxylic acid considered so far for chelation therapy, as it forms the strongest Fe(III) complexes. DT712 was therefore further investigated to extend the thermodynamic and kinetic characterization of chelation therapy-relevant properties. UV/Vis measurements were performed to determine the kinetics by which DT712 extracts Fe(III) from transferrin.DT712 resulted to have better kinetic properties than existing iron chelators. Ternary metal/DT712/citric acid complexes were studied by electrospray mass spectrometry to check the competition with a typical low molecular weight iron ligand in the blood. The formation of only binary Fe(III)/DT712 and Al(III)/DT712 complexes (and ternary complexes in aged solutions) suggests that DT712 effectively compete with citric acid in the metal complexation. Standard reduction potentials of Fe(III)/DT712 complexes, and the kinetic constants of complex formation, were obtained by cyclic voltammetry. Accordingly, no redox cycling is expected to occur at in vivo conditions, and Fe(III)/DT712 complex formation should not be kinetically limited. On the basis of the present results, DT712 can be considered as candidate for iron chelation therapy.