Psoralenquinone proteasome inhibitors: design, synthesis and biological evaluation

Proteasome is an emerging target for novel drugs development. Proteasome in fact is a complex machinery involved in the intracellular protein homeostasis, and its overexpression or deregulation could been involved in cancer onset and progression or in inflammatory diseases. Human 26S proteasome is a cylinder-shaped multimeric protein complex composed by a 20S proteasome core particle (which present the catalytic activities) and a 19S component (which is involved in activity regulation). Three proteolytic activities have been to date recognized in the 20S proteasome as function of cleavage preferences: chymotripsin-like (CT), trypsin-like (T) and peptidyl-glutamyl-peptide-hydrolising (PGPH). All these activities are located in well-defined cavities and are mediated by N-terminal Threonine residues. Several peptidomimics inhibitors have been to date developed and cocrystallized with the 20S subunit. One of them, Bortezomib, have received FDA approval in 2004 for anticancer therapy. More recently several non-peptidomimics inhibitors have been individuated through virtual screening approach. Herein we present the discovery, synthesis and biological evaluation of novel proteasome inhibitors bearing psoralenquinone structure. Depending on the scaffold decoration it has been possible to obtain PGPH selective inhibitors and CT/T selective inhibitors. This chance was not previously observed for any other classes of derivatives until developed. All compounds have been designed through a multi-docking approach and have been evaluated for their ability to inhibit the degradation of specific peptides. All biological data have been compared with those relative to Bortezomib and Lactacystin. Finally, a preliminary Structure Activity Relationship have been proposed.