title: Marine Fungi as Producers of Benzocoumarins, a New Class of Inhibitors of Glycogen-Synthase-Kinase 3β.
abstract: The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad range of diseases. Here we report pannorin (1), alternariol (2), and alternariol-9-methylether (3) to be promising inhibitors of the isoform GSK-3β showing sub-μM IC50values. The in vitro inhibition is in the range of the known highly active GSK-3β inhibitor TDZD-8. Compounds1-3have a highly oxygenated benzocoumarin core structure in common, which suggests that this may be a new structural feature for efficient GSK-3β inhibition.
authors: GEOMAR Helmholtz Center for Ocean Research Kiel, Marine Microbiology, Düsternbrooker Weg 20, 24105 Kiel, Germany. jwiese@geomar.de.
authors: Jutta
authors: J
authors: Wiese
authors: GEOMAR Helmholtz Center for Ocean Research Kiel, Marine Microbiology, Düsternbrooker Weg 20, 24105 Kiel, Germany. jimhoff@geomar.de.
authors: Johannes F
authors: JF
authors: Imhoff
authors: Biosystems Chemistry, Department of Chemistry and Center for Integrated Protein Science Munich (CISPM), Technical University of Munich, Lichtenbergstraße 4, 85748 Garching, Germany. tobias.gulder@ch.tum.de.
authors: Tobias A M
authors: TA
authors: Gulder
authors: GEOMAR Helmholtz Center for Ocean Research Kiel, Marine Microbiology, Düsternbrooker Weg 20, 24105 Kiel, Germany. alabes@geomar.de.
authors: Antje
authors: A
authors: Labes
authors: GEOMAR Helmholtz Center for Ocean Research Kiel, Marine Microbiology, Düsternbrooker Weg 20, 24105 Kiel, Germany. rschmaljohann@geomar.de.
authors: Rolf
authors: R
authors: Schmaljohann
mesh_terms: D003374:Coumarins / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005658:Fungi / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000494:pharmacology; D009284:Naphthols / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D003374:Coumarins; D004791:Enzyme Inhibitors; D007783:Lactones; D009284:Naphthols; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D013830:Thiadiazoles; C070543:pannorin; D000071679:Glycogen Synthase Kinase 3 beta; C005197:alternariol; C018206:alternariol monomethyl ether
keywords: Aspergillus; Botrytinia; GSK-3β; alternariol; alternariol-9-methyl ether; deep-sea; pannorin