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Luis M Botana - One of the best experts on this subject based on the ideXlab platform.
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targeting chloride ion channels new insights into the mechanism of action of the Marine Toxin azaspiracid
Chemical Research in Toxicology, 2021Co-Authors: Andrea Boentejuncal, Carmen M Louzao, Sandra Raposogarcia, Carmen Vale, Luis M BotanaAbstract:Azaspiracids (AZAs) are Marine Toxins produced by dinoflagellates belonging to the genera Azadinium and Amphidoma that caused human intoxications after consumption of contaminated fishery products, such as mussels. However, the exact mechanism for the AZA induced cytotoxic and neurotoxic effects is still unknown. In this study several pharmacological approaches were employed to evaluate the role of anion channels on the AZA effects that demonstrated that cellular anion dysregulation was involved in the toxic effects of these compounds. The results presented here demonstrated that volume regulated anion channels (VRACs) are affected by this group of Toxins, and, because there is not any specific activator of VRACs besides the intracellular application of GTPγ-S molecule, this group of natural compounds could represent a powerful tool to analyze the role of these channels in cellular homeostasis. In addition to this, in this work, a detailed pharmacological approach was performed in order to elucidate the anion channels present in human HEK293 cells as well as their regulation by the Marine Toxins azaspiracids. Altogether, the data presented here demonstrated that the effect of azaspiracids in human cells was completely dependent on ATP-regulated anion channels, whose upregulation by these Toxins could lead to regulatory volume decrease and underlie the reported toxicity of these compounds.
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acute and chronic in vivo toxicity of the Marine Toxin palyToxin
2021Co-Authors: Andrea Boentejuncal, Carmen M Louzao, Sandra Raposogarcia, Celia Costas, Paz Otero, Carmen Vale, Luis M BotanaAbstract:PalyToxin (PLTX) is a Marine Toxin that nowadays is recognized amongst the most toxic compounds isolated from natural products. Originally, the Toxin was only identified in a single tidal pool of the island of Maui (Hawaii). Currently, this compound is considered as an emergent Toxin in Europe and its prevalence in continental European waters has increased during the last years. The high toxicity of palyToxin is related with the binding to the Na+-K+ ATPase, converting this ubiquitously distributed enzyme in a permeant cation channel [1-3]. Several reports have shown that this Toxin is responsible for human fatal intoxications, either after inhalation of Toxin-containing Marine aerosols or after ingestion of Marine products contaminated with PLTX, such as crabs, groupers, mackerel, and parrotfish. So far, different groups have explored the acute oral toxicity of PLTX in mice however, discrepancies in the PLTX source as well as in the monitoring time for the toxic effects yielded controversial results. Although the presence of palyToxin in Marine products is not yet currently regulated in Europe, the European Food Safety Authority (EFSA) expressed its opinion on PLTX toxicity and prompted the need to obtain more data regarding the in vivo toxicity of this compound [4]. Therefore, in this study, the acute and chronic toxicity of palyToxin was evaluated after oral administration of the Toxin to mice either in a single dose and in a follow-up period of 96 hours or after chronic administration during a 28-day period. After chronic exposure of mice to the Toxin, a lethal dose 50 (LD50) of 0.44 µg/kg of PLTX, much lower than that observed in the acute experiments, and a No-Observed-Adverse-Effect Level (NOAEL) of 0.03 µg/kg for repeated daily oral administration of PLTX were determined. Therefore, these data indicate a much higher chronic toxicity of PLTX and a lower NOAEL than that previously described in shorter treatment periods remarking the need to further evaluate the potential teratogenic effects of this emerging Marine Toxin in mammals. References Artigas, P.; Gadsby, D.C. Ion occlusion/deocclusion partial reactions in individual palyToxin-modified Na+/K+ pumps. Ann N Y Acad Sci 2003, 986, 116-126. Artigas, P.; Gadsby, D.C. Na+/K+-pump ligands modulate gating of palyToxin-induced ion channels. Proc Natl Acad Sci U S A 2003, 100, 501-505. Artigas, P.; Gadsby, D.C. Large diameter of palyToxin-induced Na+/K+ pump channels and modulation of palyToxin interaction by Na+/K+ pump ligands. J Gen Physiol 2004, 123, 357-376. EFSA. Panel on contaminants in the food chain (CONTAM). Scientific Opinion on Marine bioToxins in shellfish–PalyToxin group. EFSA Journal, 2009; Vol. 7, p 1393.
