Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis

Hisanori Hattori, Kensuke Okuda, Tetsuji Murase, Yuki Shigetsura, Kosuke Narise, Gregg L Semenza, Hideko Nagasawa

Research output: Contribution to journalArticle

Abstract

The tumor microenvironment is characterized by hypoxia, low-nutrient levels, and acidosis. A natural product chemistry-based approach was used to discover small molecules that modulate adaptive responses to a hypoxic microenvironment through the hypoxia-inducible factor (HIF)-1 signaling pathways. Five compounds, such as baccharin (3), beturetol (4), kaempferide (5), isosakuranetin (6), and drupanin (9), that modulate HIF-1-dependent luciferase activity were identified from Brazilian green propolis using reporter assay. Compounds 3, 9 and 5 reduced HIF-1-dependent luciferase activity. The cinnamic acid derivatives 3 and 9 significantly inhibited expression of the HIF-1α protein and HIF-1 downstream target genes such as glucose transporter 1, hexokinase 2, and vascular endothelial growth factor A. They also exhibited significant anti-angiogenic effects in the chick chorioallantoic membrane (CAM) assay at doses of 300 ng/CAM. On the other hand, flavonoids 4 and 6 induced HIF-1-dependent luciferase activity and expression of HIF-1 target genes under hypoxia. The contents (g/100 g extract) of the HIF-1-modulating compounds in whole propolis ethanol extracts were also determined based on liquid chromatography-electrospray ionization mass spectrometry as 1.6 (3), 14.2 (4), 4.0 (5), 0.7 (6), and 0.7 (9), respectively. These small molecules screened from Brazilian green propolis may be useful as lead compounds for the development of novel therapies against ischemic cardiovascular disease and cancer based on their ability to induce or inhibit HIF-1 activity, respectively.

Original languageEnglish (US)
Pages (from-to)5392-5401
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number18
DOIs
StatePublished - Sep 15 2011

Fingerprint

Propolis
Hypoxia-Inducible Factor 1
Luciferases
Chorioallantoic Membrane
Assays
Genes
Lead compounds
Membranes
Electrospray ionization
Molecules
Hexokinase
Tumor Microenvironment
Facilitative Glucose Transport Proteins
Electrospray Ionization Mass Spectrometry
Liquid chromatography
Acidosis
Biological Products
Flavonoids
Liquid Chromatography
Vascular Endothelial Growth Factor A

Keywords

  • Angiogenesis inhibitor
  • Brazilian green propolis
  • Drupanin
  • HIF-1 modulator
  • Tumor microenvironment

ASJC Scopus subject areas

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

Cite this

Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis. / Hattori, Hisanori; Okuda, Kensuke; Murase, Tetsuji; Shigetsura, Yuki; Narise, Kosuke; Semenza, Gregg L; Nagasawa, Hideko.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 18, 15.09.2011, p. 5392-5401.

Research output: Contribution to journalArticle

Hattori, Hisanori ; Okuda, Kensuke ; Murase, Tetsuji ; Shigetsura, Yuki ; Narise, Kosuke ; Semenza, Gregg L ; Nagasawa, Hideko. / Isolation, identification, and biological evaluation of HIF-1-modulating compounds from Brazilian green propolis. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 18. pp. 5392-5401.
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