Thiol-activated DNA damage by α-bromo-2-cyclopentenone
Mostafa I Fekry1, Nathan E Price, Hong Zang
1Department of Chemistry, University of Missouri, 125 Chemistry Building Columbia, Missouri 65211, United States.
Chemical Research in Toxicology
|January 22, 2011
Summary
This study reveals how thiols activate α-haloacrolyl compounds, forming reactive intermediates that damage DNA. Understanding this bioactivation mechanism is key for medicinal chemistry and toxicology.
Area of Science:
- Medicinal Chemistry
- Toxicology
- Organic Chemistry
Background:
- Biologically active chemicals can become DNA-damaging agents after cellular biotransformation.
- The α-haloacrolyl moiety is present in various cytotoxic natural products, mutagens, and anticancer drug candidates.
Purpose of the Study:
- To investigate the bioactivation mechanism of α-haloacrolyl-containing molecules by biological thiols.
- To elucidate the role of thiols in generating DNA-alkylating intermediates.
Main Methods:
- Utilized α-bromo-2-cyclopentenone as a model compound to study thiol interactions.
- Analyzed reaction products and DNA adducts using mass spectrometry.
- Investigated reaction sequence specificity and salt dependence.
Main Results:
- Biological thiols (low molecular weight and peptide) readily undergo conjugate addition to the model compound.
- A mechanism involving conjugate addition, intramolecular bromide displacement, and episulfonium ion formation was proposed.
- Thiol-activated compound formed labile lesions at deoxyguanosine residues in DNA.
Conclusions:
- Thiols can bioactivate α-haloacrolyl compounds through a specific mechanism involving episulfonium ions.
- This research provides insight into the molecular mechanisms of DNA damage and the biological activity of related compounds.
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