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.

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.

Metal-ligand solution equilibria studied by electrospray ionization mass spectrometry: effect of instrumental parameters.

Electrospray ionization mass spectrometry (ESI-MS) is being increasingly employed in the study of metal-ligand equilibria in aqueous solution. In the present work, the ESI-MS spectral changes due to different settings of the following instrumental parameters are analyzed: the solution flow rate (F(S)), the nebulizer gas flow rate (F(G)), the sprayer potential (E), and the temperature of the entrance capillary (T). Twenty-eight spectra were obtained for each of six samples containing aluminum(III) and 2,3-dihydroxypyridine at various pH, in the absence or in the presence of a buffer and of sodium ions. Among the considered instrumental parameters, T produced the largest effects on the ionic intensities. F(S) and F(G) affected the ESI-MS spectra to a lower extent than T. In the investigated conditions E had the weakest effects on the spectra.The correlations observed between the ionic intensities and these instrumental parameters were interpreted considering the presence of three kinds of perturbations occurring in the ESI-MS ion source: formation of some dimers in the droplets, different transfer efficiencies from the droplets to the gas phase for different complexes (according to their surface activity), and subsequent partial thermal decomposition of the dimers and of one of the monomeric complexes in the gas phase. Our results show that the evaluation of the effects produced in the ESI-MS spectra by a change of instrumental parameters can allow to identify the perturbations occurring when metal-ligand solutions are studied by ESI-MS.

Evaluation of 2-methyl-3-hydroxy-4-pyridinecarboxylic acid as a possible chelating agent for iron and aluminium.

In view of a possible application to Fe and Al chelation therapy, 2-methyl-3-hydroxy-4-pyridinecarboxylic acid (DT2) was synthesised, and its complex formation, electrochemical and cytotoxic properties were studied. The complexing properties of DT2 towards Fe(III) and Al(III) were investigated in aqueous 0.6 m (Na)Cl at 25 degrees C by means of potentiometric titrations, UV-vis spectrophotometry, and 1H NMR spectroscopy. DT2 is a triprotic acid (H3L+) having pKa1 = 0.47, pKa2 = 5.64 and pKa3 = 11.18. The metal-ligand complexes observed in solution and their corresponding stability constants (log beta values) are the following: FeLH (19.38), FeL (16.01), FeLH(-1) (12.28), FeL2H2 (37.29), FeL3H3 (53.41), FeL3H2 (47.99), FeL3H (41.21) and FeL3 (34.1); AlLH (17.43), AlL2H2 (33.74), AlL2H (27.6), AlL3H3 (48.72), AlL3H2 (42.67), AlL3H (35.8) and AlL3 (27.92). The complex formation between DT2 and Fe(II) was studied by UV-vis: the weak complex FeLH (log beta = 15.8) was detected. DT2 shows a lower complexation efficiency with Fe(III) and Al(III) than that of other available chelators, but higher than that of its non-methylated analogue 3-hydroxy-4-pyridinecarboxylic acid (DT0). The electrochemical behaviour of DT2 was investigated by means of cyclic voltammetry, indicating that the oxidation of the ligand proceeds through a two electron process with a CECE mechanism. Voltammetric curves suggest that the oxidation or the reduction of DT2 in vivo is unlikely. According to the thermodynamic data, also the Fe(III)-DT2 complexes do not undergo redox cycling at physiological pH. Amperometric titrations of solutions containing Fe(III) and DT2 at pH = 5 indicated the same Fe(III) : ligand stoichiometric ratio as calculated from potentiometric data. The toxicity of DT2 and of other simple hydroxypyridinecarboxylic acids was investigated in vitro and no cytotoxic activity was observed (IC50 > 0.1 mM) on cancer cell lines and also on primary human cells, following a three day exposure.

Metal-ligand solution equilibria studied by electrospray ionization mass spectrometry: correlation between ion intensity and acid-base equilibria in solution.

Electrospray ionization mass spectrometry (ESI-MS) is increasingly used in the study of metal-ligand equilibria in aqueous solutions. However, the correlation between conditions in solution and mass spectra in the gas phase is far from being completely established. In the present work the equation i = kC(0)f was used to correlate relative ion intensity (i) in an ESI mass spectrum, the stoichiometric concentration (C(0)) in solution of the complex which produced this ion, and the fraction (f) of complex having the same protonation state as that of the ion detected in the spectrum. This equation takes into account that metal-ligand complexes have acid-base properties, and that these properties affect the efficiency by which the ions are brought from the solution to the gas phase. The equation was experimentally checked by electrospraying solutions containing aluminium(III) and any of the four ligands 3,4-dihydroxybenzoic acid, 3-hydroxy-2-(1H)pyridinone, citric acid, and ethylenediaminetetramethylenephosphonic acid at different pH values. ESI-MS experimental i values and C(0)f values calculated from literature data were plotted versus the solution pH. Values are correlated in the majority of cases, thus confirming the validity of the approach proposed. Correlation is lost, as expected, for low f or C(0) values, and when extensive gas-phase reactions occur. The equation i = kC(0)f can be used to estimate quantitative data for unknown metal-ligand solutions analyzed by ESI-MS.

Electrospray mass spectrometry (ESI-MS) in the study of metal-ligand solution equilibria.

In the 20 years, since the introduction of electrospray mass spectrometry (ESI-MS), the use of this technique in various fields of inorganic, organometallic, and analytical chemistry has been steadily increasing. In this study, the application of ESI-MS to the study of metal-ligand solution equilibria is reviewed (till 2004 included). In a first section, advantages and drawbacks of ESI-MS in this type of application are described. Subsequently, a list of ca. 300 studies is reported, in which ESI-MS was used to give number and stoichiometry of the species at equilibrium, or also to estimate their stability constants. All studies are classified according to the metal ions under examination. Other related applications, such as host-guest interactions and metal ion-protein binding studies, are briefly reviewed as well.

Electrospray ionization mass spectrometry in studies of aluminium(III)-ligand solution equilibria.

Electrospray ionization mass spectrometry (ESI-MS) has been applied to the study of solution equilibria between Al(III) and the two ligands 4-hydroxy-3-pyridinecarboxylic acid (4H3P) and 3-hydroxy-4-pyridinecarboxylic acid (3H4P). The results compare well with the speciation data obtained from potentiometric, UV-visible spectroscopy, and NMR measurements. This agreement suggests the applicability of ES-MS to the study of more complicated aluminium-ligand systems.

Chemical characterisation, plant remain analysis and radiocarbon dating of the Venetian "Manna di San Nicola".

A sample of oil coming from the case containing the relics of St. Nicholas the Great, preserved in the church of "San Nicolò al Lido" (Venice, Italy), has been characterised by the determination of its chemical composition, its age (radiocarbon dating) and the presence of particles of biological origin. Experimental results show that the sample is a vegetal oil, with a fatty acids composition modified by natural oxidation processes, containing pollen grains of plants from Northern Italy, and dating around 1300 A.D. These results together with an historical and artistic evaluation of the ceramic jar containing the oil, allow us to hypothesise that the jar was introduced into the case after the arrival of the relics in Venice (1100 A.D.) during one of the official inquisitions prior to that documented in 1399 A.D.