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.

Novel Class of Proteasome Inhibitors: In Silico and In Vitro Evaluation of Diverse Chloro(trifluoromethyl)aziridines / L. Ielo, V. Patamia, A. Citarella, T. Efferth, N. Shahhamzehei, T. Schirmeister, C. Stagno, T. Langer, A. Rescifina, N. Micale, V. Pace. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 23:20(2022 Oct 15), pp. 12363.1-12363.12. [10.3390/ijms232012363]

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

A. Citarella;
2022

Abstract

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.
anti-proliferative activity; aziridines; computational studies; in vitro assays; proteasome inhibitors
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/951690
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