title: Cylindrofridins A-C, Linear Cylindrocyclophane-Related Alkylresorcinols from the Cyanobacterium Cylindrospermum stagnale.
abstract: A rapid and exhaustive one-step biomass extraction as well as an enrichment and cleanup procedure has been developed for HPLC-UV detection and quantification of closely related [7.7]paracyclophanes and structural derivatives based on a two-phase solvent system. The procedure has been validated using the biomass of the carbamidocyclophane- and cylindrocyclophane-producing cyanobacterium Nostoc sp. CAVN2 and was utilized to perform a screening comprising 102 cyanobacterial strains. As a result, three new cylindrocyclophane-related alkylresorcinols, cylindrofridins A-C (1-3), and known cylindrocyclophanes (4-6) were detected and isolated from Cylindrospermum stagnale PCC 7417. Structures of 1-3 were elucidated by a combination of 1D and 2D NMR experiments, HRMS, and ECD spectroscopy. Cylindrofridin A (1) is the first naturally occurring [7.7]paracyclophane-related monomeric derivative. In contrast, cylindrofridins B (2) and C (3) represent dimers related to 1. Due to chlorination at the alkyl carbon atom in 1-3, the site of [7.7]paracyclophane macrocycle formation, the cylindrofridins represent linearized congeners of the cylindrocyclophanes. Compounds 1-3 were not toxic against nontumorigenic HaCaT cells (IC50 values >25 μM) compared to the respective cylindrocyclophanes, but 1 was the only cylindrofridin showing moderate activity against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae with MIC values of 9 and 17 μM, respectively.
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University , Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Preisitsch
authors.affiliation: Interfaculty Institute of Microbiology and Infection Medicine, Eberhard Karls University , Auf der Morgenstelle 28, 72076 Tübingen, Germany.|German Centre for Infection Research (DZIF) , Partner Site Tübingen, Germany.|Cyano Biotech GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Timo H J
authors.initials: TH
authors.lastname: Niedermeyer
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biotechnology, Ernst-Moritz-Arndt-University , Felix-Hausdorff-Straße 3, 17489 Greifswald, Germany.
authors.forename: Stefan E
authors.initials: SE
authors.lastname: Heiden
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University , Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Neidhardt
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biotechnology, Ernst-Moritz-Arndt-University , Felix-Hausdorff-Straße 3, 17489 Greifswald, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Kumpfmüller
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University , Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Wurster
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harmrolfs
authors.affiliation: Sealife PHARMA GmbH , Technopark 1/Obj.C/EG, 3430 Tulln, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiesner
authors.affiliation: Cyano Biotech GmbH , Magnusstraße 11, 12489 Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Enke
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University , Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mundt
mesh_terms: D000458:Cyanobacteria / Q000737:chemistry*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D012118:Resorcinols / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D012118:Resorcinols; C000608585:cylindrofridin A; C000608586:cylindrofridin B