title: Anti-inflammatory tetraquinane diterpenoids from a Crinipellis species.
abstract: The small pro-inflammatory 10kDa chemokine CXCL10 (Interferon-inducible protein 10, IP-10) plays an important role in mediating immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells to the sites of inflammation. Elevated levels of CXCL10 have been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents an attractive target for the development of new anti-inflammatory drugs. In a search for anti-inflammatory compounds from fungi inhibiting the inducible CXCL10 promoter activity, four new tetraquinane diterpenoids, crinipellin E (1), crinipellin F (2), crinipellin G (3) and crinipellin H (4) were isolated from fermentations of a Crinipellis species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1, 2, and 3 inhibited the LPS/IFN-γ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC50values of 15μM, 1.5μM, and 3.15μM respectively, whereas compound 4 was devoid of any biological activity. Moreover, compounds 1, 2 and 3 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFN-γ stimulated MonoMac6 cells.
authors.affiliation: Department of Molecular Biotechnology and Systems Biology, University of Kaiserslautern, Paul-Ehrlich-Strasse 23, D-67663 Kaiserslautern, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rohr
authors.affiliation: Department of Molecular Biotechnology and Systems Biology, University of Kaiserslautern, Paul-Ehrlich-Strasse 23, D-67663 Kaiserslautern, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Oleinikov
authors.affiliation: Institute of Biotechnology and Drug Research (IBWF), Erwin-Schrödinger-Strasse 56, D-67663 Kaiserslautern, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10-14, D-55128 Mainz, Germany; Present address: Department of Pharmaceutical Sciences, Universidade Federal de Santa Catarina, Campus Universitário - Trindade, Florianópolis 88040-970, SC, Brazil.
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. 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: D000363:Agaricales / Q000737:chemistry* / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000276:immunology; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054357:Chemokine CXCL10; D004224:Diterpenes
keywords: CXCL10; Fungal metabolites; Inflammation; Inhibitor