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activation of anion channels in human cells after long term exposure to the Marine Toxin azaspiracid
Proceedings of 1st International Electronic Conference on Toxins, 2021Co-Authors: Andrea Boentejuncal, Carmen M Louzao, Sandra Raposogarcia, Celia Costas, Paz Otero, Carmen Vale, Luis M BotanaAbstract:Azaspiracids (AZAs) comprise a group of Marine Toxins first documented in the Netherlands after ingestion of contaminated mussels, harvested in Ireland coasts, by the end of the last century [1-3]. Azaspiracids are known to be produced by dinoflagellates belonging to the genera Azadinium and Amphidoma [4]. In recent years, part of the research on Marine Toxins effects on human health have focused on their chronic effects. The presence of azaspiracid in fishery products has been regulated in Europe establishing a limit of 160 μg kg-1 AZA equivalents [5]. Since then, several acute in vitro studies were undertaken to elucidate their mechanism of action, but the results obtained showed great controversy regarding the possible cellular targets of AZAs that could contribute to the symptomatology elicited in humans after ingestion of contaminated fishery products. Our group has recently described that these Toxins partially blocked sodium entry into the cells and caused cytoskeletal alterations [6], however the effect of these Toxins on ion channels remains almost completely unexplored. Therefore, the main aim of our study was to gain more insight on the effects of azaspiracids on ionic homeostasis and cell volume regulation [7]. Thus, electrophysiological effects of nanomolar concentrations of azaspiracids (50 nM) after a 15-20 h exposition of human embryonic kidney cells (HEK293) which express the human Nav1.7 alpha subunit of the sodium channel were determined. Here, using electrophysiological techniques combined with several pharmacological approaches, we demonstrated that AZA-1 elicited a significant increase in anion efflux that could account for the pathophysiology observed in human intoxications. References McMahon, T. Winter toxicity of unknown aetiology in mussels. Harmful Algae News 1996, 14, 2. Ofuji, K.; Satake, M.; McMahon, T.; Silke, J.; James, K.J.; Naoki, H.; Oshima, Y.; Yasumoto, T. Two analogs of azaspiracid isolated from mussels, Mytilus edulis, involved in human intoxication in Ireland. Nat Toxins 1999, 7, 99-102. Satake, M.; Ofuji, K.; Naoki, H.; James, K.J.; Furey, A.; McMahon, T.; Silke, J.; Yasumoto, T. Azaspiracid, a New Marine Toxin Having Unique Spiro Ring Assemblies, Isolated from Irish Mussels, Mytilus edulis. Journal of the American Chemical Society 1998, 120, 9967-9968. Wietkamp, S.; Krock, B.; Clarke, D.; Vos, D.; Salas, R.; Kilcoyne, J.; Tillmann, U. Distribution and abundance of azaspiracid-producing dinophyte species and their Toxins in North Atlantic and North Sea waters in summer 2018. PLOS ONE 2020, 15, e0235015. European Commission. Regulation of the European Parliament and of the Council of 29 April 2004 laying down specific rules for the organisation of official controls on products of animal origin intended for human consumption, 854/2004/EC. In Official Journal, 2004; Vol. 50. Boente-Juncal, A.; Raposo-Garcia, S.; Costas, C.; Louzao, M.C.; Vale, C.; Botana, L.M. Partial Blockade of Human Voltage-Dependent Sodium Channels by the Marine Toxins Azaspiracids. Chemical research in toxicology 2020, 10.1021/acs.chemrestox.0c00216. Vale, C.; Nicolaou, K.C.; Frederick, M.O.; Vieytes, M.R.; Botana, L.M. Cell volume decrease as a link between azaspiracid-induced cytotoxicity and c-Jun-N-terminal kinase activation in cultured neurons. Toxicol Sci 2010, 113, 158-168.
