title: Inhibition of interleukin-6 signaling and Stat3 activation by a new class of bioactive cyclopentenone derivatives.
abstract: The IL-6-dependent activation of the JAK/STAT pathway plays a central role in the induction of the acute phase response in the liver. In a search for new inhibitors of the IL-6-mediated signal transduction in HepG2 cells using secreted alkaline phosphatase (SEAP) as reporter gene, four novel cyclopentenones, 2-(1-chloropropenyl)-4,5-dihydroxycyclopent-2-enone (CPDHC, 1), 4, 5-dihydroxy-2-propenylcyclopent-2-enone (DHPC, 2), 5-hydroxy-2, 3-dimethylcyclopent-2-enone (HDC, 3), and 4-methyl-5-methylenecyclopent-3-en-1,2-diol (MMCD, 4) were isolated from fermentations of the ascomycete strain A23-98. CPDHC (1) inhibits the IL-6-induced SEAP expression with IC(50) values of 4. 0-5.3 microM (0.75-1 microg/ml). The compounds DHPC (2), HDC (3), and MMCD (4) which are structurally closely related to CPDHC (1) showed no inhibitory effects on the IL-6-induced SEAP expression in HepG2 cells. Studies on the mode of action revealed that CPDHC (1) affects the IL-6-dependent pathway by inhibiting the tyrosine phosphorylation of the STAT3 and STAT1 as well as the serine phosphorylation of the Stat3 transcription factor. In addition, CPDHC (1) and DHPC (2) inhibit the AP-1 and NF-kappaB mediated SEAP expression in transiently transfected HeLa S3 cells with IC(50) values of 10-15 microM (2-3 microg/ml) and 50-100 microM (8-16 microg/ml) respectively. Our results indicate that CPDHC inhibits the NF-kappaB pathway by preventing the phosphorylation and proteolytic degradation of the IkappaBalpha protein. The novel cyclopentenones may represent lead compounds for the development of new anti-inflammatory drugs.
authors.affiliation: Institut für Biotechnologie und Wirkstoff-Forschung e.V. (IBWF), Erwin-Schrödinger-Strasse 56, Kaiserslautern, D-67663, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weidler
authors.forename: J
authors.initials: J
authors.lastname: Rether
authors.forename: T
authors.initials: T
authors.lastname: Anke
authors.forename: G
authors.initials: G
authors.lastname: Erkel
mesh_terms: D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D003517:Cyclopentanes; D004268:DNA-Binding Proteins; D005765:Gastrointestinal Agents; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C414674:2-(1-chloropropenyl)-4,5-dihydroxycyclopent-2-enone; C494086:STAT3 protein, human; C013905:cyclopentenone