title: Oxacyclododecindione, a novel inhibitor of IL-4 signaling from Exserohilum rostratum.
abstract: In a screening program for new metabolites from fungi inhibiting the IL-4 mediated signal transduction, a novel chlorinated macrocyclic lactone, designated as oxacyclododecindione, was isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure was determined by a combination of spectroscopic techniques. Oxacyclododecindione inhibits the IL-4 induced expression of the reporter gene secreted alkaline phosphatase (SEAP) in transiently transfected HepG2 cells with IC50 values of 20-25 ng/ml (54-67.5 nM). Studies on the mode of action of the compound revealed that the inhibition of the IL-4 dependent signaling pathway is caused by blocking the binding of the activated STAT6 transcription factors to the DNA binding site without inhibiting tyrosine phosphorylation. The compound has no antibacterial or antifungal activity.
authors.affiliation: Department of Biotechnology, University of Kaiserslautern, Kaiserslautern, Germany. erkel@ibwf.de
authors.forename: Gerhard
authors.initials: G
authors.lastname: Erkel
authors.forename: Hanane
authors.initials: H
authors.lastname: Belahmer
authors.forename: Annegret
authors.initials: A
authors.lastname: Serwe
authors.forename: Timm
authors.initials: T
authors.lastname: Anke
authors.forename: Horst
authors.initials: H
authors.lastname: Kunz
authors.forename: Heinz
authors.initials: H
authors.lastname: Kolshorn
authors.forename: Johannes
authors.initials: J
authors.lastname: Liermann
authors.forename: Till
authors.initials: T
authors.lastname: Opatz
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D005285:Fermentation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology*; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D003904:Mitosporic Fungi / Q000737:chemistry* / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D047028:Macrocyclic Compounds; D050800:STAT6 Transcription Factor; C532274:oxacyclododecindione; D015847:Interleukin-4