Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors

Bioorg Med Chem. 2014 Oct 1;22(19):5513-29. doi: 10.1016/j.bmc.2014.07.020. Epub 2014 Jul 30.


Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560 nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47 nM, respectively), and in vivo. Additionally, 43a (12.5-100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.

Keywords: Cancer; Hypoxia; Hypoxia-inducible factor-1; Inhibitor; Small molecule; Structure–activity relationships.

MeSH terms

  • Anilides / administration & dosage
  • Anilides / chemical synthesis
  • Anilides / chemistry*
  • Anilides / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Humans
  • Hypoxia-Inducible Factor 1 / antagonists & inhibitors*
  • Molecular Structure
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Anilides
  • Hypoxia-Inducible Factor 1
  • Small Molecule Libraries
  • benzanilide