Analysis of the structural and mechanistic factors in antioxidants that preserve mitochondrial function and confer cytoprotection

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 17; pp. 5188 - 5201
• Main Authors: Arce, Pablo M., Goldschmidt, Ruth, Khdour, Omar M., Madathil, Manikandadas M., Jaruvangsanti, Jennifer, Dey, Sriloy, Fash, David M., Armstrong, Jeffrey S., Hecht, Sidney M.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.09.2012; Elsevier
• Subjects: Animals; antagonists & inhibitors; antioxidant activity; Antioxidants; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Biochemistry & Molecular Biology; Biological and medical sciences; Cattle; Cell Survival; Cell Survival - drug effects; chemical synthesis; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Cytoprotection; Cytoprotection - drug effects; Dose-Response Relationship, Drug; drug effects; Drugs; Electron transport chain; enzymology; Humans; Idebenone; Life Sciences & Biomedicine; Lipid Peroxidation; Lipid Peroxidation - drug effects; Lymphocytes; Lymphocytes - drug effects; Lymphocytes - metabolism; Medical sciences; metabolism; Mitochondria; Mitochondria, Heart; Mitochondria, Heart - drug effects; Mitochondria, Heart - enzymology; Mitochondria, Heart - metabolism; Mitochondrial dysfunction; Mitochondrial Membranes; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - metabolism; Molecular Structure; Multienzyme Complexes; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; NADH, NADPH Oxidoreductases; NADH, NADPH Oxidoreductases - antagonists & inhibitors; NADH, NADPH Oxidoreductases - metabolism; Neuroprotection; pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Pyridones; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Reactive Oxygen Species; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Science & Technology; Structure-Activity Relationship; Tumor Cells, Cultured; Electron transport chain; Idebenone; Reactive oxygen species; Mitochondrial dysfunction; OXIDATIVE STRESS; FRIEDREICHS-ATAXIA; REACTIVITY; NEURODEGENERATIVE DISEASES; PERMEABILITY TRANSITION; COMPLEX-I; GLUTATHIONE; DYSFUNCTION; RESPIRATORY COMPLEXES; Oxidative stress; Psychotropic; Quinone; Benzoquinone derivatives; Antioxidant; Respiratory chain; Mitochondria; Cytoprotector; Nootropic agent; Cell respiration
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2012.07.005

Selected pyridinol analogues of the experimental neuroprotective drug idebenone have been synthesized and evaluated as antioxidants capable of preserving mitochondrial function. The compounds, having a different redox core but the same side chain as idebenone, exhibited a range of potencies, reflecting differences in their structures. The results obtained provide guidance in the design of such analogues with improved properties. Analogues were identified that have significantly improved antioxidant activity compared with idebenone in cultured lymphocytes, and which exhibit lesser inhibition of the electron transport chain.