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Synthesis and activity of isoxazoline vinyl ester pseudopeptides as proteasome inhibitors
Author(s) -
Marastoni Mauro,
Scotti Alessandra,
Trapella Claudio,
Ferretti Valeria,
Sforza Fabio,
Gavioli Riccardo
Publication year - 2014
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.2612
Subject(s) - proteasome , chemistry , ubiquitin , small molecule , peptide , biochemistry , enzyme , signal transduction , proteolysis , microbiology and biotechnology , biology , gene
The ubiquitin–proteasome pathway (UPP) influences essential cellular functions including cell growth, differentiation, apoptosis, signal transduction, antigen processing and inflammatory responses. The main proteolytic component of the UPP is the 26S proteasome, which is 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. We report herein the synthesis, proteasome inhibition and modelling studies of novel C‐terminal isoxazoline vinyl ester pseudopeptides. Some new compounds that contain a C‐terminal extended conjugation inhibit β 1 and especially β 5 proteasomal catalytic subunits with IC 50 values ranging from 10 to 100 µ m . These results will permit further optimization based on these structural moieties to develop more active and selective molecules. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.