Inhibitory activity of the hypoxia-inducible factor-1 pathway by tartrolone C.

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. To identify small molecule inhibitors of the HIF-1 transcriptional activation, we have established a high through-put assay system using a stable transformant of mammalian cells that express a luciferase reporter gene construct containing a HIF-1 binding site. Using this system, we screened 5000 cultured broths of microorganisms, and we found that fermentation broth produced by Streptomyces strain 1759-27 showed significant inhibition of the reporter activity induced by hypoxic conditions. The active substance NBRI759-27 was purified and determined to be tartrolone C by several methods including X-ray crystallography. In the reporter gene assay, tartrolone C inhibited the HIF-1 transcriptional activity under hypoxic conditions with an IC50 value of 0.17 microg/ml.

• Authors: Yohko Yamazaki, Tetsuya Someno, Kazuhisa Minamiguchi, Manabu Kawada, Isao Momose, Naoko Kinoshita, Hiroyasu Doi, Daishiro Ikeda
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 59 Issue 11 Pg. 693-7 (Nov 2006) ISSN: 0021-8820 [Print] England
• PMID: 17256467 (Publication Type: Journal Article)

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Macrolides
• tartrolone C

Topics

• Animals
• Blotting, Western
• CHO Cells
• Cell Hypoxia
• Cell Line, Tumor
• Cricetinae
• Cricetulus
• Crystallography, X-Ray
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, metabolism)
• Inhibitory Concentration 50
• Macrolides (chemistry, isolation & purification, pharmacology)
• Models, Molecular
• Nuclear Magnetic Resonance, Biomolecular
• Optical Rotation
• Spectrometry, Mass, Electrospray Ionization
• Spectrophotometry, Ultraviolet
• Streptomyces (chemistry, metabolism)