1314531-75-3Relevant academic research and scientific papers
Design and NMR conformational analysis in solution of β5i-selective inhibitors of immunoproteasome
Rotondo, Archimede,Zappalà, Maria,Previti, Santo,Di Chio, Carla,Allegra, Alessandro,Ettari, Roberta
, (2020/11/24)
The identification of effective and selective immunoproteasome inhibitors could greatly promote smart treatment of many autoimmune, inflammatory and tumor diseases. This paper explores the activity of some pyridone derivatives which are taking advantage of peptide mimicking moieties and other functional groups whose related effects are taken into consideration. The target compounds were designed and synthesized starting from a lead, next their in vitro biological activity was tested; the following structural and conformational analysis sheds light over the different activity of the tested compounds. Compound 3 bearing a phenylalanine at the P2 site and an allyloxycarbonyl group spanning the P3 region, was found to be a selective inhibitor of β5 subunit of immunoproteasome. It has been demonstrated by Nuclear Magnetic Resonance (NMR) that, in solution, this substrate displays a more rigid conformation respect to the others, especially in apolar media, this feature is likely crucial for the enhancement of the activity towards immunoproteasome. The specific conformational analysis enables insights of the biological activity of new chemicals driving possible advancements based on the suitable structural features to identify novel selective β5 immunoproteasome inhibitor.
Development of Novel Peptidomimetics Containing a Vinyl Sulfone Moiety as Proteasome Inhibitors
Ettari, Roberta,Bonaccorso, Cinzia,Micale, Nicola,Heindl, Cornelia,Schirmeister, Tanja,Calabro, Maria Luisa,Grasso, Silvana,Zappala, Maria
, p. 1228 - 1237 (2012/04/18)
Proteasome inhibition is a topic of great interest in anticancer research. The proteolytic activity of this multicatalytic complex relies on three subunits, β1, β2 and β5, containing a caspase-like, a trypsin-like and a chymotrypsin-like active site, respectively. Several studies have demonstrated that, of the three activities, the chymotrypsin-like activity was the most necessary for cell viability and protein processing. Thus, most efforts towards the development of proteasome inhibitors have focused on the selective inhibition of the β5 subunit active site. Herein, we report the design and synthesis of a series of conformationally constrained tripeptidyl vinyl sulfones were determined to be good inhibitors of the chymotrypsin-like activity of proteasome, with KI values in the sub-micromolar to micromolar range. These compounds were also tested against bovine pancreatic α-chymotrypsin and human cathepsinB and L, revealing a good selectivity for the target enzyme over these related enzymes. Molecular straitjackets! Conformationally constrained tripeptidyl vinyl sulfones were identified as good inhibitors of proteasome chymotrypsin-like activity, with KI values in the sub-micromolar to micromolar range. Derivatives were also tested against bovine pancreatic α-chymotrypsin and human cathepsins B andL, revealing a good selectivity for the target enzyme.
