The speciations of two drug candidate ligands, 2-hydroxypyridine-N-oxide (Hhpno) and 2-mercaptopyridine-N-oxide (Hmpno), with vanadate (V(V)) were determined at 25.0 degrees C and 0.20 mol dm(-3) KCl by pH-metric and (51)V-NMR methods. At pH 7.4, the two predominant compounds with both ligands are the VO(2)L(2) and VO(2)L(OH). NH(4)[VO(2)(hpno)(2)] x 3 H(2)O was prepared in solid form, and its crystal structure was determined by X-ray diffraction. The stabilities of the complexes VO(2)L(2) of five drug candidate ligands were compared at pH 7.4. In view of the stability sequence hpno > maltol approximately hdp (Hhdp: 3-hydroxy-1,2-dimethyl-4-pyridinone) >> mpno > picolinic acid, the first two of these ligands were chosen for equilibrium studies with apotransferrin (apoTf) competition. The V(V)-apoTf stability constants (log K(1) = 6.03 +/- 0.10; log K(2) = 5.46 +/- 0.18) determined by (51)V-NMR spectroscopy were confirmed by ultrafiltration. Both methods proved that there seems to be no hydrogencarbonate-vanadate competition for the apoTf anion-binding positions. The other potential high molecular mass V(V) binder in the serum is human serum albumin (HSA). As no interaction was detected by (51)V-NMR spectroscopy or fluorimetry, the binding properties of HSA were quantified on the basis of literature data. As a final conclusion, speciation modeling calculations suggest that, under serum conditions, apoTf is probably the primary metal ion binder, even in the presence of the most stable V(V) carrier ligands hpno and maltol and HSA plays a negligible role in V(V) binding.

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Our objective is to illustrate the activity of the groups operating in Italy involved in identification and study of new chelating agents, mainly intended for treatment of human pathology correlated with metal overload. The objective of "chelation therapy" is removal of toxic metal ions from the human body or attenuation of their toxicity by transforming them into less toxic compounds or by dislocating them from the site at which they exert a toxic action. Because most of this research activity is related to chelating agents for iron and aluminium, diseases related to these two metal ions are briefly treated. Iron overload is the most common metal toxicity disease worldwide. The toxicity of aluminium in dialysis patients was a serious problem for haemodialysis units in the seventies and eighties of the last century. In particular, this review focuses on research performed by the group at Cagliari and Ferrara, and by that at Padova. The former is studying, above all, bisphosphonate and kojic acid derivatives, and the latter is investigating 3,4-hydroxypyridinecarboxylic acids with differently substituted pyridinic rings.

Electrospray ionization mass spectrometry (ESI-MS) is very often employed to study metal/ligand equilibria in aqueous solution. However, the ionization process can introduce perturbations which affect the speciation results in an unpredictable way. It is necessary to identify these perturbations in order to correctly interpret the ESI-MS speciation results. Aluminium(III)/1,6-dimethyl-4-hydroxy-3-pyridinecarboxylate (DQ716) aqueous solutions at various pH were analysed by ESI-MS, and speciation results were compared with those obtained by equilibrium techniques. Differences observed were both qualitative and quantitative. The ESI-MS spectral changes due to different settings of the following instrumental parameters were analyzed: the solution flow rate (F(S)), the nebulizer gas flow rate (F(G)), the potential applied at the entrance capillary (E(C)), and the temperature of the drying gas (T(G)). The effects produced by F(S) and E(C) on the spectra strongly suggest the key role of surface activity in determining the relative fraction of the ions reaching the detector. The experimental effects of F(S) and T(G) were interpreted considering the presence of at least two reactions in the gas phase and a dimerization occurring in the droplets. These perturbations cannot be generalized because they appear to be chemical system-related and instrument-dependent. Therefore, the identification of perturbations is a required task for any metal-ligand equilibrium study performed by ESI-MS. Our results indicate that perturbations can be identified by evaluating the effects produced in the spectra by a change of instrumental parameters.

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.