Jeffrey L. C. Wright

Isolation of a new diarrhetic shellfish poison from Irish mussels

A new marine toxin dinophysistoxin-2 (DTX-2)4, isolated from toxic Irish mussels and biogenetically related to the toxins okadaic acid 1 and dinophysistoxin-1 (DTX-1)2, the principal agents responsible for diarrhetic shellfish poisoning (DSP), is reported.

Biogenetic Diversity of Cyanobacterial Metabolites

Publisher Summary This chapter reviews the biogenetic and chemical diversity of secondary metabolites produced by cyanobacteria. The ability of cyanobacteria to biosynthesize complex toxins underscores their innate ability to biosynthesize complex secondary metabolites in general, and more recently, the structural diversity of cyanobacterial metabolites has attracted the attention of scientists searching for new pharmaceutical leads. Today, cyanobacteria are recognized as an exciting resource of new compounds with pharmaceutical potential. In recent years, the biosynthesis of cyanobacterial metabolites has grown to include the identification of the appropriate biosynthetic genes and has even raised the possibility of engineering such genes to produce new “semibiosynthetic” compounds. The biosynthetic pathways of all cyanobacterial metabolites have not been elucidated and some groupings have been created based on comparison with other cyanobacterial compounds, as well as secondary metabolites from other organisms including bacteria, fungi, and microalgae.

Structure and relative potency of several karlotoxins from Karlodinium veneficum.

The karlotoxins are a family of amphidinol-like compounds that play roles in avoiding predation and in prey capture for the toxic dinoflagellate Karlodinium veneficum. The first member of the toxin group to be reported was KmTx 1 (1), and here we report an additional five new members of this family (3-7) from the same strain. Of these additional compounds, KmTx 3 (3) differs from KmTx 1 (1) in having one less methylene group in the saturated portion of its lipophilic arm. In addition, 64-E-chloro-KmTx 3 (4) and 10-O-sulfo-KmTx 3 (5) were identified. Likewise, 65-E-chloro-KmTx 1 (6) and 10-O-sulfo-KmTx 1 (7) were also isolated. Comparison of the hemolytic activities of the newly isolated compounds to that of KmTx 1 shows that potency correlates positively with the length of the lipophilic arm and is disrupted by sulfonation of the polyol arm.

Structure and Biosynthesis of Amphidinol 17, a Hemolytic Compound from Amphidinium carterae

Amphidinol 17 (AM17; 1), a novel amphidinol, has been isolated from a Bahamas strain of Amphidinium carterae. This new congener contains the signature hairpin region and a Delta(6) polyene arm, whereas the polyol arm is distinct from those of other amphidinols. The pattern of acetate incorporation in 1 was directly determined by feeding a single labeled substrate, [2-(13)C]acetate. While the highly conserved regions within the amphidinol family of AM17 have exhibited identical occurrences of cleaved acetates to other amphidinols for which the biosynthesis has been explored, the polyol arm for AM17 displays a higher degree of nascent chain processing that shows similarities to amphidinolide biosynthesis. AM17 exhibited an EC(50) of 4.9 microM in a hemolytic assay using human red blood cells but displayed no detectable antifungal activity.

Total synthesis and structural confirmation of brevisamide, a new marine cyclic ether alkaloid from the dinoflagellate Karenia brevis.

The first total synthesis of brevisamide (1) has been accomplished in 21 linear steps starting from cis-but-2-ene-1,4-diol. A synthetic highlight is the Suzuki-Miyaura coupling between an ether ring fragment and a dienol side chain. This result confirmed the structure of 1 isolated from the dinoflagellate Karenia brevis.

Further Studies on the Chemistry of the Flustra Alkaloids from the Bryozoan Flustra foliacea

Since 1980, over a dozen novel brominated alkaloids, named flustramines, have been isolated from Scandinavian and Canadian collections of the marine bryozoan Flustra foliacea. This paper describes the reisolation of the known compound dihydroflustramine C (1) and the isolation of 11 new flustramines (2-4, 6-13), including two dimers (12, 13) that may be isolation artifacts. Together these compounds, some with an unexpected aryl substitution pattern, reveal an intricate network of metabolites present in the extracts of the bryozoan. The structures of these metabolites were solved using a variety of spectroscopic techniques and chemical derivatization and modification. This work also led to the recognition of an unusual rearrangement reaction that occurred slowly over a number of years.