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in vivo evaluation of the chronic oral toxicity of the Marine Toxin palyToxin
Toxins, 2020Co-Authors: Andrea Boentejuncal, Carmen M Louzao, Sandra Raposogarcia, Paz Otero, Carmen Vale, Luis M BotanaAbstract:PalyToxin (PLTX) is one of the most poisonous substances known to date and considered as an emergent Toxin in Europe. PalyToxin binds to the Na+-K+ ATPase, converting the enzyme in a permeant cation channel. This Toxin is known for causing human fatal intoxications associated with the consumption of contaminated fish and crustaceans such as crabs, groupers, mackerel, and parrotfish. Human intoxications by PLTX after consumption of contaminated fishery products are a serious health issue and can be fatal. Different reports have previously explored the acute oral toxicity of PLTX in mice. Although the presence of palyToxin in Marine products is currently not regulated in Europe, the European Food Safety Authority expressed its opinion on PLTX and demanded assessment for chronic toxicity studies of this potent Marine Toxin. In this study, the chronic toxicity of palyToxin was evaluated after oral administration to mice by gavage during a 28-day period. After chronic exposure of mice to the Toxin, a lethal dose 50 (LD50) of 0.44 µg/kg of PLTX and a No-Observed-Adverse-Effect Level (NOAEL) of 0.03 µg/kg for repeated daily oral administration of PLTX were determined. These results indicate a much higher chronic toxicity of PLTX and a lower NOAEL than that previously described in shorter treatment periods, pointing out the need to further reevaluate the levels of this compound in Marine products.
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first identification of palyToxin like molecules in the atlantic coral species palythoa canariensis
Analytical Chemistry, 2017Co-Authors: Maria Fraga, Carmen M Louzao, Natalia Vilarino, Lucia Molina, Yanira Lopez, Mark Poli, Luis M BotanaAbstract:PalyToxin (PLTX) is a complex Marine Toxin produced by Zoanthids (Palyhtoa), dinoflagellates (Ostreopsis), and cyanobacteria (Trichodesmium). Contact with PLTX-like compounds present in aerosols or Marine organisms has been associated with adverse effects on humans. The worldwide distribution of producer species and seafood contaminated with PLTX-like molecules illustrates the global threat to human health. The identification of species capable of palyToxin production is critical for human safety. We studied the presence of PLTX analogues in Palythoa canariensis, a coral species collected in the Atlantic Ocean never described as a PLTX-producer before. Two methodologies were used for the detection of these Toxins: a microsphere-based immunoassay that offered an estimation of the content of PLTX-like molecules in a Palythoa canariensis extract and an ultrahigh-pressure liquid chromatography coupled to an ion trap with a time-of-flight mass spectrometer (UPLC-IT-TOF-MS) that allowed the characterization of ...
Ulrich Blank - One of the best experts on this subject based on the ideXlab platform.
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yessoToxin a Marine Toxin exhibits anti allergic and anti tumoural activities inhibiting melanoma tumour growth in a preclinical model
PLOS ONE, 2016Co-Authors: Araceli Tobio, Luis M Botana, Amparo Alfonso, Iris K Maderasalcedo, Ulrich BlankAbstract:YessoToxins (YTXs) are a group of Marine Toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug.
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yessoToxin a Marine Toxin exhibits anti allergic and anti tumoural activities inhibiting melanoma tumour growth in a preclinical model
PLOS ONE, 2016Co-Authors: Araceli Tobio, Luis M Botana, Amparo Alfonso, Iris K Maderasalcedo, Ulrich BlankAbstract:YessoToxins (YTXs) are a group of Marine Toxins produced by the dinoflagellates Protoceratium reticulatum, Lingulodinium polyedrum and Gonyaulax spinifera. They may have medical interest due to their potential role as anti-allergic but also anti-cancer compounds. However, their biological activities remain poorly characterized. Here, we show that the small molecular compound YTX causes a slight but significant reduction of the ability of mast cells to degranulate. Strikingly, further examination revealed that YTX had a marked and selective cytotoxicity for the RBL-2H3 mast cell line inducing apoptosis, while primary bone marrow derived mast cells were highly resistant. In addition, YTX exhibited strong cytotoxicity against the human B-chronic lymphocytic leukaemia cell line MEC1 and the murine melanoma cell line B16F10. To analyse the potential role of YTX as an anti-cancer drug in vivo we used the well-established B16F10 melanoma preclinical mouse model. Our results demonstrate that a few local application of YTX around established tumours dramatically diminished tumour growth in the absence of any significant toxicity as determined by the absence of weight loss and haematological alterations. Our data support that YTX may have a minor role as an anti-allergic drug, but reveals an important potential for its use as an anti-cancer drug.
Daniel Romo - One of the best experts on this subject based on the ideXlab platform.
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Total synthesis of the spirocyclic imine Marine Toxin (-)-gymnodimine and an unnatural C4-epimer.
