RESUMEN
Given the recognized major problem of microbial drug resistance for human health, new metal-based drugs have been currently explored for their antimicrobial properties, including gallium-based compounds as potential metallophores that could perturb Fe's interactions with proteins. Herein we have designed and synthesized two bis-kojate ligands (named L4 and L6) and studied their Ga(III) complexes for their physico-chemical and biological properties. In particular a detailed study of their complexation properties in aqueous solution, showed equilibrium models with formation of quite stable dinuclear 2:3 metal:ligand complexes, though with different stability. Solid state complexes were also prepared and characterized and complementary DFT studies indicated that [Ga2(L4)3] complex, with higher stability, seems to adopt a three-ligand bridging conformation, while that for L6 adopt a one ligand bridging conformation. Preliminary investigation of the antibacterial activity of these gallium complexes showed antipseudomonal activity, which appeared higher for the complex with L4, a feature of potential interest for the scientific community.
Asunto(s)
Antibacterianos , Complejos de Coordinación , Galio , Pruebas de Sensibilidad Microbiana , Galio/química , Galio/farmacología , Antibacterianos/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , LigandosRESUMEN
Because of their capacity to bind metals, metal chelators are primarily employed for therapeutic purposes, but they can also find applications as colorimetric reagents and cleaning solutions as well as in soil remediation, electroplating, waste treatment, and so on. For instance, iron-chelation therapy, which is used to treat iron-overload disorders, involves removing excess iron from the blood through the use of particular molecules, like deferoxamine, that have the ability to chelate the metal. The creation of bioinspired and biodegradable chelating agents is a crucial objective that draws inspiration from natural products. In this context, starting from bioavailable molecules such as maltol and pyrogallol, new molecules have been synthetized and characterized by potentiometry, infrared spectroscopy and cyclic voltammetry. Finally, the ability of these to bind iron has been investigated, and the stability constants of ferric complexes are measured using spectrophotometry. These compounds offer intriguing scaffolds for an innovative class of versatile, multipurpose chelating agents.
Asunto(s)
Productos Biológicos , Quelantes del Hierro , Hierro , Terapia por Quelación , Colorimetría , LigandosRESUMEN
This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe3+, Al3+, Cu2+ and Zn2+ ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium. The stability of the formed complexes with Fe3+ and Al3+ are high enough to consider the new ligand for further studies for its clinical applications as a chelating agent. Biodistribution studies were carried out to assess the capacity the ligand for mobilization of gallium in 67Ga-citrate injected mice. These studies demonstrated that this ligand efficiently chelates the radiometal in our animal model, which suggests that it can be a promising candidate as sequestering agent of iron and other hard trivalent metal ions. Furthermore, the good zinc complexation capacity appears as a stimulating result taking into a potential use of this new ligand in analytical chemistry as well as in agricultural and environmental applications.
Asunto(s)
Quelantes del Hierro/farmacología , Piranos/farmacología , Pironas/farmacología , Aluminio/química , Animales , Cobre/química , Teoría Funcional de la Densidad , Femenino , Radioisótopos de Galio/química , Hierro/química , Quelantes del Hierro/síntesis química , Quelantes del Hierro/farmacocinética , Ratones , Modelos Químicos , Piranos/síntesis química , Piranos/farmacocinética , Pironas/síntesis química , Pironas/farmacocinética , Distribución Tisular , Zinc/químicaRESUMEN
This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe3+, Al3+, Cu2+ and Zn2+. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2. The different anchoring position of the linker, as well as the linker length, can affect both protonation and complex formation equilibria. A thorough study of the protonation and complex formation equilibria of the three ligands toward the metal ions is presented based on combined potentiometric and spectroscopic studies, and 1H NMR. The obtained results allow remarking that the orientation of the oxygen atoms in the kojic acid units, related to the anchoring position of the linker, strongly affects the protonation constants, while the chelating ability is practically unaffected. The trivalent metal ions form stable complexes with a 2:3 metal to ligand stoichiometry through the oxygen donor atoms of the ligands, whereas divalent metal ions form binuclear complexes for which the nitrogen atoms from the linker might be involved in the coordination sphere. The stability of the complexes decreases with linker length, and the selectivity of the ligands toward metal ions grows in the order Zn2+â¯<â¯Cu2+â¯<â¯Al3+â¯<â¯Fe3+.
