The comparative study of new proteasome inhibitors based on salicylic acid-modified pseudo-tripeptides terminated with aldehyde or vinylsulfone is presented. We described the synthesis of 11 pairs of pseudopeptides and their properties related to the proteasome inhibition were determined. The effects of integrated amino acids (combinations of leucine, phenylalanine, tryptophan, proline, cyclohexylalanine or norleucine residues) on the activity of the proteasome were investigated. Compounds preferentially inhibited the chymotrypsin β5-subunit of the proteasome in cell-based assays compared with the β1- and β2-subunits, with IC50 values in mid-nanomolar ranges being obtained for the most active members. Our comparative study demonstrated that aldehydes were able to inhibit the proteasome in cells more effectively than vinylsulfones. These results were corroborated by the accumulation of polyubiquitinated proteins in treated cells, GFP accumulation in a reporter cell line and the ability of new compounds to induce apoptotic cell death.

Department of Experimental Biology Faculty of Science Palacký University Šlechtitelů 27 78371 Olomouc Czech Republic

Department of Experimental Biology Faculty of Science Palacký University Šlechtitelů 27 78371 Olomouc Czech Republic; Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacký University Hněvotínská 5 77900 Olomouc Czech Republic

Institute of Organic Chemistry and Technology Faculty of Chemical Technology University of Pardubice Studentská 573 532 10 Pardubice Czech Republic

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