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Synthesis of spin traps specific for hydroxyl radical
1Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 22710.
Journal of Medicinal Chemistry
|February 1, 1988
Summary
New nitrones, DEDMPO and M4PO, show increased lipophilicity and varied radical trapping abilities. M4PO traps both hydroxyl and superoxide radicals, while DEDMPO traps only hydroxyl radicals, aiding cellular metabolism studies.
Area of Science:
- Organic Chemistry
- Biochemistry
- Free Radical Chemistry
Background:
- Nitrones are crucial spin traps for detecting reactive oxygen species.
- Lipophilicity influences the efficacy and localization of spin traps.
- Understanding radical generation in cellular metabolism is vital for disease research.
Purpose of the Study:
- Synthesize novel lipophilic nitrones: 3,3-diethyl-5,5-dimethylpyrroline 1-oxide (DEDMPO) and 3,3,5,5-tetramethylpyrroline 1-oxide (M4PO).
- Evaluate their lipophilicity and spin trapping capabilities for hydroxyl and superoxide radicals.
- Investigate radical generation during endothelial cell metabolism of specific compounds.
Main Methods:
- Synthesis of DEDMPO and M4PO via reduction and Grignard addition.
- Determination of partition coefficients for lipophilicity assessment.
- Electron paramagnetic resonance (EPR) spin trapping to identify trapped radicals and measure hyperfine coupling constants.
Main Results:
- DEDMPO and M4PO exhibit significantly higher lipophilicity than DMPO.
- M4PO successfully spin traps both hydroxyl and superoxide radicals.
- DEDMPO selectively traps hydroxyl radicals.
- Cellular metabolism studies indicate superoxide generation from quinones and nitroaromatics, not hydroxyl radicals.
Conclusions:
- Novel lipophilic nitrones DEDMPO and M4PO offer enhanced spin trapping properties.
- Differential radical trapping by DEDMPO and M4PO provides mechanistic insights.
- Endothelial cell metabolism of quinones and nitroaromatics primarily generates superoxide radicals.