2. Academic Validation
  3. 4-Dechloro-14-deoxy-oxacyclododecindione and 14-deoxy-oxacylododecindione, two inhibitors of inducible connective tissue growth factor expression from the imperfect fungus Exserohilum rostratum

4-Dechloro-14-deoxy-oxacyclododecindione and 14-deoxy-oxacylododecindione, two inhibitors of inducible connective tissue growth factor expression from the imperfect fungus Exserohilum rostratum

  • Bioorg Med Chem. 2015 Feb 1;23(3):556-63. doi: 10.1016/j.bmc.2014.12.004.
Julia Richter 1,  Louis P Sandjo 2,  Johannes C Liermann 2,  Till Opatz 3,  Gerhard Erkel 4
Affiliations

Affiliations

  • 1 Department of Molecular Biotechnology and Systems Biology, University of Kaiserslautern, Paul-Ehrlich-Strasse 23, D-67663 Kaiserslautern, Germany.
  • 2 Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany.
  • 3 Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany. Electronic address: opatz@uni-mainz.de.
  • 4 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.
PMID: 25537529 DOI: 10.1016/j.bmc.2014.12.004
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.

Keywords

CTGF; Fibrosis; Inhibitor; β-Resorcylic acid lactones.

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