1029997-39-4Relevant academic research and scientific papers
A Minimal β-Lactone Fragment for Selective β5c or β5i Proteasome Inhibitors
Groll, Michael,Korotkov, Vadim S.,Huber, Eva M.,De Meijere, Armin,Ludwig, Antje
, p. 7810 - 7814 (2015)
Broad-spectrum proteasome inhibitors are applied as anticancer drugs, whereas selective blockage of the immunoproteasome represents a promising therapeutic rationale for autoimmune diseases. We here aimed at identifying minimal structural elements that confer β5c or β5i selectivity on proteasome inhibitors. Based on the natural product belactosin C, we synthesized two β-lactones featuring a dimethoxybenzyl moiety and either a methylpropyl (pseudo-isoleucin) or an isopropyl (pseudo-valine) P1 side chain. Although the two compounds differ only by one methyl group, the isoleucine analogue is six times more potent for β5i (IC50=14 nM) than the valine counterpart. Cell culture experiments demonstrate the cell-permeability of the compounds and X-ray crystallography data highlight them as minimal fragments that occupy primed and non-primed pockets of the active sites of the proteasome. Together, these results qualify β-lactones as a promising lead-structure motif for potent nonpeptidic proteasome inhibitors with diverse pharmaceutical applications.
Synthesis and biological activity of simplified belactosin C analogues
De Meijere, Armin,Korotkov, Vadim S.,Lygin, Alexander V.,Larionov, Oleg V.,Sokolov, Viktor V.,Graef, Tine,Es-Sayed, Mazen
, p. 6363 - 6374 (2012/09/05)
Successful biochemical studies of the natural products belactosin A and C and their acylated congeners have shown a β-lactonecarboxamide moiety to be a possible core structure of powerful proteasome inhibitors. As a part of further investigations, variously decorated simplified β- lactonecarboxamides have been synthesized in order to understand structure-biological activity relations in detail, to find ways of improving their biological activity and stability and to reduce the complexity of their preparation. Biological tests showed that the best compounds possess a high potential against phytopathogenic fungi in the greenhouse. The Royal Society of Chemistry 2012.
