1. Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial Oxidative Stress Models.
- Author
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Teixeira J, Cagide F, Benfeito S, Soares P, Garrido J, Baldeiras I, Ribeiro JA, Pereira CM, Silva AF, Andrade PB, Oliveira PJ, and Borges F
- Subjects
- Animals, Antioxidants chemical synthesis, Antioxidants toxicity, Caffeic Acids chemical synthesis, Caffeic Acids toxicity, Glutamic Acid metabolism, Glutathione metabolism, Hep G2 Cells, Humans, Iron chemistry, Iron Chelating Agents chemical synthesis, Iron Chelating Agents pharmacology, Iron Chelating Agents toxicity, Lipid Peroxidation drug effects, Malates metabolism, Membrane Potential, Mitochondrial drug effects, Microsomes, Liver metabolism, Mitochondrial Membrane Transport Proteins antagonists & inhibitors, Mitochondrial Permeability Transition Pore, Rats, Succinic Acid metabolism, Antioxidants pharmacology, Caffeic Acids pharmacology, Mitochondria metabolism, Oxidative Stress drug effects
- 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.
- Published
- 2017
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