Cylindrofridins A-C, Linear Cylindrocyclophane-Related Alkylresorcinols from the Cyanobacterium Cylindrospermum stagnale

  • J Nat Prod. 2016 Jan 22;79(1):106-15. doi: 10.1021/acs.jnatprod.5b00768.
Michael Preisitsch  1 ,  Timo H J Niedermeyer  2  3  4 ,  Stefan E Heiden  5 ,  Inga Neidhardt  1 ,  Jana Kumpfmüller  5 ,  Martina Wurster  1 ,  Kirsten Harmrolfs  6 ,  Christoph Wiesner  7 ,  Heike Enke  4 ,  Rolf Müller  6 ,  Sabine Mundt  1
Affiliations
  • 1. Institute of Pharmacy, Department of Pharmaceutical Biology, Ernst-Moritz-Arndt-University , Friedrich-Ludwig-Jahn-Straße 17, 17489 Greifswald, Germany.
  • 2. Interfaculty Institute of Microbiology and Infection Medicine, Eberhard Karls University , Auf der Morgenstelle 28, 72076 Tübingen, Germany.
  • 3. German Centre for Infection Research (DZIF) , Partner Site Tübingen, Germany.
  • 4. Cyano Biotech GmbH , Magnusstraße 11, 12489 Berlin, Germany.
  • 5. Institute of Pharmacy, Department of Pharmaceutical Biotechnology, Ernst-Moritz-Arndt-University , Felix-Hausdorff-Straße 3, 17489 Greifswald, Germany.
  • 6. Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
  • 7. Sealife PHARMA GmbH , Technopark 1/Obj.C/EG, 3430 Tulln, Austria.
PMID: 26684177 DOI: 10.1021/acs.jnatprod.5b00768
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.