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Synthetic Methodology for Asymmetric Ferrocene Derived Bio-conjugate Systems via Solid Phase Resin-based Methodology
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CETZOLE Analogs as Potent Ferroptosis Inducers and Their Target Identification Using Covalent/Affinity Probes.

Samkeliso Dlamini1, Shahrzad Mohajeri1, Nishanth Kuganesan2

  • 1Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, 2801, W. Bancroft Street, Toledo, Ohio 43606, United States.

Journal of Medicinal Chemistry
|September 12, 2024
PubMed
Summary

New CETZOLE compounds induce ferroptosis (iron-dependent cell death) in cancer cells by increasing reactive oxygen species (ROS). These potent inducers target proteins involved in cellular antioxidant pathways, offering a promising cancer therapy strategy.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Ferroptosis is an iron-dependent cell death pathway involving lipid peroxidation.
  • Previous work identified CETZOLEs as ferroptosis inducers with low micromolar potency.

Purpose of the Study:

  • To develop more potent CETZOLE analogs for ferroptosis induction.
  • To investigate the molecular targets and cancer cell sensitivity of novel CETZOLEs.

Main Methods:

  • Structure-activity relationship studies to optimize CETZOLEs.
  • Cell-based assays to assess ferroptosis hallmarks (ROS accumulation, cell death).
  • Proteomic approaches (covalent/affinity probes) and Western blotting to identify and validate protein targets.

Main Results:

  • Developed highly potent CETZOLE analogs with nanomolar CC50 values.
  • CETZOLE treatment induced hallmarks of ferroptosis, including ROS accumulation.
  • Cancer cells exhibited greater sensitivity to CETZOLEs than normal cells.
  • Identified cystathionine β-synthase, peroxiredoxins, ADP/ATP carriers, and glucose dehydrogenase as CETZOLE-binding proteins, alongside GPX4.

Conclusions:

  • Novel CETZOLE derivatives are potent inducers of ferroptosis.
  • These compounds exhibit selective toxicity towards cancer cells.
  • CETZOLEs target key proteins within cellular antioxidant defense systems, highlighting a new therapeutic avenue for cancer treatment.