Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands

J Med Chem. 2024 Apr 25;67(8):6081-6098. doi: 10.1021/acs.jmedchem.3c01036. Epub 2024 Feb 24.

Abstract

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,2'-Dipyridyl* / chemistry
  • 2,2'-Dipyridyl* / pharmacology
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology
  • Crystallography, X-Ray
  • Drug Resistance, Neoplasm / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Ligands
  • Phosphines* / chemistry
  • Phosphines* / pharmacology
  • Silver* / chemistry
  • Silver* / pharmacology
  • Structure-Activity Relationship

Substances

  • Phosphines
  • Antineoplastic Agents
  • Silver
  • 2,2'-Dipyridyl
  • Coordination Complexes
  • phosphine
  • Ligands