Conception de dérivés 2-aryl-benzothiazoles pour la reconnaissance d'agrégats du peptide amyloïde-β par diverses approches physico-chimiques

Abstract : Alzheimer's disease (AD) is a neurodegenerative disease which is the most common cause of dementia in elderly people. It is proposed that it originates from the aggregation of amyloid-ß peptide (Aß), produced in the monomeric state, which is found as senile plaques in the brain of patients. During aggregation, the peptide is found in several forms, including oligomeric forms that are the most toxic to neurons. Although there is a wide variety of chemical structures used as probes for senile plaques, the development of tools to detect early forms of the aggregation process remains a major scientific challenge. To accomplish this, it is necessary to know, at the molecular level, the nature of the interaction site(s) between the probe and the peptide. This would allow the rational design of more specific ligands for each form of the Aß peptide (monomer, oligomer,...). As part of this thesis work, the development of modular syntheses of various derivatives of the 2-aryl-benzothiazole scaffold, known for its interaction with aggregates, was carried out. These derivatives allow the study of the aggregation and identification of the interaction site(s) by different techniques. During this work, the synthesis and study of four main 2-aryl-benzothiazole derivatives were carried out; (i) a derivative containing a secondary amine with interesting photophysical properties, obtained in 11 steps with an overall yield of 23%; (ii) a derivative with a ferrocene unit for electrochemistry studies, obtained with 13% yield in 11 steps; (iii) a derivative with a radical TEMPO moiety for EPR and NMR studies, obtained with a 16% yield in 10 steps; and (iv) a derivative with a diazirine unit obtained with an overall yield of 8% in 19 steps for photoaffinity labelling study (creation of a covalent bond after irradiation) followed by mass spectrometry analysis. In addition to the syntheses of these probes, preliminary results of studies conducted by fluorescence, electrochemistry, EPR, NMR and mass spectrometry will be presented in this manuscript.
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Alexandre Pocinho. Conception de dérivés 2-aryl-benzothiazoles pour la reconnaissance d'agrégats du peptide amyloïde-β par diverses approches physico-chimiques. Chimie de coordination. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30125⟩. ⟨tel-02276954⟩



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