Medusamide A, a Panamanian Cyanobacterial Depsipeptide with Multiple β‑Amino Acids

From a collection of marine cyanobacteria made in the Coiba National Park along the Pacific coast of the Republic of Panama a novel cyclic depsipeptide, given the trivial name medusamide A, has been isolated and fully characterized. Medusamide A contains four contiguous β-amino acid (2<i>R</i>,3<i>R</i>)-3-amino-2-methylhexanoic acid (Amha) residues. This is the first report of multiple Amha residues and contiguous β-amino acid residues within a single cyclic peptide-type natural product. Stereochemical assignment of the Amha residues was completed following the synthesis of reference standards for this β-amino acid and the subsequent derivatization with Marfey’s reagent and LC–MS analysis

Carriebowlinol, an Antimicrobial Tetrahydroquinolinol from an Assemblage of Marine Cyanobacteria Containing a Novel Taxon

A combined biodiversity- and bioassay-guided natural products discovery approach was used to explore new groups of marine cyanobacteria for novel secondary metabolites with ecologically relevant bioactivities. Phylogenetic analysis of cyanobacterial collections from Belize revealed a new taxon not previously well explored for natural products. The new alkaloid 5-hydroxy-4-(chloromethyl)-5,6,7,8-tetrahydroquinoline (<b>1</b>), named carriebowlinol, and the known compound lyngbic acid (<b>2</b>) were isolated from a nonpolar extract and identified by NMR and MS techniques. Compounds <b>1</b> and <b>2</b> inhibited the growth of pathogenic and saprophytic marine fungi, and <b>1</b> inhibited the growth of marine bacteria, suggesting an antimicrobial ecological function

Santacruzamate A, a Potent and Selective Histone Deacetylase Inhibitor from the Panamanian Marine Cyanobacterium cf. <i>Symploca</i> sp.

A dark brown tuft-forming cyanobacterium, morphologically resembling the genus <i>Symploca</i>, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for <i>Symploca</i> and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (<b>1</b>), which has several structural features in common with suberoylanilide hydroxamic acid [(<b>2</b>), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of <b>1</b> and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (<b>1</b> and <b>2</b>), were achieved and evaluated for their HDAC activity and specificity

Credneramides A and B: Neuromodulatory Phenethylamine and Isopentylamine Derivatives of a Vinyl Chloride-Containing Fatty Acid from cf. <i>Trichodesmium</i> sp. nov.

Credneramides A (<b>1</b>) and B (<b>2</b>), two vinyl chloride-containing metabolites, were isolated from a Papua New Guinea collection of cf. <i>Trichodesmium</i> sp. nov. and expand a recently described class of vinyl chloride-containing natural products. The precursor fatty acid, credneric acid (<b>3</b>), was isolated from both the aqueous and organic fractions of the parent fraction as well as from another geographically and phylogenetically distinct cyanobacterial collection (Panama). Credneramides A and B inhibited spontaneous calcium oscillations in murine cerebrocortical neurons at low micromolar concentrations (<b>1</b>, IC₅₀ 4.0 μM; <b>2</b>, IC₅₀ 3.8 μM)

Biosynthetically Intriguing Chlorinated Lipophilic Metabolites from Geographically Distant Tropical Marine Cyanobacteria

Five new vinylchlorine-containing metabolites, the lipoamides janthielamide A and kimbeamides A–C and the ketide-extended pyranone kimbelactone A, have been isolated from collections of marine cyanobacteria made in Curaçao and Papua New Guinea. Both janthielamide A and kimbeamide A exhibited moderate sodium channel blocking activity in murine Neuro-2a cells. Consistent with this activity, janthielamide A was also found to antagonize veratridine-induced sodium influx in murine cerebrocortical neurons. These lipoamides represent the newest additions to a relatively rare family of marine cyanobacterial-derived lipoamides and a new structural class of compounds exhibiting neuromodulatory activities from marine cyanobacteria

Coibacins A–D, Antileishmanial Marine Cyanobacterial Polyketides with Intriguing Biosynthetic Origins

Four unsaturated polyketide lactone derivatives, coibacins A–D, were isolated from a Panamanian marine cyanobacterium, cf. <i>Oscillatoria</i> sp. The two different types of termini observed in these co-occurring metabolites, either a methyl cyclopropyl ring as seen in curacin A or a methyl vinyl chloride similar to that observed in the jamaicamides, suggest an intriguing flexibility in the “beta branch” forming biosynthetic process. The coibacins possess selective antileishmanial activity as well as potent anti-inflammatory activity

Bastimolide A, a Potent Antimalarial Polyhydroxy Macrolide from the Marine Cyanobacterium <i>Okeania hirsuta</i>

Bastimolide A (<b>1</b>), a polyhydroxy macrolide with a 40-membered ring, was isolated from a new genus of the tropical marine cyanobacterium <i>Okeania hirsuta</i>. This novel macrolide was defined by spectroscopy and chemical reactions to possess one 1,3-diol, one 1,3,5-triol, six 1,5-diols, and one <i>tert</i>-butyl group; however, the relationships of these moieties to one another were obscured by a highly degenerate ¹H NMR spectrum. Its complete structure and absolute configuration were therefore unambiguously determined by X-ray diffraction analysis of the nona-<i>p</i>-nitrobenzoate derivative (<b>1d</b>). Pure bastimolide A (<b>1</b>) showed potent antimalarial activity against four resistant strains of <i>Plasmodium falciparum</i> with IC₅₀ values between 80 and 270 nM, although with some toxicity to the control Vero cells (IC₅₀ = 2.1 μM), and thus represents a potentially promising lead for antimalarial drug discovery. Moreover, rigorous establishment of its molecular arrangement gives fresh insight into the structures and biosynthesis of cyanobacterial polyhydroxymacrolides