Psoralen Derivatives as Inhibitors of Proteasome.

Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the proteasome in low micromolar concentrations. The best inhibitors, i.e., , , and , exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. -(cyanomethyl)acetamide ( = 5.6 µM) and carboxaldehyde-based derivative ( = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters and irreversibly inhibited the enzyme with values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, , is a noncompetitive irreversible inhibitor of the mycobacterial proteasome ( = 5.2 ± 1.9 µM, / = 96 ± 41 M·s). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.