Journal of the American Chemical Society, 2011Co-Authors: Ke Kong, Changsuk Lee, Ziad Moussa, Daniel RomoAbstract:The first total synthesis of the Marine Toxin (−)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels–Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki–Hiyama–Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide, and a few additional steps provided (−)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.
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Enantioselective total synthesis of the Marine Toxin (-)-gymnodimine employing a Barbier-type macrocyclization.
Angewandte Chemie, 2009Co-Authors: Ke Kong, Daniel Romo, Changsuk LeeAbstract:Gymnodimine (1, Figure 1) is a member of the spirocyclic imine family of Marine Toxins initially isolated from oysters collected off the coast of New Zealand. The gross structure was initially reported by Yasumoto in 1995[i] and subsequently, Munro and Blunt reported the relative and absolute stereochemistry elucidated through X-ray crystallographic analysis of a reduced, N-acylated derivative.[ii] This Toxin is produced by the dinoflagellate Karenia selliforms (formerly Gymnodinium selliforme) and is active in the mouse bioassay for neurotoxic shellfish poisoning.[iii] Recently, gymnodimine was found to sensitize neurons to the effects of okadaic acid[iv] and there is evidence that it binds to a subset of muscle nicotinic acetylcholine receptors.[v] Two additional analogs, differing only by an allylic oxidation at the C17–C18 olefin, were isolated and named gymnodimine B (2) and C (3), respectively.[vi] Other members of this growing family of spirocyclic imine Toxins include the pinnaToxins,[vii] spirolides,[viii] pteriaToxins,[ix] prorocentrolide,[x] and spiro-prorocentrimine.[xi]
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studies toward a Marine Toxin immunogen enantioselective synthesis of the spirocyclic imine of gymnodimine
Organic Letters, 2005Co-Authors: Ke Kong, Ziad Moussa, Daniel RomoAbstract:[reaction: see text] An enantioselective Diels-Alder reaction catalyzed by an Evans' copper-bis(oxazoline) complex was utilized to construct a highly functionalized spirolactam, a key intermediate in our projected total synthesis of the Marine Toxin, gymnodimine. Additional transformations, including a mild N-tosyl group deprotection, afforded a keto spirocyclic imine moiety, the proposed pharmacophore of gymnodimine. Thus, the prepared ketone is a potentially useful intermediate for conjugation to provide an immunogen for eventual monitoring of gymnodimine and congeners.
Takeshi Yasumoto - One of the best experts on this subject based on the ideXlab platform.
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inhibition of actin polymerization by Marine Toxin pectenoToxin 2
Journal of Veterinary Medical Science, 2017Co-Authors: Masatoshi Hori, Takeshi Yasumoto, Futoshi Yazama, Yasuhiro Matsuura, Ryo Yoshimoto, Takeharu Kaneda, Hiroshi Ozaki, Hideaki KarakiAbstract:PectenoToxin-2 (PCTX-2) is one of the polyether macrolide Toxins isolated from scallops involved in diarrheic shellfish poisoning via actin depolymerization. In the present study, we examined the bioactive mechanism of PCTX-2 in smooth muscle cells and clarify mode of action of the PCTX-2-induced actin depolymerization using purified skeletal actin. PCTX-2 (300 nM-3 µM) non-selectively inhibited vascular smooth muscle contractions elicited by high K+ or phenylephrine in a dose-dependent manner. However, elevated cytosolic Ca2+ and myosin light chain phosphorylation stimulated by high K+ were only slightly inhibited by PCTX-2. By monitoring the fluorescent intensity of pyrenyl-actin, PCTX-2 was found to inhibit both the velocity and degree of actin polymerization. The critical concentration of G-actin was linearly increased in accordance with the concentration of PCTX-2, indicating sequestration of G-actin with 1 to 1 ratio. The kinetics of F-actin depolymerization by dilution assay indicated that PCTX-2 does not sever F-actin. Transmission electron microscopic and confocal microscopic observations demonstrated that PCTX-2 selectively depolymerized filamentous actin without affecting tublin. In conclusion, PCTX-2 is a potent natural actin depolymerizer which sequesters G-actin without severing F-actin.
