Abstract
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC50 values in the sub-µm range.
Highlights
The proteasome enzymatic complex is widely involved in the cytosolic and nuclear catabolism of most proteins behaving as a protease with multiple catalytic sites[1]
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division[3,4]
The synthesised compounds were evaluated for their potency in inhibiting the b1, b2 and b5 catalytic activities of the 20 S proteasome isolated from LCLs31
Summary
The proteasome enzymatic complex is widely involved in the cytosolic and nuclear catabolism of most proteins behaving as a protease with multiple catalytic sites[1]. The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division[3,4]. According to this system, the degradation of proteins is the result of their conjugation with multiple ubiquitin units that allow the recognition by the 26 S proteasome. The 26 S proteasome is composed of multiple subunits and is characterised by a central 20 S core and two distal regions (19 S) displaying regulatory activity. The 20 S core exerts three typical catalytic activities that are located in the b1 (the peptidyl glutamyl peptide hydrolysing activity, PGPH), b2 (the trypsin-like activity, T-L) and b5 (the chymotrypsin-like, ChT-L) subunits[5]. Any alteration of this system may result in important pathologies, including cancer
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