The eukaryotic proteasome is the centre of the ubiquitin-proteasome system, which is responsible for the regulation of different cellular processes and the protein homeostasis. We differentiate two major types of proteasomes. The constitutive proteasome is expressed in all eukaryotic cells while the immunoproteasome is expressed in haematopoietic cells and in other eukaryotic cells during acute stress and/or immune responses. Inhibitors of both proteasome types are being investigated as potential therapeutic approaches for various diseases, including neurodegenerative disorders. In recent years, advances in the understanding of the immunoproteasome and its pathophysiological functions enabled significant progress in the development of immunoproteasome inhibitors. At the Faculty of Pharmacy, compounds with a psoralen core are being investigated as selective immunoproteasome inhibitors. The initial lead compound was discovered through virtual screening of the ZINC compound library. This doctoral thesis describes the synthesis and biochemical evaluation of psoralen-based compounds with changes in the substituents at positions 3 and 4' of the psoralen core. We synthesised derivatives with improved selectivity for the [beta]5i subunit of the immunoproteasome. The synthesised compounds also provided information necessary to further describe the structure-activity relationships of the psoralen-based immunoproteasome inhibitors. This doctoral thesis also includes the development of compounds with the aim of simultaneously inhibiting the immunoproteasome, chelating metal ions and acting as antioxidants. This type of multitarget approach to treat neurodegenerative disorders has not yet been described. We developed an innovative synthesis route for a known selective immunoproteasome inhibitor (2-cyclohexyl-4-oxo-4-((7-(4-phenylthiazol-2-yl)quinolin-2-yl)amino)butanoic acid) and the synthesis of its 8-hydroxyquinoline derivative. The 8-hydroxyquinoline structural motif was incorporated for its metal chelating properties. The incorporation of this motif led to loss of inhibitory activity against the immunoproteasome but the results of this work, nevertheless, represent a good starting point for further development of compounds with the described multitarget approach for the treatment of neurodegenerative diseases.
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