title: 4-Dechloro-14-deoxy-oxacyclododecindione and 14-deoxy-oxacylododecindione, two inhibitors of inducible connective tissue growth factor expression from the imperfect fungus Exserohilum rostratum.
abstract: Connective tissue growth factor (CTGF/CCN2), a member of the CCN superfamily of secreted cysteine-rich glycoproteins, is a central mediator of tissue remodeling and fibrosis. CTGF is suggested to be an important down-stream effector of transforming growth factor-beta (TGF-β) signaling and has therefore reached considerable pathophysiological relevance because of its involvement in the pathogenesis of fibrotic diseases, atherosclerosis, skin scarring, and other conditions with excess production of connective tissue. In a search for inhibitors of inducible CTGF expression from fungi, two new macrocyclic lactones, namely 4-dechloro-14-deoxy-oxacyclododecindione (1) and 14-deoxy-oxacylododecindione, (2) along with the previously described congener oxacyclododecindione (3) were isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1 and 2 turned out to inhibit TGF-β induced CTGF promoter activity in transiently transfected HepG2 cells in a dose-dependent manner with IC50 values of 1.8 μM and 336 nM, respectively, and also antagonized TGF-β induced cellular effects including CTGF mRNA levels, CTGF protein expression and tube formation.
authors.affiliation: Department of Molecular Biotechnology and Systems Biology, University of Kaiserslautern, Paul-Ehrlich-Strasse 23, D-67663 Kaiserslautern, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.affiliation: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany.
authors.forename: Louis P
authors.initials: LP
authors.lastname: Sandjo
authors.affiliation: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Liermann
authors.affiliation: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany. Electronic address: opatz@uni-mainz.de.
authors.forename: Till
authors.initials: T
authors.lastname: Opatz
authors.affiliation: Department of Molecular Biotechnology and Systems Biology, University of Kaiserslautern, Paul-Ehrlich-Strasse 23, D-67663 Kaiserslautern, Germany. Electronic address: erkel@bio.uni-kl.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Erkel
mesh_terms: D001203:Ascomycota / Q000187:drug effects* / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047028:Macrocyclic Compounds; C532274:oxacyclododecindione; D055513:Connective Tissue Growth Factor
keywords: CTGF; Fibrosis; Inhibitor; β-Resorcylic acid lactones