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transcriptional profiling and inhibition of cholesterol biosynthesis in human t lymphocyte cells by the Marine Toxin azaspiracid
Genomics, 2008Co-Authors: Michael J Twiner, Masayuki Satake, James C Ryan, Jeanine S Morey, Kent J Smith, Samar M Hammad, Frances M Van Dolah, Philipp Hess, Terry Mcmahon, Takeshi YasumotoAbstract:Azaspiracid-1 (AZA-1) is a Marine bioToxin reported to accumulate in shellfish from several countries, including eastern Canada, Morocco, and much of western Europe, and is frequently associated with severe gastrointestinal human intoxication. As the mechanism of action of AZA-1 is currently unknown, human DNA microarrays and qPCR were used to profile gene expression patterns in human T lymphocyte cells following AZA-1 exposure. Some of the early (1 h) responding genes consisted of transcription factors, membrane proteins, receptors, and inflammatory genes. Four- and 24-h responding genes were dominated by genes involved in de novo lipid biosynthesis of which 17 of 18 involved in cholesterol biosynthesis were significantly up regulated. The up regulation of synthesis genes was likely in response to the ca. 50% reduction in cellular cholesterol, which correlated with up regulated protein expression levels of the low-density lipoprotein receptor. These data collectively detail the inhibition of de novo cholesterol synthesis, which is the likely cause of cytotoxicity and potentially a target pathway of the Toxin.
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chronic effects in mice caused by oral administration of sublethal doses of azaspiracid a new Marine Toxin isolated from mussels
Toxicon, 2002Co-Authors: Emiko Ito, Masayuki Satake, Terry Mcmahon, Katsuya Ofuji, Morihiro Higashi, Kenichi Harigaya, Takeshi YasumotoAbstract:Abstract Toxicological effects of orally administered azaspiracid (AZA), a new Toxin isolated from mussels, were investigated. First, a total of 25 mice were administered AZA twice at 300–450 μg/kg doses and observed for recovery processes from severe injuries. Slow recoveries from injuries were revealed: erosion and shortened villi persisted in the stomach and small intestine for more than 3 months: edema, bleeding, and infiltration of cells in the alveolar wall of the lung for 56 days; fatty changes in the liver for 20 days; and necrosis of lymphocytes in the thymus and spleen for 10 days. Secondly, low doses of AZA (50, 20, 5 and 1 μg/kg) were administered twice a week up to 40 times to four groups of mice. Many mice, nine out of ten at 50 μg/kg and three out of ten at 20 μg/kg, became so weak that they were sacrificed before completion of 40 injections. All these mice showed interstitial pneumonia and shortened small intestinal villi. Most importantly, lung tumor were observed in four mice, one out of ten (10%) at 50 μg/kg and three out of ten (30%) at 20 μg/kg. Tumors were not observed in 11 mice treated at lower doses and in 19 control mice. Hyperplasia of epithelial cells was also observed in the stomach of six mice out of ten administered at 20 μg/kg.
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transient ca2 dependent activation of erk1 and erk2 in cytotoxic responses induced by maitoToxin in breast cancer cells
FEBS Letters, 1999Co-Authors: Claudia Malaguti, Takeshi Yasumoto, Gian Paolo RossiniAbstract:Abstract Treatment of MCF-7 breast cancer cells with the Marine Toxin maitoToxin (MTX) induces cell death. The cytotoxic effects are clearly detectable within 2–4 h after cell treatment with 10 −10 –10 −9 M concentrations of MTX. The response was found to depend on extracellular Ca 2+ , inasmuch as cell death was prevented when culture dishes received MTX, following addition of EGTA. MTX caused transient phosphorylation of extracellular signal-regulated kinase isoforms 1 and 2 (ERK1 and ERK2) mitogen-activated protein kinase isoforms in MCF-7 cells, which was maximal 15 min after Toxin addition to culture vessels. The effect was dependent on influx of extracellular Ca 2+ , as it was abolished by EGTA, and was induced by ionophores, such as A23187 and ionomycin. Our findings show that signaling pathways involving Ca 2+ ions may cause activation of ERK1 and ERK2 in cell death responses.
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gymnodimine a new Marine Toxin of unprecedented structure isolated from new zealand oysters and the dinoflagellate gymnodinium sp
Tetrahedron Letters, 1995Co-Authors: Takeshi Seki, Masayuki Satake, Lincoln Mackenzie, Heinrich F Kaspar, Takeshi YasumotoAbstract:Abstract A new Marine Toxin, gymnodimine, was isolated from New Zealand oysters, Tiostrea chilensis, and the dinoflagellate Gymnodinium cf. mikimotoi. Its unique structure was elucidated by spectroscopic methods.
