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Development of Chelators and Fluorescent Sensors for Deleterious Metals Implicated in Neurodegenerative Diseases


The recent approaches to Alzheimer’s and Parkinson’s diseases reflect the current concepts of copper(II) and iron(III) involvement in the ethiology of these disorders. Therefore, the development of imaging tools capable of sensing the distribution of these two deleterious metals as well as the design of novel treatment strategies are currently at the focus of attention. In my return project to the Faculty of Chemistry, University of Wroclaw, Poland, and in the framework of internationa l scientific collaborations, I would like to study new chelators designed to selectively bind copper(II) and iron(III) cations and to pass the blood-brain-barrier. A series of ligands possessing two or three bidentate groups based on oxygen and nitrogen do nor sets will be examined. The attachement of the fluorescent probes to these compounds or the presence of fluorescent binding sites will lead to a quenching process induced by the coordination of copper(II) and iron(III) and provide very sensitive analyti cal tool for the determination of traces of these cations. This phenomenon could also be used to image and localise accumulations of these metals in physiological tissues. A powerful combination of potentiometry, absorption and emission spectrophotometry a nd electrospray mass spectrometry will be used to determine the stoichiometry of the cupric and ferric complexes and the corresponding stability constants. Zn(II) and Ga(III) will be chosen as probes of Cu(II) and Fe(III) respectively for NMR measurements. Cyclic voltammetry will be used to determine the electrochemical properties of the metal complexes as well as the electron transfer mechanisms. The coordination processes of Cu(II) and Fe(III) with the newly synthesised ligands will be also determined by kinetic measurements in the milliseconds range. The predictive information given by the key steps will guide the strategy of synthesis of new ferric and cupric ligands and probes.

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