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

Preisitsch, Michael, Niedermeyer, Timo H. J., Heiden, Stefan E., Neidhardt, Inga, Kumpfmüller, Jana, Wurster, Martina, Harmrolfs, Kirsten, Wiesner, Christoph, Enke, Heike, Müller, Rolf, Mundt, Sabine
Journal of natural products 2016 v.79 no.1 pp. 106-115
Cyanobacterium (genus), Cylindrospermum stagnale, Nostoc, Streptococcus pneumoniae, alkylresorcinols, antibiotic resistance, biomass, carbon, chlorination, high performance liquid chromatography, inhibitory concentration 50, methicillin, methicillin-resistant Staphylococcus aureus, minimum inhibitory concentration, nuclear magnetic resonance spectroscopy, screening, solvents, toxicity
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.