title: Anti-inflammatory drimane sesquiterpene lactones from an Aspergillus species.
abstract: IFN-γ inducible protein 10 (IP-10, CXCL10) is a 10 kDa chemokine, which is secreted from various cell types after exposure to pro-inflammatory stimuli. This chemokine is a ligand for the CXCR3 receptor and regulates immune responses by activating and recruiting leukocytes such as T cells, eosinophils, monocytes, and NK cells to sites of inflammation. Altered expression of CXCL10 has been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents a promising target for the development of new anti-inflammatory drugs. In a search for inhibitors of CXCL10 promoter activity, three structurally related drimane sesquiterpene lactones (compounds 1-3) were isolated from fermentations of an Aspergillus species. Compounds 1 and 2 inhibited the IFN-γ/TNF-α/IL-1β induced CXCL10 promoter activity in transiently transfected human DLD-1 colon carcinoma cells in a dose-dependent manner with IC50 values of 12.4 μM for 1 and 55 μM for 2, whereas 3 was devoid of any biological activity. Moreover, compounds 1 and 2 reduced CXCL10 mRNA levels and synthesis in IFN-γ/TNF-α/IL-1β stimulated DLD-1 cells.
authors.affiliation: Institute of Biotechnology and Drug Research (IBWF), Erwin-Schrödinger-Strasse 56, D-67663 Kaiserslautern, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Felix
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. 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: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001230:Aspergillus / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000081223:Polycyclic Sesquiterpenes; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007783:Lactones; D000081223:Polycyclic Sesquiterpenes; D012333:RNA, Messenger; D012717:Sesquiterpenes; C437376:drimane
keywords: CXCL10; Fungal metabolites; Inflammation; Inhibitor