Structure-activity relationship for branched oxyquinoline HIF activators: Effect of modifications to phenylacetamide "tail"

Biochimie. 2017 Feb;133:74-79. doi: 10.1016/j.biochi.2016.12.004. Epub 2016 Dec 19.


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 EC50 in 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.

Keywords: 7-Substituted 8-hydroxyquinoline; HIF prolyl hydroxylase; HIF1 ODD-luc reporter; Hepatotoxicity; Liver-on-a-chip; Luciferase assay.

MeSH terms

  • Acetamides / chemistry
  • Gene Expression Regulation, Enzymologic / drug effects
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors
  • Hypoxia-Inducible Factor-Proline Dioxygenases / biosynthesis*
  • Neurons / drug effects
  • Neurons / metabolism
  • Oxyquinoline / chemistry*
  • Oxyquinoline / pharmacology
  • Structure-Activity Relationship


  • Acetamides
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Oxyquinoline
  • acetamide
  • Hypoxia-Inducible Factor-Proline Dioxygenases