Complex formation equilibria of ligands with metal ions of biomedical interest

In a healthy situation, the body is provided with homeostatic mechanisms and buffers to maintain physiological concentrations of free metal ions, thus preventing their abnormal decompartmentalization, release and trafficking. The main reasons for the anomalous accumulation of non-essential metal ions in the body are environmental exposure and administration of metallodrugs for therapy or diagnosis, which may cause competition for biometals, generation of oxidative stress and disregulation of several metal-enzyme systems. Inorganic medicinal chemistry has to deal with the introduction of metal ions in the body, but also with their removal or passivation through the use of chelators. In these terms, thermodynamics and kinetics of complex formation are very important for a correct understanding of the role of metal ions in human diseases. During my PhD work, some new ligands were synthesized and their complex formation equilibria with toxic, essential and other metal ions of biomedical interest were studied. In particular, some derivatives of kojic acid have been synthesized and their protonation and chelating properties toward the target metal ions Fe3+ and Al3+, and the two essential Cu2+ and Zn2+ have been characterized. Furthermore, the complex formation equilibria of some drugs actually in clinical use with the essential metal ions Cu2+ and Zn2+ were studied to give evidence of their possible implications in copper chelation. Moreover, the tyrosinase inhibitory properties of the kojic derivative[1] (5-hydroxy-4-oxo-4H-pyran-2-yl)methyl3-({[(5-hydroxy-4-oxo-4H-pyran-2yl)methoxy]carbonyl} amino)propanoate and its complex formation equilibria with copper have been studied, since the inhibitory effect may result from the interaction with copper ions in the active center of the enzyme. This thesis is divided in an Introduction, dedicated to a description of metals, to their chemistry and their overload or deficiency, to chelation therapy, to the characteristics of chelators for metal overload treatment and to the improvements induced on some pathological conditions in diabetic patients. Further attention is devoted to tyrosinase inhibition and radiopharmaceutical labelling. An Experimental part describes the synthesis of new chelators and the methods used for a complete characterization. In the section Results and Discussion the determination of protonation constants for all ligands, together with that of their complex formation constants with metals of interest like Fe3+, Al3+, Ga3+, Cu2+ and Zn2+, is presented, in order to evaluate their therapeutic application in metal overload diseases. Complex stability studies of two new ligands with lanthanum to be used in the treatment of bone disorders are also presented as a part of a collaboration during my three month period at the University of British Columbia, Vancouver-Canada. A brief section Conclusions summarizes the presented results.