Discovery of bicyclo[3,3,1]non-2-ene as a novel skeleton for HIF-1 inhibitors

Bioorg Med Chem. 2018 Jul 23;26(12):3345-3351. doi: 10.1016/j.bmc.2018.05.002. Epub 2018 May 3.

Abstract

Bicyclo[3,3,1]non-2-ene was used as a novel three-dimensional skeleton for the design and synthesis of hypoxia-inducible factor (HIF)-1 inhibitors. Among the compounds synthesized, compound 4b was found to be a potent inhibitor of HIF-1α protein accumulation under hypoxia and inhibited HIF-1α transcriptional activity in HeLa (human cervical carcinoma) cells (half maximal inhibitory concentration [IC50] = 3.0 μM). The inhibition of HIF-1α accumulation induced by compound 4b was attenuated by treating the cells with MG132, a proteasome inhibitor, in a concentration-dependent manner, indicating that the compound 4b induces oxygen-independent proteasomal degradation of HIF-1α.

Keywords: Hypoxia inducible factor (HIF)-1α; Inhibitor; Proteasomal degradation; Transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bridged Bicyclo Compounds / chemical synthesis
  • Bridged Bicyclo Compounds / chemistry*
  • Bridged Bicyclo Compounds / pharmacology
  • Drug Design
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Leupeptins / pharmacology
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Endopeptidase Complex / metabolism
  • Transcription, Genetic / drug effects

Substances

  • Bridged Bicyclo Compounds
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Leupeptins
  • bicyclo(3.3.1)nonane
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde