The ubiquitin proteasome system has a very important role in cells, because it allows about 80 % of all proteins to be degraded. Proteasome, whose activity is greatly increased in certain diseases, has a key function in this system. In cells, during infections, the catalytic subunits of the proteasome transform to their induced isoforms, changes are also made in the regulatory subunit and immunoprotasome is formed. The action of the immunoproteasome is important in the formation of peptides that bind to the MHC I molecules. Proteasome is also involved in some diseases such as cancer, autoimmune diseases, neurodegenerative diseases and virus replication. Because in these cases, the proteasome activity is usually increased, it is an attractive therapeutic target. The development of active ingredients with inhibitory activity towards the proteasome started from simple peptides and boronates, continued with non-selective inhibitors all the way to selective inhibitors. With certain modifications in the structure of the substances greater selectivity may be achieved, thus leading to less undesired side effects and greater effectiveness of treatment.
Our goal was to synthesize eight final compounds, 1-(4-morpholinobenzoyl)piperidine inhibitors, which would target the β5i subunit of the imunoproteasome. With certain structural modifications we also tried to influence the solubility and therefore improve their potency and physico-chemical properties. We have divided our work in two parts, the first part comprising of the preparation of acetamide derivates and the second part, which comprises of the synthesis of acryloylamide derivates of 1-(4-morpholinobenzoyl)amino(methyl)piperidine. All eight final compounds were prepared in a three-step synthesis. Firstly, we used coupling agents to form an amide bond between the carboxylic group of 4-morpholinobenzoic acid and the amino group of the BOC-protected aminopiperidine or (aminomethyl)piperidine taking the “priority scale of binding” into account. Afterwards with acidolysis, we removed the protecting group on the second amine and once again performed N-acylation with acid and coupling reagents or N-acylation with acid chloride.
All of the eight final compounds were biochemicaly evaluated against β5i subunit of the immunoproteasome, however all the final compounds were inactive. Also, we did not satisfactory improve the solubility in any of the final compounds in the medium for biochemical evaluation, as they precipitated under evaluation conditions.
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