Synthesis and biological evaluation of 1,2-dithiol-3-thiones and pyrrolo[1,2-a]pyrazines as novel hypoxia inducible factor-1 (HIF-1) inhibitor

Bioorg Med Chem. 2016 Jun 15;24(12):2843-51. doi: 10.1016/j.bmc.2016.04.054. Epub 2016 Apr 26.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor which is strongly associated with tumor survival, progression, and therapeutic resistance. Accordingly, it has been suggested that the inhibition of the HIF-1 pathway can suppress tumor, and it has become an important therapeutic target. In present study, oltipraz, its metabolite M2, and their derivatives were synthesized and evaluated as HIF-1α inhibitors. Among the synthesized, benzyl-substituted pyrrolo[1,2-a]pyrazine 2g most potently inhibited HIF-1α protein accumulation (81% at 10μM) and VEGF, GLUT-1 transcription (77% and 92% at 10μM, respectively).

Keywords: GLUT-1; Hypoxia inducible factor-1; Oltipraz; Pyrrolopyrazine; VEGF.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Glucose Transporter Type 1 / genetics
  • HCT116 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin / metabolism
  • Pyrazines / chemical synthesis
  • Pyrazines / chemistry*
  • Pyrazines / pharmacology*
  • Thiones / chemical synthesis
  • Thiones / chemistry*
  • Thiones / pharmacology*
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology*
  • Transcriptional Activation / drug effects
  • Vascular Endothelial Growth Factor A / genetics

Substances

  • Antineoplastic Agents
  • Glucose Transporter Type 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Insulin
  • Pyrazines
  • Thiones
  • Thiophenes
  • Vascular Endothelial Growth Factor A
  • oltipraz
  • 1,2-dithiol-3-thione