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Possible Chelating Agents for Iron and Aluminium – 4‐Hydroxy‐5‐methyl‐ and 4‐Hydroxy‐1,5‐dimethyl‐3‐pyridinecarboxylic Acid
Author(s) -
Dean Annalisa,
Sija Éva,
Zsigó Éva,
Ferlin Maria Grazia,
Marton Daniele,
Gandin Valentina,
Marzano Cristina,
Badocco Denis,
Pastore Paolo,
Venzo Alfonso,
Bertani Roberta,
Kiss Tamás,
Di Marco Valerio
Publication year - 2013
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201201040
Subject(s) - chemistry , chelation , potentiometric titration , metal , electrochemistry , ligand (biochemistry) , aqueous solution , inorganic chemistry , metal ions in aqueous solution , redox , nuclear chemistry , medicinal chemistry , ion , organic chemistry , electrode , receptor , biochemistry
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 °C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI‐MS and (in the case of Al III ) by 1 H 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 IC 50 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.