Speciation Studies of Bifunctional 3-Hydroxy-4-Pyridinone Ligands in the Presence of Zn2+ at Different Ionic Strengths and Temperatures.

The acid-base properties of two bifunctional 3-hydroxy-4-pyridinone ligands and their chelating capacity towards Zn2+, an essential bio-metal cation, were investigated in NaCl aqueous solutions by potentiometric, UV-Vis spectrophotometric, and 1H NMR spectroscopic titrations, carried out at 0.15 ≤ I/mol -1 ≤ 1.00 and 288.15 ≤ T/K ≤ 310.15. A study at I = 0.15 mol L-1 and T = 298.15 K was also performed for other three Zn2+/Lz- systems, with ligands belonging to the same family of compounds. The processing of experimental data allowed the determination of protonation and stability constants, which showed accordance with the data obtained from the different analytical techniques used, and with those reported in the literature for the same class of compounds. ESI-MS spectrometric measurements provided support for the formation of the different Zn2+/ligand species, while computational molecular simulations allowed information to be gained on the metal-ligand coordination. The dependence on ionic strength and the temperature of equilibrium constants were investigated by means of the extended Debye-Hückel model, the classical specific ion interaction theory, and the van't Hoff equations, respectively.

A new bis-3-hydroxy-4-pyrone as a potential therapeutic iron chelating agent. Effect of connecting and side chains on the complex structures and metal ion selectivity.

This work reports the synthesis, characterization and study of complex formation equilibria of the new ligand 6,6'-(2-(diethylamino)ethylazanediyl)bis(methylene)bis(5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) with Fe(III), Al(III), Cu(II) and Zn(II). On the basis of previous encouraging results with tetradentate bis-kojic acid chelators, this ligand was designed to improve the pharmacokinetic properties: increase the solubility, neutral at physiological pH7.4, and enhancement of membrane crossing ability. Fe(III) and Al(III) complexation gave evidence of high metal-sequestering capacity of L9. Cellular assays showed that the ligand is capable of crossing cellular membranes and it does not present toxic effects. Complex formation equilibria with the essential metal ions Cu(II) and Zn(II) have been furthermore studied to evaluate disturbances of this chelator on the homeostatic equilibria of these essential metal ions. A variety of techniques (potentiometry, UV-visible spectrophotometry, 1D and 2D NMR spectroscopy, ESI-MS (electrospray ionization-mass spectrometry), quantum mechanical calculations and X-ray diffraction) have facilitated the characterization of the ligand, and the corresponding iron and zinc complexes, together with an exhaustive analysis of the protonation and complex equilibria.

New tripodal hydroxypyridinone based chelating agents for Fe(III), Al(III) and Ga(III): Synthesis, physico-chemical properties and bioevaluation.

Two new tris-hydroxypyridinone based compounds (KEMPPr(3,4-HP)(3) and KEMPBu(3,4-HP)(3)) have been developed and studied as strong sequestering agents for iron and the group III of metal ions, aimed as potential pharmacological applications on metal-chelation therapy. Their structure is based on the KEMP acid scaffold to which three 3-hydroxy-4-pyridinone chelating moieties are attached via two different size spacers. After the preparation and characterization of the compounds their physico-chemical properties were studied, in relation with their metal binding affinity and lipophilicity. The KEMPPr(3,4-HP)(3) ligand was also bioassayed to evaluate its in vivo metal sequestering capacity from most organs using an animal model overload with (67)Ga. These studies showed that, for both in solution and in vivo conditions, the compounds have higher metal chelating efficacy than Deferriprone, the commercially available iron chelator in medical application, thus some perspectives are envisaged as potential pharmaceutical drug candidates for chelating therapy.

Combined chelation of bi-functional bis-hydroxypiridinone and mono-hydroxypiridinone: synthesis, solution and in vivo evaluation.

