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Keywords:

  • Iron;
  • Aluminum;
  • Medicinal chemistry;
  • Chelation therapy;
  • Cytotoxic­ity;
  • Potentiometry

Abstract

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 FeIII or AlIII was investigated in aqueous NaCl solution (0.6 m) at 25 °C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI-MS and (in the case of AlIII) by 1H 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 FeIII/DQ715 complexes and their kinetic constants. These results indicate that FeIII/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 FeIII sensibly reduced antiproliferative activity promoted by the metal ion, which suggests an FeIII 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.