1,6-Dimethyl-4-hydroxy-3-pyridinecarboxylic acid and 4-hydroxy-2-methyl-3-pyridinecarboxylic acid as new possible chelating agents for iron and aluminium

Abstract

1,6-Dimethyl-4-hydroxy-3-pyridinecarboxylic acid (DQ716) and 4-hydroxy-2-methyl-3-pyridinecarboxylic acid (DQ2) were evaluated for possible application to iron (Fe) and aluminium (Al) chelation therapy. Metal/ligand solution chemistry, electrochemistry, cytotoxicity, octanol/water partitioning (D(o/w)), and chelation efficiency, were studied. The Fe(iii)/DQ716, Fe(iii)/DQ2, Al(iii)/DQ716, and Al(iii)/DQ2 solution chemistry was investigated in aqueous 0.6 mol kg(-1) (Na)Cl at 25 degrees C by means of potentiometric titrations, UV-vis spectrophotometry, and (1)H-NMR spectroscopy. DQ716 exhibited the highest coordination efficiency towards Fe(iii) and Al(iii) among all hydroxypyridinecarboxylic acids examined so far, whereas DQ2 complexes were significantly less stable. These results were confirmed by chelation efficiency measurements performed in an octanol-aqueous solution in the presence of those ligands and metals. Partitioning experiments at pH 7.4 showed both DQ716 and DQ2, and their Fe(iii) and Al(iii) complexes, to be hydrophilic. According to the voltammetric data, the free ligands (DQ716 and DQ2) and their metal complexes are not predicted to undergo redox cycling at in vivo conditions. The standard reduction potentials of these complexes, and the kinetics of their formation and dissociation, were obtained. The toxicity of DQ716 and of DQ2 was investigated with human cancer cell lines and normal human fibroblasts. Cytotoxic effects were observed only for DQ2 at 0.1 mM, following 3 d exposure. According to our results, DQ716 has the required favourable properties to be a chelating agent for Fe and Al.

Perturbations produced by electrospray ionization mass spectrometry in the speciation of aluminium(III)/1,6‐dimethyl‐4‐hydroxy‐3‐pyridinecarboxylate aqueous solutions

“…No useful ESI‐MS signals were observed working in negative ion mode, apart from those of deprotonated DQ716 ( m / z 166) and, when added, of CF 3 COO − ( m / z 113). The absence of negative peaks related to Al(III)/DQ716 complexes was expected, as in solution they are neutral or positively charged 10. Therefore, all spectra were obtained in positive ion mode.…”

“…The NH(CH 2 CH 3 ) + peak (at m/z 102.131) is not observable at acidic pH but it becomes predominant at higher pH, as the solutions were basified by triethylamine additions. The absence of peaks related to the 1:1 aluminium‐ligand complex (AlL 2+ ), and the presence of a minor peak due to a dimer, are the qualitative differences observed between the results of ESI‐MS and of equilibrium techniques 10…”

“…1). The Al(III)/DQ716 solution chemistry has been already fully characterized by well‐established equilibrium techniques such as potentiometry, UV‐Vis, NMR, and chelation efficiency measurements 10. The presence of the complexes Al(DQ716) 2+ , Al(DQ716), and Al(DQ716) 3 was demonstrated.…”

“…The agreement between data obtained by a multimethodologic approach confirms the accuracy of those speciation results, which therefore will be considered as correct in the following discussion section. The importance of identifying and characterizing Al(III)/DQ716 complexes is related to the role of DQ716 as a new possible chelating agent for Al and Fe 10…”

Iron Chelating Agents for Iron Overload Diseases

“…Numerous studies on the design, synthesis and complex formation equilibria of variously substituted hydroxypyridinecarboxylic acids have been presented by the group of Di Marco: these ligands are characterized by two coordinating groups (-OH and -COOH) in various positions (2,3; 3,2; 3,4; 4,3) and differently methylated. [50][51][52][53][54][55] A study of our group on bisphosphonate ligands showed their high efficiency as iron chelating agents, reaching pFe values higher than that of deferiprone. 56 To further improve bisphosphonate chelating properties the conjugation with other strong coordinating groups was proposed.…”