Possible Chelating Agents for Iron and Aluminium – 4‐Hydroxy‐5‐methyl‐ and 4‐Hydroxy‐1,5‐dimethyl‐3‐pyridinecarboxylic Acid

4-Hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 4-hydroxy-1,5-dimethyl-3-pyridinecarboxylic acid (DQ715) were synthesized and evaluated for possible application in iron and aluminium chelation therapy. Metal ion/ligand solution chemistry, electrochemistry, cytotoxicity and chelation efficiency in vitro were studied. The solution chemistry of each ligand with Fe-III or Al-III was investigated in aqueous NaCl solution (0.6 m) at 25 degrees C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI-MS and (in the case of Al-III) by H-1 NMR measurements. Accordingly, the effects of the 5-methyl substitution of 4-hydroxy-3-pyridinecarboxylic acid on the stability of Fe and Al complexes were rationalized. Electrochemical measurements allowed to obtain the standard reduction potentials of some Fe-III/DQ715 complexes and their kinetic constants. These results indicate that Fe-III/DQ715 complexes do not redox cycle in vivo and complex formation is not kinetically limited. The lack of cytotoxicity of DQ715 was demonstrated on human embryonic kidney cells (HEK-293): the IC50 values calculated from the dose-survival curves were 1.4 (after 24 h treatment) and 0.8 mmol/L (after 48 h treatment). The treatment of cells with DQ715 in the presence of Fe-III sensibly reduced antiproliferative activity promoted by the metal ion, which suggests an Fe-III chelate effect induced by DQ715. According to our results, DQ715 is a chelator for both metal ions, whereas DQ5 is more suitable as a selective Al chelator.