title: Structure-activity relationship for branched oxyquinoline HIF activators: Effect of modifications to phenylacetamide "tail".
abstract: HIF prolyl hydroxylase is a major regulator of HIF stability. Branched tail oxyquinolines have been identified as specific inhibitors of HIF prolyl hydroxylase and recently demonstrated clear benefits in various scenarios of neuronal failure. The structural optimization for branched tail oxyquinolines containing an acetamide bond has been performed in the present study using HIF1 ODD-luc reporter assay. The special attention has been paid to the length of a linker between acetamide group and phenyl ring, as well as substitutions in the phenyl ring in the other branch of the tail. The optimized version of branched tail oxyquinolines is 3-fold more potent than the original one identified before and shows a submicromolar EC50in the reporter assay. The compounds have been studied in a "liver-on-a-chip" device to question their hepatotoxicity towards differentiated human HepaRG "hepatocytes": the absence of hepatotoxicity is observed up to 200 μM concentrations for all studied derivatives of branched tail oxyquinolines.
authors.affiliation: D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, 117997, Moscow, Russia. Electronic address: andrey.poloznikov@gmail.com.
authors.forename: A A
authors.initials: AA
authors.lastname: Poloznikov
authors.affiliation: BioClinicum Research and Development Center, Ugreshskaya 2, Bldg 85, Moscow, 115088, Russia.
authors.forename: A A
authors.initials: AA
authors.lastname: Zakhariants
authors.affiliation: D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, 117997, Moscow, Russia; Moscow Institute of Physics and Technology, Kerchenskaya 1A, 117303, Moscow, Russia.
authors.forename: S V
authors.initials: SV
authors.lastname: Nikulin
authors.affiliation: D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, 117997, Moscow, Russia.
authors.forename: N A
authors.initials: NA
authors.lastname: Smirnova
authors.affiliation: D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, 117997, Moscow, Russia.
authors.forename: D M
authors.initials: DM
authors.lastname: Hushpulian
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL, 60612, USA.
authors.forename: I N
authors.initials: IN
authors.lastname: Gaisina
authors.affiliation: BioClinicum Research and Development Center, Ugreshskaya 2, Bldg 85, Moscow, 115088, Russia.
authors.forename: A G
authors.initials: AG
authors.lastname: Tonevitsky
authors.affiliation: A.N. Bach Institute of Biochemistry, Federal Research Center "Fundamentals of Biotechnology" of Russian Academy of Sciences, Leninsky Prospect 33, 119071, Moscow, Russia; Department of Chemical Enzymology, Faculty of Chemistry, M.V.Lomonosov Moscow State University, Moscow, 119992, Russia; Innovation and High Technologies MSU Ltd, Tsymlyanskaya, 16, of 96, Moscow, 109599, Russia.
authors.forename: V I
authors.initials: VI
authors.lastname: Tishkov
authors.affiliation: D. Rogachev Federal Scientific and Clinical Center for Pediatric Hematology, Oncology, and Immunology, Samory Mashela 1, 117997, Moscow, Russia; Department of Chemical Enzymology, Faculty of Chemistry, M.V.Lomonosov Moscow State University, Moscow, 119992, Russia.
authors.forename: I G
authors.initials: IG
authors.lastname: Gazaryan
mesh_terms: D000081:Acetamides / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000737:chemistry; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015125:Oxyquinoline / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015125:Oxyquinoline; C030686:acetamide; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: 7-Substituted 8-hydroxyquinoline; HIF prolyl hydroxylase; HIF1 ODD-luc reporter; Hepatotoxicity; Liver-on-a-chip; Luciferase assay