Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors
| Autor: | Federica Mannino, Giuseppe Bruno, Rosaria Ottanà, Silvana Grasso, Santo Previti, Francesco Nicolò, Alexandra Naß, Gerhard Wolber, Ilenia Adornato, Rosanna Maccari, Maria Zappalà, Alessandra Bitto, Roberta Ettari, Federica Aliquò |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Clinical Biochemistry Pharmaceutical Science Imidazolidines Biochemistry Immunoproteasome Structure-Activity Relationship 03 medical and health sciences Proteasome Immunoproteasome 5-Arylidene-2-thioxoimidazolidin-4-ones Non-covalent inhibitors Docking studies Drug Discovery Non-covalent inhibitors Humans Docking studies Molecular Biology 5-Arylidene-2-thioxoimidazolidin-4-ones Biological evaluation Dose-Response Relationship Drug Molecular Structure Proteasome Chemistry Organic Chemistry Molecular Docking Simulation 030104 developmental biology Docking (molecular) Molecular Medicine Proteasome Inhibitors |
| Popis: | This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with Ki values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits. |
| Databáze: | OpenAIRE |
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