The ubiquitin-proteasome pathway represents an attractive target in the
development of new drug therapies.
In particular, the proteasome 26S, a multicatalytic threonine protease
complex, is involved in intracellular ubiquitinated-protein degradation and
many biological processes, such as cell cycle control and differentiation,
apoptosis and generation of antigenic peptides presented by major
histocompatibility complex class I (MHC I) molecules.
The activity of 26S proteasome is located in a central 20S core, the proteoliytic
chamber is composed of four stacked rings capped by two 19S regulatory
complexes. Each ring is composed for seven b subunits with three different
active sites: in particular, the b1 subunit contains a peptidyl-glutamyl peptide
hydrolizing active site (PGPH), the b2 subunit expresses tryptic-like (T-L)
activity, and b5 contains a chimotryptic-like (ChT-L) activity.
Modulation of the proteasome activity by specific inhibitors may represent an
useful tool for the treatment of tumors, metabolic and autoimmune disorders.
The aim of this PhD work is the design, sythesis and evaluation of the
biological activity of several classes peptide-based proteasome inhibitors,
containing different pharmacophoric moieties at the C-terminal position as a
potential substrate for Michael addiction by the catalytic threonine through a
mechanism similar to that of the well-known inhibitors.
Herein we reported studies of the molecules bearing as pharmacophoric Cterminal
function: N-allyl vinil ester, a,b-unsaturated N-acylpyrrole, vinyl
ketone, butadienyl vinyl ester, divinyl ketone and isoxazolin vinyl ester groups.
In accordance with the results obtained in previous series, the
pharmacophoric units are linked to oligopeptidic sequences functionalized at
the N-terminal by appropriated groups.
Biological evaluation of the all new compounds was carried out to assess their
inhibition of the trypsin-like, chymotrypsin-like and post-acidic activities of
proteasome using the isolated enzyme purified from lymphoblastoid cell lines.
Some compounds as a,b-unsaturated N-acylpyrrole and vinyl ketone analogs
showed selective inhibition of the proteasome subunits in a mM range, while
other derivatives bearing different pharmacophoric units don’t provide a
favorable biological response
