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Induction of the Endoplasmic Reticulum Stress Pathway by Highly Cytotoxic Organoruthenium Schiff-Base Complexes

Mun Juinn Chow1, Maria V Babak2, Kwan Wei Tan2

  • 1Centre for Translational Medicine , Cancer Science Institute of Singapore, National University of Singapore , MD6 Centre for Translational Medicine, 14 Medical Drive , 117599 Singapore.

Molecular Pharmaceutics
|July 7, 2018
PubMed

Insights

Researchers developed novel ruthenium(II)-arene Schiff-Base (RAS) complexes that induce cancer cell death by targeting the endoplasmic reticulum (ER). Structural modifications allow tuning of reactive oxygen species (ROS) induction for targeted ER stress pathways.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Inorganic Chemistry

Background:

  • Current chemotherapy primarily targets DNA, necessitating novel anticancer agents with distinct mechanisms.
  • Endoplasmic reticulum (ER) stress induction is an emerging strategy for cancer therapy, but limited compounds are available.
  • Rational design of ER stress-inducing agents requires further study of compound mechanisms.

Purpose of the Study:

  • To synthesize and characterize novel ruthenium(II)-arene Schiff-Base (RAS) complexes as potential anticancer agents.
  • To investigate the ability of these RAS complexes to induce endoplasmic reticulum (ER) stress and cancer cell death.
  • To explore the role of structural modifications in modulating the mechanism of action, specifically reactive oxygen species (ROS) induction.

Main Methods:

  • Synthesis and characterization of a series of Ru(II)-arene Schiff-Base (RAS) complexes with iminoquinoline ligands.
  • Evaluation of the cytotoxicity of the synthesized complexes against cancer cell lines.
  • Assessment of ER stress induction and cell death pathways, including ROS generation.
  • Structure-activity relationship studies involving modifications of the iminoquinoline ligand.

Main Results:

  • A series of highly cytotoxic RAS complexes capable of inducing ER stress were successfully synthesized.
  • Structural modifications to the iminoquinoline ligand influenced the π-acidity of the complexes.
  • The study demonstrated the ability to switch between ROS-mediated and non-ROS-mediated ER stress pathways through ligand tuning.
  • These findings highlight the potential for rational design of ER stress-inducing anticancer agents.

Conclusions:

  • The developed RAS complexes represent a promising new class of ER stress-inducing anticancer agents.
  • Structural modulation of iminoquinoline ligands offers a strategy to control the mechanism of action (ROS-dependent vs. independent).
  • This work contributes valuable insights for the rational design of novel endoplasmic reticulum-targeting cancer therapeutics.
Keywords:
anticancerendoplasmic reticulum stressp53-independent activityreactive oxygen speciesruthenium arene Schiff-base complexes

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