José J. Fernández

Dinoflagellate polyether within the yessotoxin, pectenotoxin and okadaic acid toxin groups: Characterization, analysis and human health implications

Diarrhetic Shellfish Poisoning (DSP) is a specific type of food poisoning, characterized by severe gastrointestinal illness due to the ingestion of filter feeding bivalves contaminated with a specific suite of toxins. It is known that the problem is worldwide and three chemically different groups of toxins have been historically associated with DSP syndrome: okadaic acid (OA) and dinophysistoxins (DTXs), pectenotoxins (PTXs) and yessotoxins (YTXs). PTXs and YTXs have been considered as DSP toxins because they can be detected with the bioassays used for the toxins of the okadaic acid group, but diarrhegenic effects have only been proven for OA and DTXs. Whereas, some PTXs causes liver necrosis and YTXs damages cardiac muscle after intraperitoneal injection into mice. On the other hand, azaspiracids (AZAs) have never been included in the DSP group, but they cause diarrhoea in humans. This review summarizes the origin, characterization, structure, activity, mechanism of action, clinical symptoms, method for analysis, potential risk, regulation and perspectives of DSP and associated toxins produced by marine dinoflagellates.

Yessotoxins, a Group of Marine Polyether Toxins: an Overview

Yessotoxin (YTX) is a marine polyether toxin that was first isolated in 1986 from the scallop Patinopecten yessoensis. Subsequently, it was reported that YTX is produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. YTXs have been associated with diarrhetic shellfish poisoning (DSP) because they are often simultaneously extracted with DSP toxins, and give positive results when tested in the conventional mouse bioassay for DSP toxins. However, recent evidence suggests that YTXs should be excluded from the DSP toxins group, because unlike okadaic acid (OA) and dinophyisistoxin-1 (DTX-1), YTXs do not cause either diarrhea or inhibition of protein phosphatases. In spite of the increasing number of molecular studies focused on the toxicity of YTX, the precise mechanism of action is currently unknown. Since the discovery of YTX, almost forty new analogues isolated from both mussels and dinoflagellates have been characterized by NMR or LC-MS/MS techniques. These studies indicate a wide variability in the profile and the relative abundance of YTXs in both, bivalves and dinoflagellates. This review covers current knowledge on the origin, producer organisms and vectors, chemical structures, metabolism, biosynthetic origin, toxicological properties, potential risks to human health and advances in detection methods of YTXs.

Evaluation of the effects of several zoanthamine-type alkaloids on the aggregation of human platelets.

Ten zoanthamine-type alkaloids from two marine zoanthids belonging to the Zoanthus genus (Zoanthus nymphaeus and Zoanthus sp.) along with one semisynthetic derivative were evaluated for their antiplatelet activities on human platelet aggregation induced by several stimulating agents. 11-Hydroxyzoanthamine (11) and a synthetic derivative of norzoanthamine (16) showed strong inhibition against thrombin-, collagen- and arachidonic acid-induced aggregation, zoanthenol (15) displayed a selective inhibitory activity induced by collagen, while zoanthaminone (10) behaved as a potent aggregant agent. These evaluations allowed us to deduce several structure-activity relationships and suggest some mechanisms of action for this type of compounds.

Okadaic acid : a proton and carbon NMR study

Abstract Okadaic acid is an extremely interesting toxin responsible for diarrhetic shellfish poisoning (DSP). This interest is due not only to its fascinating structure but also to its unknown biosynthetic origin. In this paper we report on the full NMR study of this molecule including the appropriate 2D homo and heteronuclear NMR experiments neccesary to carried out its biosynthetic study. Okadaic acid is an extremely interesting toxin responsible for diarrhetic shellfish poisoning (DSP). This interest is due not only to its fascinating structure but also to its unknown biosynthetic origin. In this paper we report on the full NMR study of this molecule, including the appropriate 2D homo and heteronuclear NMR experiments, necessary to carried out its biosynthetic study.

Studies on the biosynthesis of the polyether marine toxin dinophysistoxin-1 (DTX-1)

Abstract The biosynthetic origin of DTX-1 is establish on the basis of the NMR spectral data of samples obtained by addition of labelled [1- 13 C 1 ], [2- 13 C 1 ] and [1,2- 13 C 2 ] sodium acetate to artificial cultures of the dinoflagellate Prorocentrum lima.

Structural determination and biosynthetic origin of two ester derivatives of okadaic acid isolated from Prorocentrum lima

Abstract The dinoflagellate Prorocentrum lima is responsible for the production of the toxins involved in the red tide phenomenon known as diarrhetic shellfish poisoning (DSP). In this paper we report on the isolation, structural elucidation and biosynthetic origin of two ester derivatives of okadaic acid on the basis of their spectroscopical data. Its biosynthetic origin was indicated by addition of labelled sodium [1- 13 C 1 ], [2- 13 C 2 ] and [1,2- 13 C 2 ] acetate to artificial cultures of the dinoflagellate.

Cytotoxic oxasqualenoids from the red alga Laurencia viridis.

Three new polyether squalene derivatives 15-dehydroxythyrsenol A (2), prethyrsenol A (3) and 13-hydroxyprethyrsenol A (4) have been isolated from the red alga Laurencia viridis. Their structures were determined through the interpretation of NMR spectroscopic data and chemical correlations. In addition, four semi-synthetic compounds modulating the solubility of the lead compound dehydrothyrsiferol (1) were prepared without loss of activity. The cytotoxicity of the new compounds exhibited low μM activities. In order to explain their biological properties, docking simulations of the natural and synthetic compounds onto the αvβ3 integrin binding region were carried out.

On the Configuration of Five-Membered Rings: A Spin-Spin Coupling Constant Approach

Five-membered rings are clearly among the most common structural motifs found in chemistry and biology. Nevertheless, the configuration of conformationally mobile five-membered rings is often difficult to assign from nuclear magnetic resonance (NMR) data. A simple, reliable, and efficient approach for the stereochemical analysis of five-membered rings based on the measurement of NMR coupling constants is presented. Density functional theory calculations using representative conformations of the full conformational space available to rings with different substitution patterns were used to identify differences between the accessible coupling constant values for cis and trans relative orientations of the substituents. The calculations were assessed experimentally using NMR data obtained from a number of models. This approach can be easily used to analyze different five-membered rings, such as oxolanes, cyclopentanes, furanosides and pyrrolidines, and their relative configuration can be determined without the need for making further conformational considerations.

Novel marine polyethers

Abstract The red seaweed Laurencia viridis is a rich source of secondary metabolites derived from squalene. Novel polyethers, clavidol 4 , 3-epi-1111-dehydrothyrsiferol 5 , and lactodehydrothyrsiferol 6 , have been isolated and their structures established by spectroscopical methods. The relative stereochemistry proposed for these compounds is based on ROESY and NOEDIFF data. Possible biogenetic pathways are also discussed.

Several new squalene-derived triterpenes from Laurencia

Abstract Four new triterpenoids with a squalene carbon skeleton martiriol 7, pseudodehydrothyrsiferol 8, dioxepandehydrothyrsiferol 9 and 16-epihydroxydehydrothyrsiferol 10 have been isolated from the red alga Laurencia viridis. The structures were determined through the interpretation of their spectral data and the relative stereochemistries were proposed on the basis of ROESY and NOEDIFF data. Their cytotoxic activities were evaluated.