Ke Kong - One of the best experts on this subject based on the ideXlab platform.
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Total synthesis of the spirocyclic imine Marine Toxin (-)-gymnodimine and an unnatural C4-epimer.
Journal of the American Chemical Society, 2011Co-Authors: Ke Kong, Changsuk Lee, Ziad Moussa, Daniel RomoAbstract:The first total synthesis of the Marine Toxin (−)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels–Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki–Hiyama–Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide, and a few additional steps provided (−)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.
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Enantioselective total synthesis of the Marine Toxin (-)-gymnodimine employing a Barbier-type macrocyclization.
Angewandte Chemie, 2009Co-Authors: Ke Kong, Daniel Romo, Changsuk LeeAbstract:Gymnodimine (1, Figure 1) is a member of the spirocyclic imine family of Marine Toxins initially isolated from oysters collected off the coast of New Zealand. The gross structure was initially reported by Yasumoto in 1995[i] and subsequently, Munro and Blunt reported the relative and absolute stereochemistry elucidated through X-ray crystallographic analysis of a reduced, N-acylated derivative.[ii] This Toxin is produced by the dinoflagellate Karenia selliforms (formerly Gymnodinium selliforme) and is active in the mouse bioassay for neurotoxic shellfish poisoning.[iii] Recently, gymnodimine was found to sensitize neurons to the effects of okadaic acid[iv] and there is evidence that it binds to a subset of muscle nicotinic acetylcholine receptors.[v] Two additional analogs, differing only by an allylic oxidation at the C17–C18 olefin, were isolated and named gymnodimine B (2) and C (3), respectively.[vi] Other members of this growing family of spirocyclic imine Toxins include the pinnaToxins,[vii] spirolides,[viii] pteriaToxins,[ix] prorocentrolide,[x] and spiro-prorocentrimine.[xi]
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Studies toward the total synthesis of the Marine Toxin, (-)-gymnodimine
2009Co-Authors: Ke KongAbstract:(-)-Gymnodimine is a member of a growing family of spirocylic imine containing Marine natural products. The construction of the complete skeleton of (-)- gymnodimine has been accomplished in a convergent manner in 23 steps (the longest linear sequence). A highly diastereo- and enantioselective Diels-Alder reaction employing bis(oxazoline)·Cu(II) catalyst provided the spirolactam core structure of gymnodimine bearing a quaternary carbon stereogenic center. An improved procedure for hydrostannylation of the hindered internal triple bond in 96a was discovered by slow addition of tributyltin hydride to minimize formation of hydrogenated byproduct. Fragment coupling featured a Nozaki-Hiyama-Kishi reaction between a vinyl iodide derived from the spirolactam and a tetrahydrofuran moiety. The macrocyclization was realized through a rather unusual intramolecular opening of an activated Ntosyllactam by an alkyllithium species generated in situ. The butenolide was appended through a vinylogous Mukaiyama aldol addition of silyloxyfuran 155 to the ketone 163 under meticulously controlled conditions. The generality of this process was explored in some detail. Addition of silyloxyfurans to cyclohexanones proceeds with moderate to good diastereoselectivities. The potential application of this process to the synthesis of butenolide and g-lactone containing natural products was demonstrated by further transformations of the addition adducts. Finally, toward our goal of developing an enzyme-linked immunosorbent assay (ELISA) for gymnodimine monitoring a hapten derived from the tetrahydrofuran has been synthesized. Even though the raised antibodies failed to recognize the natural product itself, the results provided some information regarding the essential structural elements of an efficient hapten
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studies toward a Marine Toxin immunogen enantioselective synthesis of the spirocyclic imine of gymnodimine
Organic Letters, 2005Co-Authors: Ke Kong, Ziad Moussa, Daniel RomoAbstract:[reaction: see text] An enantioselective Diels-Alder reaction catalyzed by an Evans' copper-bis(oxazoline) complex was utilized to construct a highly functionalized spirolactam, a key intermediate in our projected total synthesis of the Marine Toxin, gymnodimine. Additional transformations, including a mild N-tosyl group deprotection, afforded a keto spirocyclic imine moiety, the proposed pharmacophore of gymnodimine. Thus, the prepared ketone is a potentially useful intermediate for conjugation to provide an immunogen for eventual monitoring of gymnodimine and congeners.