Synthesis and biological evaluation of kresoxim-methyl analogues as novel inhibitors of hypoxia-inducible factor (HIF)-1 accumulation in cancer cells

Bioorg Med Chem Lett. 2017 Jul 1;27(13):3026-3029. doi: 10.1016/j.bmcl.2017.05.024. Epub 2017 May 9.

Abstract

We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC50 values of 0.60-0.94µM. Under hypoxic condition, compounds 11b, 11c, and 11d increased the intracellular oxygen contents, thereby attenuating the hypoxia-induced accumulation of HIF-1α protein.

Keywords: Cancer; Hypoxia-inducible factor-1 inhibitor; Kresoxim analogues; Mitochondrial respiration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • HCT116 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Methacrylates / chemical synthesis
  • Methacrylates / chemistry
  • Methacrylates / pharmacology
  • Molecular Structure
  • Phenylacetates / chemical synthesis
  • Phenylacetates / chemistry
  • Phenylacetates / pharmacology*
  • Strobilurins
  • Structure-Activity Relationship

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Methacrylates
  • Phenylacetates
  • Strobilurins
  • kresoxim-methyl