Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1α prolyl hydroxylases-1, -2, and -3 with altered selectivity

J Comb Chem. 2010 Sep 13;12(5):676-86. doi: 10.1021/cc100073a.


Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1α, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool. Although several chemical series of PHD inhibitors have been described, significant isoform selectivity has not been reported. Here we report the synthesis and activity of dipeptidyl analogues derived from a potent but non-selective quinolone scaffold. The compounds were prepared by Pd-catalyzed reductive carbonylation of the 6-iodoquinolone derivative to form the aldehyde directly, which was then attached to a solid support via reductive amination. Amino acids were coupled, and the resulting dipeptidyl-quinolone derivatives were screened, revealing retention of PHD inhibitory activity but an altered PHD1, 2, and 3 selectivity profile. The compounds were found to be ∼10-fold more potent against PHD1 and PHD3 than against PHD2, whereas the specific parent compound had shown no appreciable selectivity among the different PHD isoforms.

MeSH terms

  • Combinatorial Chemistry Techniques
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Isoenzymes / antagonists & inhibitors*
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Molecular Structure
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors*
  • Procollagen-Proline Dioxygenase / chemistry
  • Procollagen-Proline Dioxygenase / metabolism
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Dipeptides
  • Enzyme Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoenzymes
  • Quinolones
  • Procollagen-Proline Dioxygenase