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Investigations of marine cyanobacterial secondary metabolites : isolation, structure elucidation, and synthesis

  • Author(s): Nunnery, Joshawna Kay
  • et al.
Abstract

Marine cyanobacteria, especially of the genus Lyngbya, have been a prolific source of bioactive natural products over the past forty years. While the most prevalent biological activity reported for marine cyanobacterial secondary metabolites is anticancer activity, the propensity of marine cyanobacteria to produce neuromodulatory active secondary metabolites has been realized in recent years. Neuromodulatory activity may have therapeutic relevance in the treatment of spinal cord injury, chronic pain, CNS disorders including stroke and epilepsy, and treatment of cardiovascular, inflammatory and neurodegenerative disorders. While a number of compounds exhibiting neuromodulatory activities have been isolated from Lyngbya sp., relatively few have been reported from other species belonging to the Oscillatoriaceae. The primary focus of the research herein was to evaluate the natural products richness of marine cyanobacteria belonging to the genera Schizothrix and Symploca spp. with particular emphasis on isolating compounds from extracts and fractions exhibiting neuromodulatory activity. In total, seven novel compounds from marine cyanobacteria were isolated and characterized, including four lipopeptides, janthielamide A and kimbeamides A-C, a polyketide-extended pyranone, kimbelactone A, a new iodinated and brominated diterpene, tasihalide C, and a novel lipophilic carboxylic acid, palmyric acid. Janthielamide A displayed sodium channel blocking activity in murine Neuro-2a cells with an IC₅₀ of 11.5 [mu]M and antagonized veratridine-induced sodium influx in murine cerebrocortical neurons with an IC₅₀ of 5.2 [mu]M. Kimbeamide A also exhibited modest sodium channel blocking activity with an IC₅₀ of 60 [mu]M in murine Neuro-2a cells. Meanwhile, tasihalide C was found to possess potent anti-inflammatory activity with an IC₅₀ of 1.3 [mu]M in a mouse macrophage cell line. In addition to studies regarding isolation and characterization of novel marine cyanobacterial natural products, investigations utilizing synthetic methodology to address questions regarding absolute stereochemistry of some of these compounds, as well as several depsipeptides containing an [alpha],[alpha]-dimethyl-[beta]-hydroxy octynoic acid residue, were undertaken. An improved synthetic route for the generation of [alpha],[alpha]- dimethyl-[beta]-hydroxy octynoic acid and related residues was achieved and standards generated by this methodology have been utilized to determine the absolute configuration of the [beta]-hydroxy stereocenter of this fragment in ten depsipeptides of marine cyanobacterial origins thus far

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