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

Autoren

Julia Richter
Louis P Sandjo
Johannes C Liermann
Till Opatz
Gerhard Erkel

DOI

10.1016/j.bmc.2014.12.004

ISSN

0968-0896

Ausgabe der Veröffentlichung

3

Zeitschrift

Bioorganic & Medicinal Chemistry

Sprache

en

Paginierung

556 - 563

Datum der Veröffentlichung

2015

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.bmc.2014.12.004

Datum der Datenerfassung

2018

Titel

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

Ausgabe der Zeitschrift

23

Datenquelle: Crossref

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.

Addresses

Department of Molecular Biotechnology and Systems Biology, University of Kaiserslautern, Paul-Ehrlich-Strasse 23, D-67663 Kaiserslautern, Germany.

Autoren

Julia Richter
Louis P Sandjo
Johannes C Liermann
Till Opatz
Gerhard Erkel

DOI

10.1016/j.bmc.2014.12.004

eISSN

1464-3391

Externe Identifier

PubMed Identifier: 25537529

Open access

false

ISSN

0968-0896

Ausgabe der Veröffentlichung

3

Zeitschrift

Bioorganic & medicinal chemistry

Schlüsselwörter

Humans
Ascomycota
Macrocyclic Compounds
Connective Tissue Growth Factor
Hep G2 Cells

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

556 - 563

Datum der Veröffentlichung

2015

Status

Published

Datum der Datenerfassung

2014

Titel

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

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

23

Datenquelle: Europe PubMed Central

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.

Date of acceptance

2014

Autoren

Julia Richter
Louis P Sandjo
Johannes C Liermann
Till Opatz
Gerhard Erkel

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/25537529

DOI

10.1016/j.bmc.2014.12.004

eISSN

1464-3391

Ausgabe der Veröffentlichung

3

Zeitschrift

Bioorg Med Chem

Schlüsselwörter

CTGF
Fibrosis
Inhibitor
β-Resorcylic acid lactones
Ascomycota
Connective Tissue Growth Factor
Hep G2 Cells
Humans
Macrocyclic Compounds

Sprache

eng

Country

England

Paginierung

556 - 563

PII

S0968-0896(14)00842-6

Datum der Veröffentlichung

2015

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

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

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

23

Datenquelle: PubMed

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

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