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.
Young Hun Lee  1 ,  Jung Min Lee  2 ,  Sang Geon Kim  2 ,  Yong Sup Lee  3
Affiliations
  • 1. Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 2. Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 3. Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: [email protected].
PMID: 27157007 DOI: 10.1016/j.bmc.2016.04.054
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.
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