Design, synthesis, and evaluation of indeno[2,1-c]pyrazolones for use as inhibitors against hypoxia-inducible factor (HIF)-1 transcriptional activity

Bioorg Med Chem. 2020 Jan 1;28(1):115207. doi: 10.1016/j.bmc.2019.115207. Epub 2019 Nov 9.

Abstract

HIF-1 is regarded as a promising target for the drugs used in cancer chemotherapy, and creating readily accessible templates for the development of synthetic drug candidates that could inhibit HIF-1 transcriptional activity is an important pursuit. In this study, indeno[2,1-c]pyrazolones were designed as readily available synthetic inhibitors of HIF-1 transcriptional activity. Nine compounds were synthesized in 4-5 steps from commercially available starting materials. In evaluations of the ability to inhibit the hypoxia-induced transcriptional activity of HIF-1, compound 3c showed a higher level compared with that of known inhibitor, YC-1. The compound 3c suppressed HIF-1α protein accumulation without affecting the levels of HIF-1α mRNA.

Keywords: Cancer chemotherapy; Fused-ring; Hypoxia-inducible factor-1; Indenopyrazolone; Pyrazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Molecular Structure
  • Pyrazolones / chemical synthesis
  • Pyrazolones / chemistry
  • Pyrazolones / pharmacology*
  • Structure-Activity Relationship
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics

Substances

  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Pyrazolones