title: 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.affiliation: Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, 18-24 Miyamoto, Numazu-shi, Shizuoka 410-0301, Japan yamako@bikaken.or.jp
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Someno
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Minamiguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawada
authors.forename: Isao
authors.initials: I
authors.lastname: Momose
authors.forename: Naoko
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Doi
authors.forename: Daishiro
authors.initials: D
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009904:Optical Rotation; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013302:Streptomyces / Q000737:chemistry / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018942:Macrolides; C474531:tartrolone C