Naphthoquinone amino acid derivatives, synthesis and biological activity as proteasome inhibitors.
Mauro MarastoniClaudio TrapellaAlessandra ScottiAnna FantinatiValeria FerrettiErika MarzolaGallerani EleonoraRiccardo GavioliDelia PretiPublished in: Journal of enzyme inhibition and medicinal chemistry (2017)
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.
Keyphrases
- amino acid
- multiple myeloma
- structure activity relationship
- oxidative stress
- single cell
- endoplasmic reticulum stress
- cell death
- small molecule
- cell therapy
- squamous cell
- stem cells
- cell cycle arrest
- atomic force microscopy
- cell proliferation
- mesenchymal stem cells
- high resolution
- combination therapy
- drug discovery
- high speed
- smoking cessation