Biosynthesis of the neurotoxin domoic acid by the marine diatom Nitzschia pungens forma multiseries, determined with [13C]-labelled precursors and nuclear magnetic resonance

Labelling experiments with [1-13C]acetate and [1,2-13C]acetate provide evidence that the neurotoxin domoic acid, produced by the diatom Nitzschia pungens, is derived by the novel condensation of a geranyl unit with an activated citric acid cycle derivative and subsequent cyclisation to form a proline ring system.

Improvement of vascular dysfunction and blood lipids of insulin-resistant rats by a marine oil-based phytosterol compound.

The syndrome that is characterized by obesity, insulin resistance, and hyperlipidemia is increasingly prevalent in all prosperous societies. It is now recognized as a major contributor to cardiovascular disease. Vascular dysfunction in the form of hypercontractility and impaired nitric oxide-mediated relaxation is a significant component of cardiovascular disease, predisposing to ischemic events. The JCR:LA-cp strain of rats exhibits all major aspects of the obesity/insulin resistance syndrome, including vascular dysfunction and ischemic lesions of the heart. Dietary lipid intake may have a marked effect on plasma lipid levels and, potentially, on vascular disease. We have investigated the effects of a novel preparation, ONC101 (a phytosterol esterified with fish oil), on plasma lipids and vascular function in the insulin-resistant JCR:LA-cp rat. Treatment of obese male rats with ONC101 from 8 to 12 wk of age resulted in no change in plasma lipid concentrations at 0.5 g/kg body weight. At the higher dose of 2.6 g/kg, plasma TG fell 50% (1.26 vs. 2.59 mmol/L, P<0.002) and cholesterol esters were significantly reduced (1.34 vs. 1.61 mmol/l, P<0.002). Food intake and body weights were unaffected by ONC101 treatment. At the low dose of 86 mg/kg, the hypercontractility of aortic rings in response to phenylephrine was normalized and the relaxant response to acetylcholine was significantly improved. The results indicate that ONC101 at high doses has significant hypolipidemic effects and, at very low doses, has beneficial effects on endothelial and vascular smooth muscle cell function.

Identification of micromonolactam, a new polyene macrocyclic lactam from two marine Micromonospora strains using chemical and molecular methods: clarification of the biosynthetic pathway from a glutamate starter unit

Through a combination of chemical and molecular analysis, a new polyene macrolactam named micromonolactam was obtained from two marine-derived Micromonospora species. This new polyene metabolite is a constitutional isomer of salinilactam A but contains a different polyene pattern and one cis double bond, in contrast to the all trans structure reported for salinilactam A. The molecular analysis data also established that micromonolactam is a hybrid polyketide derived from 11 polyketide units and a modified glutamate starter unit.

Microcystins and two new micropeptin cyanopeptides produced by unprecedented Microcystis aeruginosa blooms in North Carolina's Cape Fear River

The Cape Fear River is the largest river system in North Carolina. It is heavily used as a source of drinking water for humans and livestock as well as a source of irrigation water for crops, and production water for industry. It also serves as a major fishery for both commercial and recreational use. In recent years, possibly related to increased eutrophication of the river, massive blooms of cyanobacteria, identified as Microcystis aeruginosa have been observed. Bloom samples collected in 2009 and 2012 were chemically analyzed to determine if they contained cyanobacterial toxins known as microcystins. Both blooms were found to produce microcystins in high yields. Microcystins are potent hepatotoxins that can be bio-accumulated in the food chain. Recent biological studies have also shown a host of other potentially harmful effects of low level microcystin exposure. Detailed chemical analysis of these blooms led us to discover that these blooms produce an additional family of cyanobacterial peptides know as the micropeptins, including two new members named micropeptins 1106 and 1120. The biological activities of these new molecules have not yet been determined, although protease activity has been well documented for this peptide group. These data indicate a need for thorough monitoring of toxin levels especially during bloom events in addition to additional biological testing of other cyanopeptides present in blooms.