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Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial
José Teixeira1,2, Fernando Cagide1, Sofia Benfeito1
1CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto , Porto 4169-007, Portugal.
Abstract:
Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22-27) based on a dietary antioxidant (caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure-activity-toxicity-property relationships, and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants. In general, AntiOxCINs derivatives prevented lipid peroxidation and acted as inhibitors of the mitochondrial permeability transition pore. AntiOxCINs toxicity profile was found to be dependent on the structural modifications performed on the dietary antioxidant. On the basis of mitochondrial and cytotoxicity/antioxidant cellular data, compound 25 emerged as a potential candidate for the development of a drug candidate with therapeutic application in mitochondrial oxidative stress-related diseases. Compound 25 increased GSH intracellular levels and showed no toxicity on mitochondrial morphology and function.
Insights
Researchers developed novel mitochondriotropic antioxidants (AntiOxCINs) based on caffeic acid to combat mitochondrial oxidative stress. Compound 25 showed promise as a therapeutic candidate, effectively reducing oxidative damage without harming mitochondria.
Area of Science:
- Biochemistry
- Pharmacology
- Mitochondrial Medicine
Background:
- Mitochondrial oxidative stress contributes to various diseases.
- Targeting mitochondria with antioxidants is a promising therapeutic strategy.
- Caffeic acid is a known dietary antioxidant.
Purpose of the Study:
- To rationally design and synthesize novel mitochondriotropic antioxidants (AntiOxCINs).
- To evaluate the antioxidant activity, mitochondrial targeting, and toxicity of AntiOxCINs.
- To identify a potential drug candidate for treating mitochondrial oxidative stress-related diseases.
Main Methods:
- Design and synthesis of caffeic acid-based mitochondriotropic compounds (AntiOxCINs).
- Assessment of structure-activity-toxicity-property relationships.
- Evaluation of lipid peroxidation inhibition and mitochondrial permeability transition pore modulation.
- In vitro cytotoxicity and mitochondrial function assays.
Main Results:
- Novel AntiOxCINs were successfully synthesized and demonstrated mitochondriotropic antioxidant activity.
- Most AntiOxCINs prevented lipid peroxidation and inhibited the mitochondrial permeability transition pore.
- Compound 25 exhibited a favorable toxicity profile, increased intracellular GSH levels, and preserved mitochondrial morphology and function.
- Toxicity was dependent on structural modifications of the parent compound.
Conclusions:
- Novel AntiOxCINs are effective mitochondriotropic antioxidants.
- Compound 25 is a promising drug candidate for therapeutic intervention in diseases linked to mitochondrial oxidative stress.
- The design strategy effectively leveraged triphenylphosphonium cations for mitochondrial targeting.
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