A Fluorescent Benzo[g]isoquinoline‐Based HIF Prolyl Hydroxylase Inhibitor for Cellular Imaging. (21st December 2018) - Mayer, Marleen
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. Abstract : Treating hypoxia/ischemia : A potent benzoisoquinoline‐based HIF prolyl hydroxylase inhibitor (HIF‐PHI) is described. The fluorescence features of the compound permit its application to HIF prolyl hydroxylase imaging in cells. This work will increase our understanding of HIF activation and the selectivity of prolyl hydroxylation domain (PHD) inhibitors for optimizing therapeutic strategies. These results will also be useful for future studies on the pharmacodynamics and pharmacokinetics of PHIs and should be adaptable to the study of other oxygenases.