Asunto(s)
Aluminio/química , Cobre/química , Compuestos Férricos/química , Zinc/química , Espectroscopía de Resonancia Magnética , Estructura MolecularRESUMEN
The reaction of the dimer [Rh(III)(pentamethylcyclopentadienyl)(µ-Cl)Cl]2 ([Rh(III)(Cp*)(µ-Cl)Cl]2) with the hydroxypyrone ligands maltol and allomaltol affords complexes of the general formula [Rh(III)(Cp*)(L)Cl] under standard and microwave conditions. The organometallic compounds were characterized by standard analytical methods and in the case of the allomaltol derivative in the solid state by single-crystal X-ray diffraction analysis. The complexes showed similar cytotoxicity profiles and were proved to be moderately active against various human cancer cell lines. The stoichiometry and stability of these complexes were determined in aqueous solution by pH-potentiometry, (1)H NMR spectroscopy and UV-visible spectrophotometry. Speciation was studied in the presence and in the absence of chloride ions. Hydrolysis of [Rh(III)(Cp*)(H2O)3](2+) gave dimeric mixed hydroxido species [(Rh(III)(Cp*))2(µ-OH)3](+) and [(Rh(III)(Cp*))2(µ-OH)2Z2] (Z=H2O/Cl(-)). Formation of the mononuclear complexes [Rh(III)(Cp*)(L)Z] of maltol and allomaltol with similar and moderate stability was found. These species predominate at physiological pH and decompose only partially at micromolar concentrations. In addition, hydrolysis of the aqua complex or a chlorido/hydroxido co-ligand exchange resulted in the formation of the mixed-hydroxido species [Rh(III)(Cp*)(L)(OH)] in the basic pH range. Replacement of the chlorido by an aqua ligand in the complex [Rh(III)(Cp*)(L)Cl] was monitored and with the help of the equilibrium constants the extent of aquation at various chloride concentrations of the extra- and intracellular milieu can be predicted. Complexation of these Rh(III) complexes was compared to analogous [Ru(II)(η(6)-p-cymene)] species and higher conditional stabilities were found in the case of the Rh(III) compounds at pH7.4.
Asunto(s)
Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Pironas/química , Rodio/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Estabilidad de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Cinética , Ligandos , Rutenio/química , Relación Estructura-ActividadRESUMEN
Attention is devoted to the role of chelating agents in the treatment of aluminium related diseases. In fact, in spite of the efforts that have drastically reduced the occurrence of aluminium dialysis diseases, they so far constitute a cause of great medical concern. The use of chelating agents for iron and aluminium in different clinical applications has found increasing attention in the last thirty years. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives containing two kojic units joined by different linkers. A huge advantage of these molecules is that they are cheap and easy to produce. Previous works on complex formation equilibria of a first group of these ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The aluminium(III) complex formation equilibria studied by potentiometry, electrospray ionization mass spectroscopy (ESI-MS), quantum-mechanical calculations and (1)H NMR spectroscopy are here described and discussed, and the structural characterization of one of these new ligands is presented. The in vivo studies show that these new bis-kojic derivatives induce faster clearance from main organs as compared with the monomeric analog.
Asunto(s)
Aluminio/química , Quelantes/química , Quelantes/farmacología , Animales , Quelantes/síntesis química , Quelantes/farmacocinética , Técnicas de Química Sintética , Femenino , Radioisótopos de Galio/farmacocinética , Ligandos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Pironas/química , Espectrometría de Masa por Ionización de Electrospray , Distribución TisularRESUMEN
The use of chelating agents for iron and aluminum in different clinical applications has found increasing attention in the last thirty years. Desferal, deferiprone and deferasirox, chelating agents nowadays in use, are based on hydroxamic groups, hydroxyl-substituted pyridinones or aromatic ring systems. With the aim of designing new chelators, we synthesized a series of kojic acid derivatives composed by two kojic units joined by linkers variously substituted. The huge advantages of these molecules are that they are easy and cheap to produce. Preliminary works on complex formation equilibria of the first group of ligands with iron and aluminium highlighted extremely good pMe values and gave evidence of the ability to scavenge iron from inside cells. On these bases a second set of bis-kojic ligands, whose linkers between the kojic chelating moieties are differentiated both in terms of type and size, has been designed, synthesized and characterized. The structural characterization of these new ligands is presented, and the protonation and iron(III) complex formation equilibria studied by potentiometry, UV-Visible spectrophotometry, electrospray ionization mass (ESI-MS) and (1)H NMR spectroscopy will be described and discussed.