Furan- and thiophene-2-carbonyl amino acid derivatives activate hypoxia-inducible factor via inhibition of factor inhibiting hypoxia-inducible factor-1

Shin ichi Kawaguchi, Yuhei Gonda, Takuya Yamamoto, Yuki Sato, Hiroyuki Shinohara, Yohsuke Kobiki, Atsuhiko Ichimura, Takashi Dan, Motohiro Sonoda, Toshio Miyata, Akiya Ogawa, Tadayuki Tsujita

Research output: Contribution to journalArticlepeer-review

Abstract

Induction of a series of anti-hypoxic proteins protects cells during exposure to hypoxic conditions. Hypoxia-inducible factor-α (HIF-α) is a major transcription factor that orchestrates this protective effect. To activate HIF exogenously, without exposing cells to hypoxic conditions, many small-molecule inhibitors targeting prolyl hydroxylase domain-containing protein have been developed. In addition, suppression of factor inhibiting HIF-1 (FIH-1) has also been shown to have the potential to activate HIF-α. However, few small-molecule inhibitors of FIH-1 have been developed. In this study, we synthesized a series of furan- and thiophene-2-carbonyl amino acid derivatives having the potential to inhibit FIH-1. The inhibitory activities of these compounds were evaluated in SK-N-BE(2)c cells by measuring HIF response element (HRE) promoter activity. Several furan- and thiophene-2-carbonyl amino acid derivatives inhibited FIH-1 based on correlations among the docking score of the FIH-1 active site, the chemical structure of the compounds, and biological HIF-α/HRE transcriptional activity.

Original languageEnglish
Article number885
JournalMolecules
Volume23
Issue number4
DOIs
Publication statusPublished - 2018

Keywords

  • Factor inhibiting hypoxia inducible factor
  • Furan
  • Hypoxia inducible factor
  • Thiophene

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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