Effects of alkyl side chain modification of coenzyme Q₁₀ on mitochondrial respiratory chain function and cytoprotection

The effect of the alkyl side chain length of coenzyme Q₁₀ on mitochondrial respiratory chain function has been investigated by the use of synthetic ubiquinone derivatives. Three analogues (3, 4 and 6) were identified that exhibited significantly improved effects on mitochondrial oxygen consumption a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-04, Vol.21 (8), p.2346-2354
Main Authors: Fash, David M, Khdour, Omar M, Sahdeo, Sunil J, Goldschmidt, Ruth, Jaruvangsanti, Jennifer, Dey, Sriloy, Arce, Pablo M, Collin, Valérie C, Cortopassi, Gino A, Hecht, Sidney M
Format: Article
Language:English
Subjects:
Animals
Cattle
Cell Line
Cell Line, Tumor
chemistry
Coenzyme Q10
Cytoprotection
Electron Transport - drug effects
Electron Transport - physiology
electron transport chain
glutathione
Humans
Leukemia - metabolism
Leukemia - pathology
maleates
mammals
membrane potential
Membrane Potential, Mitochondrial - drug effects
Mitochondria - drug effects
Mitochondria - metabolism
mitochondrial membrane
oxygen consumption
Oxygen Consumption - drug effects
Reactive Oxygen Species - metabolism
Retinal Ganglion Cells - cytology
Retinal Ganglion Cells - drug effects
Retinal Ganglion Cells - metabolism
Structure-Activity Relationship
Ubiquinone - analogs & derivatives
Ubiquinone - chemistry
Ubiquinone - metabolism
Ubiquinone - pharmacology
ubiquinones
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Summary:The effect of the alkyl side chain length of coenzyme Q₁₀ on mitochondrial respiratory chain function has been investigated by the use of synthetic ubiquinone derivatives. Three analogues (3, 4 and 6) were identified that exhibited significantly improved effects on mitochondrial oxygen consumption and mitochondrial membrane potential, and also conferred significant cytoprotection on cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate. The analogues also exhibited lesser inhibition of the electron transport chain than idebenone. The results obtained provide guidance for the design of CoQ₁₀ analogues with improved activity compared to that of idebenone (1), the latter of which is undergoing evaluation in the clinic as a therapeutic agent.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.01.075