3-Hydroxy-4-pyridinones (3,4-HP) are well known iron-chelators with applications in medicinal chemistry, mainly associated with their high affinity towards trivalent hard metal ions (e.g. M(3+), M=Fe, Al, Ga) and use as decorporating agents in situations of metal accumulation. The polydenticity and the extra-functionality of 3,4-HP derivatives have been explored, aimed at improving the chelating efficacy and the selectivity of the interaction with specific biological receptors. However, the ideal conjugation of both features in one molecular unity usually leads to high molecular weight compounds which can have crossing-membrane limitations. Herein, a different approach is used combining a arylpiperazine-containing bis-hydroxypyridone (H(2)L(1)) with a biomimetic mono-hydroxypyridinone, ornithine-derivative (HL(2)), to assess the potential coadjuvating effect that could result from the administration of both compounds for the decorporation of hard metal ions. This work reports the results of solution and in vivo studies on their chelating efficacy either as a simple binary or a ternary system (H(2)L(1):HL(2):M(3+)), using potentiometric and spectrophotometric methods. The solution complexation studies with Fe(III) indicate that the solubility of the complexes is considerably increased in the ternary system, an important feature for the metal complex excretion, upon the metal sequestration. The results of the in vivo studies with (67)Ga-injected mice show differences on the biodistribution profiles of the radiotracer, upon the administration of each chelating agent, that are mainly ascribed to the differences of their extra-functional groups and lipo/hydrophilic character. However, administration of both chelating agents leads to a more steady metal mobilization, which may be attributed to an improved access to different cellular compartments.

A new bis(3-hydroxy-4-pyridinone)-IDA derivative as a potential therapeutic chelating agent. Synthesis, metal-complexation and biological assays.

A new bis(3-hydroxy-4-pyridinone) derivative of iminodiacetic acid, imino-bis(acetyl(1-(3'-aminopropyl)-3-hydroxy-2-methyl-4-pyridinone)), IDAPr(3,4-HP)(2), has been prepared and studied in its interaction with a set of hard metal ions. This tetradentate ligand presents a much higher chelating efficiency for trivalent hard metal ions (Fe, Ga, Al) than the monodentate derivative Deferriprone, namely at the diluted conditions prevailing in physiological conditions and at low clinical doses. A similar behaviour was also observed for the complexation with Zn(II) but at a significantly lower extent. This compound presents a moderate hydrophilic character at physiological pH (logD=-1.72). In vivo assays showed much more rapid clearance of (67)Ga from most tissues of metal-loaded mice than the drug Deferriprone and the radioactivity excretion occurs mostly through the kidneys. Therefore, results from in vitro and in vivo studies indicated good perspectives for this compound to be a potential decorporating agent for hard metal ions in overload situations without depletion of essential metal ions such as zinc.

Succinylhydroxamic derivatives of alpha-amino acids as MMP inhibitors. Study of complex-formation equilibria with Cu2+, Ni2+ and Zn2+.

A series of Pro- and Phe-succinyl hydroxamate derivatives, whose nanomolar inhibitory activity towards a series of matrix metalloproteinases (MMPs) was previously reported, have been studied and described herein in their interaction with Cu(2+), Zn(2+), Ni(2+) in aqueous solution, by using potentiometric, spectroscopic and ESI-MS (electrospray ionization mass) spectrometric techniques. A systematic study at various ligand-to-metal molar ratios allowed the determination of the stability constants of the complexes as well as the estimation of the coordination modes. The similarity in the biological activity of these compounds seems to be paralleled by the identical metal-complexation behaviour at neutral pH, namely in terms of chelating effectiveness and coordination modes, irrespective of the presence of one carboxylic or hydroxamate as extra groups, or also of the type of amino-acid residue at the other flank of the succinyl chain, which seems to be enough away from the succinyl hydroxamate metal-binding group. The stability order of the metal complexes with these ligands follows the Irving-Williams trend for this type of complex systems. Noteworthy is the identification of an interesting pentanuclear copper(II) species with the monohydroxamic ligands which structure was ascribed to a 12-metallacrown-4.