title: Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases.
abstract: As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψm) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation.
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Mohammad Parvez
authors.initials: MP
authors.lastname: Alam
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Khdour
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Arce
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Yana
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Basab
authors.initials: B
authors.lastname: Roy
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Walter G
authors.initials: WG
authors.lastname: Johnson
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States.
authors.forename: Sriloy
authors.initials: S
authors.lastname: Dey
authors.affiliation: Center for BioEnergetics, Biodesign Institute, and Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287, United States. Electronic address: sidney.hecht@asu.edu.
authors.forename: Sidney M
authors.initials: SM
authors.lastname: Hecht
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D011725:Pyridines; D017382:Reactive Oxygen Species
keywords: Cytoprotection; Lipid peroxidation; Microsomal stability; Mitochondria; Reactive oxygen species