Immunoproteasome is protease complex, which is very important in human body. It can be found mostly in cells of immune system, where its role is antigen presentation, synthesis and secretion of cytokines, and differentiation and proliferation of lymphocytes T. In non-physiological stress conditions its synthesis is induced in other cells too. When expression of immunoproteasome is too high, it leads to many diseases, such as inflammatory diseases, different types of cancers, autoimmune diseases, and neurodegenerative diseases. Inhibition of immunoproteasome is very important therapeutically. In the beginning of the century scientists were discovering mostly non-selective proteasome inhibitors, but in recent years researchers aim towards exploring and finding inhibitors, that work specifically on immunoproteasome. More selective drugs show less side effects, which are the consequence of non-selective inhibition. Active site of immunorpteasome is structural little different than constitutive proteasome. With change of substituents that bind into these sites we can provide selectivity to immunoproteasome.
In our research we prepared heteroarylamide derivatives of selective inhibitors of chymotrypsine-like catalytic subunit of immunoproteasome. We devised new molecules from previously prepared compounds, that contained piperidine ring and biphenyl or p-morpholine fragment, connected through methylene or carbonyl group. With replacement of biphenyl or p-morpholine ring with different heteroaryl moieties we tried to enhance potency and selectivity of our compounds and at the same time our intention was to improve their water solubility. We were planning to synthesize two chemically similar groups of compounds, piperidine(methyl)acrylamide derivatives and acryloylpiperidine derivatives. Through 4-stage synthesis that included reactions of formation amide bond and reactions of acidolysis, we managed to synthesize eleven final compounds. These compounds are similar in piperidine part and electrophilic group, but differ in aromatic part of molecule. All eleven compounds were biochemically tested in Faculty of Pharmacy as inhibitors of catalytically active β5i-unit of immunoproteasome. Unfortunately, none of the synthesized compounds showed inhibition of immunoproteasome, which means that we were unsuccessful in improving potency and selectivity. Otherwise, we improved water solubility of compounds, which helped us to carry out the testing.
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