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

Int J Mol Sci. 2022 Oct 15;23(20):12363. doi: 10.3390/ijms232012363.

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.

Keywords: anti-proliferative activity; aziridines; computational studies; in vitro assays; proteasome inhibitors.

MeSH terms

  • Alkylating Agents
  • Antineoplastic Agents* / therapeutic use
  • Aziridines* / chemistry
  • Aziridines* / pharmacology
  • Humans
  • Neoplasms* / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use
  • Ubiquitins

Substances

  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex
  • Antineoplastic Agents
  • Aziridines
  • Alkylating Agents
  • Ubiquitins

Grants and funding

This research received no external funding.