Progettazione, sintesi ed attività di inibitori del Proteasoma a base peptidica

The ubiquitin-proteasome pathway (UPP) influences essential cellular functions including cell growt, differetiation, apoptosis, signal transduction, antigen processind and inflammatory responses. Themain proteolytic component of the ubiquitin-proteasome pathway (UPP)is the 26S proteasome, responsible for the turnover of many cellular proteins and represents an attractive target for the treatment of pathologies such as cancer, as well as inflammatory, immune and neurodegenerative diseases.Natural and synthetic proteasome inhibitors having different chemical structures and potency have been discovered.In my PhD I worked on the design, synthesis and biological activity of molecules bearing pseudopeptidiche farmacoforiche different units at the C-terminus, as potential substrates for the interaction with the catalytic enzyme threonine, can inhibit specifically and selectively multicatalytic complex.Based on the data obtained from other series of inhibitors developed in our research group, which provided interesting biological results, I have designed and prepared based molecules peptides bearing new units farmacoforiche C-terminal, represented by groups isoxazolin vinyl-ester and dichloro- naftochinonici. Another series of derivatives instead, presents the methyl ester of trans-trans-muconic which pharmacophore linked to the side chain of a lysine residue common to all pseudo-tripeptides of the series.The new compounds were tested on the enzyme isolated based on their ability to inhibit three different catalytic activities of the proteasome: some of these, such as derivatives dichloro-naftochinonici, have shown a good ability of inhibition of the site post-acidic β1 and site chyme-tryptic β5.