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

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.

Autoren

Laura Ielo
Vincenzo Patamia
Andrea Citarella
Thomas Efferth
Nasim Shahhamzehei
Tanja Schirmeister
Claudio Stagno
Thierry Langer
Antonio Rescifina
Nicola Micale
Vittorio Pace

DOI

10.3390/ijms232012363

eISSN

1422-0067

Ausgabe der Veröffentlichung

20

Zeitschrift

International Journal of Molecular Sciences

Sprache

en

Online publication date

2022

Paginierung

12363 - 12363

Status

Published online

Herausgeber

MDPI AG

Herausgeber URL

http://dx.doi.org/10.3390/ijms232012363

Datum der Datenerfassung

2022

Titel

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

Ausgabe der Zeitschrift

23

Data source: Crossref

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.

Addresses

Department of Chemistry, University of Turin, Via P. Giuria 7, 10125 Torino, Italy.

Autoren

Laura Ielo
Vincenzo Patamia
Andrea Citarella
Thomas Efferth
Nasim Shahhamzehei
Tanja Schirmeister
Claudio Stagno
Thierry Langer
Antonio Rescifina
Nicola Micale
Vittorio Pace

DOI

10.3390/ijms232012363

eISSN

1422-0067

Externe Identifier

PubMed Identifier: 36293216
PubMed Central ID: PMC9603864

Open access

true

ISSN

1422-0067

Ausgabe der Veröffentlichung

20

Zeitschrift

International journal of molecular sciences

Schlüsselwörter

Humans
Neoplasms
Aziridines
Proteasome Endopeptidase Complex
Ubiquitins
Antineoplastic Agents
Alkylating Agents
Proteasome Inhibitors

Sprache

eng

Medium

Electronic

Online publication date

2022

Open access status

Open Access

Paginierung

12363

Datum der Veröffentlichung

2022

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2022

Titel

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

Sub types

research-article
Journal Article

Ausgabe der Zeitschrift

23

Files

https://www.mdpi.com/1422-0067/23/20/12363/pdf?version=1665832387 https://europepmc.org/articles/PMC9603864?pdf=render

Data source: Europe PubMed Central

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.

Date of acceptance

2022

Autoren

Laura Ielo
Vincenzo Patamia
Andrea Citarella
Thomas Efferth
Nasim Shahhamzehei
Tanja Schirmeister
Claudio Stagno
Thierry Langer
Antonio Rescifina
Nicola Micale
Vittorio Pace

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/36293216

DOI

10.3390/ijms232012363

eISSN

1422-0067

Externe Identifier

PubMed Central ID: PMC9603864

Ausgabe der Veröffentlichung

20

Zeitschrift

Int J Mol Sci

Schlüsselwörter

anti-proliferative activity
aziridines
computational studies
in vitro assays
proteasome inhibitors
Humans
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Antineoplastic Agents
Aziridines
Neoplasms
Alkylating Agents
Ubiquitins

Sprache

eng

Country

Switzerland

PII

ijms232012363

Datum der Veröffentlichung

2022

Status

Published online

Datum, an dem der Datensatz öffentlich gemacht wurde

2022

Titel

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

Sub types

Journal Article

Ausgabe der Zeitschrift

23

Data source: PubMed

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

Files

Tools