Development of hypoxia-inducible factor (HIF)-1α inhibitors: Effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia

Hiroyuki Nakamura, Yuka Yasui, Minako Maruyama, Hidemitsu Minegishi, Hyun Seung Ban, Shinichi Sato

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI50) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC50: 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC50: 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC50: 10.9 ± 0.63 μM).

Original languageEnglish
Pages (from-to)806-810
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number3
DOIs
Publication statusPublished - 2013 Feb 1
Externally publishedYes

Keywords

  • Angiogenesis
  • Hsp60
  • Hypoxia-inducible factor (HIF)-1α
  • Inhibitor
  • ortho-Carborane

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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