A Fluorescent Benzo[g]isoquinoline-Based HIF Prolyl Hydroxylase Inhibitor for Cellular Imaging

ChemMedChem. 2019 Jan 8;14(1):94-99. doi: 10.1002/cmdc.201800483. Epub 2018 Dec 21.

Abstract

Prolyl hydroxylation domain (PHD) enzymes catalyze the hydroxylation of the transcription factor hypoxia-inducible factor (HIF) and serve as cellular oxygen sensors. HIF and the PHD enzymes regulate numerous potentially tissue-protective target genes which can adapt cells to metabolic and ischemic stress. We describe a fluorescent PHD inhibitor (1-chloro-4-hydroxybenzo[g]isoquinoline-3-carbonyl)glycine which is suited to fluorescence-based detection assays and for monitoring PHD inhibitors in biological systems. In cell-based assays, application of the fluorescent PHD inhibitor allowed co-localization with a cellular PHD enzyme and led to live cell imaging of processes involved in cellular oxygen sensing.

Keywords: HIF system; PHD inhibitors; fluorescence microscopy; hypoxia; oxygen sensing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzylisoquinolines / chemical synthesis
  • Benzylisoquinolines / chemistry
  • Benzylisoquinolines / pharmacology*
  • Biocatalysis / drug effects
  • Dose-Response Relationship, Drug
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology*
  • HeLa Cells
  • Humans
  • Molecular Imaging / methods*
  • Molecular Structure
  • Optical Imaging / methods*
  • Prolyl Hydroxylases / metabolism*
  • Prolyl-Hydroxylase Inhibitors / chemical synthesis
  • Prolyl-Hydroxylase Inhibitors / chemistry
  • Prolyl-Hydroxylase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Benzylisoquinolines
  • Fluorescent Dyes
  • Prolyl-Hydroxylase Inhibitors
  • Prolyl Hydroxylases