Psoralenquinones as a Novel Class of Proteasome Inhibitors: Design, Synthesis and Biological Evaluation

The proteasome is a complex machinery involved in the intracellular protein homeostasis, and its overexpression or deregulation may be 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 presents 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. All these activities are located in well-defined cavities and are mediated by N-terminal Threonine residues. Both peptidomimics and not-peptidomimics inhibitors have been to date discovered. Herein we present the design, synthesis and biological evaluation of novel proteasome inhibitors bearing the psoralenquinone structure. Depending on the scaffold decoration, it has been possible to obtain PGPH or CT/T selective inhibition. This feature was not previously observed for any other class 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. Cytotoxicity and inhibition of proteasome activity in 2008 cells have been also determined. Finally, a preliminary Structure Activity Relationship has been proposed. Depending on the scaffold decoration, the compounds demonstrated interesting subunit specificity. Interactions with Thr1, Thr21 and Ser129 are the keystone for the inhibition