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 5,000 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 NBR1759-27 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 μg/ml.
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Yamazaki, Y., Someno, T., Minamiguchi, K. et al. Inhibitory Activity of the Hypoxia-inducible Factor-1 Pathway by Tartrolone C. J Antibiot 59, 693–697 (2006). https://doi.org/10.1038/ja.2006.92
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DOI: https://doi.org/10.1038/ja.2006.92
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