title: Simplified bicyclic pyridinol analogues protect mitochondrial function.
abstract: Bicyclic pyridinol antioxidants have been reported to suppress the autoxidation of methyl linoleate more effectively than α-tocopherol in benzene solution. A few novel lipophilic analogues have recently been synthesized by conjugating a pyridinol core with the phytyl side chain of α-tocopherol; these have been shown to possess potent antioxidant activity. However, the complexity of the synthetic routes has hampered their further development. Herein, we describe a facile approach, involving only five synthetic steps, to simplified analogues (1a-1c) and their acetate ester precursors (2a-2c). Simple alkyl chains of different lengths were attached to the 6-methyl group of the antioxidant core via regioselective metalation. These analogues were found to retain biological activity and exhibit protective behaviour under conditions of induced oxidative stress, which could lead to the development of more readily accessible analogues as potential antioxidants capable of preserving mitochondrial function.
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Cai
authors.forename: Omar M
authors.initials: OM
authors.lastname: Khdour
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jaruvangsanti
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Hecht
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D055601:Organic Chemistry Phenomena; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D024502:alpha-Tocopherol / Q000031:analogs & derivatives
chemical_list: D000975:Antioxidants; D011725:Pyridines; D011728:Pyridones; D017382:Reactive Oxygen Species; C534143:4-pyridone; D024502:alpha-Tocopherol