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Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines

The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed...

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Detalles Bibliográficos
Autores principales: Ielo, Laura, Patamia, Vincenzo, Citarella, Andrea, Efferth, Thomas, Shahhamzehei, Nasim, Schirmeister, Tanja, Stagno, Claudio, Langer, Thierry, Rescifina, Antonio, Micale, Nicola, Pace, Vittorio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9603864/
https://www.ncbi.nlm.nih.gov/pubmed/36293216
http://dx.doi.org/10.3390/ijms232012363
Descripción
Sumario:The ubiquitin-proteasome pathway (UPP) is the major proteolytic system in the cytosol and nucleus of all eukaryotic cells. The role of proteasome inhibitors (PIs) as critical agents for regulating cancer cell death has been established. Aziridine derivatives are well-known alkylating agents employed against cancer. However, to the best of our knowledge, aziridine derivatives showing inhibitory activity towards proteasome have never been described before. Herein we report a new class of selective and nonPIs bearing an aziridine ring as a core structure. In vitro cell-based assays (two leukemia cell lines) also displayed anti-proliferative activity for some compounds. In silico studies indicated non-covalent binding mode and drug-likeness for these derivatives. Taken together, these results are promising for developing more potent PIs.