Binding ability of bifunctional 3-hydroxy-4-pyridinone ligands towards divalent metal cations of biological interest

The 3-hydroxy-4-pyridinones are an important family of compounds that have been developed in view of several pharmaceutical applications, but mainly for metal-chelation therapy and for the detoxification of human body from hard metal cations, as the drug Deferiprone [1-3]. They represent a good alternative to the use of Deferoxamine [4], since they are effective in all biological conditions, not involving relevant undesired effects [5-8]. On the sequence of our previous studies on the ability of a set of five bifunctional 3-hydroxy-4-pyridinone ligands (L1-L5) for the Al3+ sequestration [8], the potential competition with biologically relevant divalent metal cations appears as a quite relevant issue. These ligands are derivatives of Deferiprone, thus featuring an aromatoid N-heterocyclic ring with a hydroxyl and a ketone group in ortho position, conferring them a high complexing ability towards M2+ and M3+ [9]. Furthermore, these 3-hydroxy-4-pyridinones are N-extrafunctionalized with alkyl-(amino-carboxylic) groups aimed to introduce differentiation in terms of pharmacokinetic parameters and potential interaction with proteins. Since the synthesis and acid-base properties were already reported, this contribution is focused on the results of a speciation study in aqueous solution in the presence of three divalent metal cations of biological interest, namely Ca2+, Cu2+, Zn2+. The investigation on the binding ability of the ligands towards Ca2+, Cu2+, Zn2+ was performed by means of potentiometric (ISE-H+), UV-Vis spectrophotometric and 1H NMR spectroscopic measurements at I = 0.15 mol L-1 in NaCl(aq) and T = 298.15 K. The elaboration of the experimental data led to the determination of speciation models consisting of MpLqHr species with different stoichiometry, considered the best possible ones on the base of some criteria, such as simplicity, probability, formation percentages of the species, statistical parameters and, if possible, literature data comparison. The stability constants (logβ) determined were in good agreement among the different analytical techniques and, as an example, for the common [ML](2-z) species the values follow the trend: Cu2+ > Zn2+ > Ca2+. Furthermore, the sequestering ability of the ligands towards the metal cations was investigated by the determination, at different pH conditions, of an empirical parameter, pL0.5, already proposed by the research group. It represents the total concentration of ligand required to sequester the 50% of the metal cation present in trace in solution [10].