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Identification of 2-thioxoimidazolidin-4-one derivatives as novel noncovalent proteasome and immunoproteasome inhibitors.
Maccari, Rosanna; Ettari, Roberta; Adornato, Ilenia; Naß, Alexandra; Wolber, Gerhard; Bitto, Alessandra; Mannino, Federica; Aliquò, Federica; Bruno, Giuseppe; Nicolò, Francesco; Previti, Santo; Grasso, Silvana; Zappalà, Maria; Ottanà, Rosaria.
  • Maccari R; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
  • Ettari R; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy. Electronic address: rettari@unime.it.
  • Adornato I; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
  • Naß A; Department of Pharmaceutical and Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
  • Wolber G; Department of Pharmaceutical and Medicinal Chemistry, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
  • Bitto A; Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy.
  • Mannino F; Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy.
  • Aliquò F; Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy.
  • Bruno G; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy.
  • Nicolò F; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy.
  • Previti S; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
  • Grasso S; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
  • Zappalà M; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
  • Ottanà R; Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Polo Annunziata, Viale SS. Annunziata, 98168 Messina, Italy.
Bioorg Med Chem Lett ; 28(3): 278-283, 2018 02 01.
Article en En | MEDLINE | ID: mdl-29292224
ABSTRACT
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 (ß5c) and immunoproteasome (ß5i and ß1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Imidazolidinas / Complejo de la Endopetidasa Proteasomal / Inhibidores de Proteasoma Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Año: 2018 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Imidazolidinas / Complejo de la Endopetidasa Proteasomal / Inhibidores de Proteasoma Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Año: 2018 Tipo del documento: Article