Synthesis and characterization of mitoQ and idebenone analogues as mediators of oxygen consumption in mitochondria

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 17; pp. 6429 - 6441
• Main Authors: Duveau, Damien Y., Arce, Pablo M., Schoenfeld, Robert A., Raghav, Nidhi, Cortopassi, Gino A., Hecht, Sidney M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.09.2010; Elsevier
• Subjects: Antioxidants - chemical synthesis; Antioxidants - pharmacology; Biological and medical sciences; Cell structures and functions; Cytoprotection; Fundamental and applied biological sciences. Psychology; Glutathione - metabolism; Humans; Idebenone; Medical sciences; Miscellaneous; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria and cell respiration; Mitochondrial respiration; Molecular and cellular biology; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - pharmacology; Oxygen consumption; Oxygen Consumption - drug effects; Pharmacology. Drug treatments; Ubiquinone - analogs & derivatives; Ubiquinone - chemical synthesis; Ubiquinone - pharmacology; Ubiquinones; PPCDXNUUEBNVQC-UHFFFAOYSA-N; OIIMUKXVVLRCAF-UHFFFAOYSA-N; UQLZBRVPQAIQGR-UHFFFAOYSA-N; Oxygen consumption; Idebenone; JGPMMRGNQUBGND-UHFFFAOYSA-N; QVDQFOODKGSLRP-UHFFFAOYSA-N; IJSMMRLMQNSMGI-UHFFFAOYSA-N; JOWGTYQKFTXUSP-UHFFFAOYSA-N; CLVCBSVAECZIHD-UHFFFAOYSA-N; Mitochondrial respiration; Ubiquinones; Cytoprotection; Quinone; Benzoquinone derivatives; In vitro; Phosphorus Organic compounds; Quaternary phosphonium compound; Mitochondria; Cytoprotector; Structure activity relation; Chemical synthesis; Lymphocyte; Cell respiration
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.06.104

Analogues of mitoQ and idebenone were synthesized to define the structural elements that support oxygen consumption in the mitochondrial respiratory chain. Eight analogues were prepared and fully characterized, then evaluated for their ability to support oxygen consumption in the mitochondrial respiratory chain. While oxygen consumption was strongly inhibited by mitoQ analogues 2–4 in a chain length-dependent manner, modification of idebenone by replacement of the quinone methoxy groups by methyl groups (analogues 6– 8) reduced, but did not eliminate, oxygen consumption. Idebenone analogues 6– 8 also displayed significant cytoprotective properties toward cultured mammalian cells in which glutathione had been depleted by treatment with diethyl maleate.