Total Synthesis and Confirmation of the Revised Structures of Azaspiracid‐2 and Azaspiracid‐3

Nicolaou, K. C.; Frederick, Michael O.; Petrović, Goran; Cole, Kevin P.; Loizidou, Eriketi Z.

doi:10.1002/ange.200600295

Cited by 21 publications

(12 citation statements)

References 53 publications

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“…In addition, there was a weak COSY correlation from 5.32 (H-7) to 4.70 ppm (H-6) and an HMBC correlation from C-6 (72.3 ppm) to 5.32 ppm (H-7). This leads to the assignment of this vinylic proton resonance (5.32 ppm) to H-7, and it defines the double bond as between C-7 and C-8 in 6, consistent with the structural revision of 1 by Nicolaou et al 39 A detailed analysis of NMR data for 1 and 2 (unpublished results) gave essentially identical results, so the original assignments 2,3 for 1−3 for C-7−C-9 and their attached protons and methyl groups are revised accordingly ( Table 2).…”

Section: Journal Of Agricultural and Food Chemistrysupporting

confidence: 85%

Improved Isolation Procedure for Azaspiracids from Shellfish, Structural Elucidation of Azaspiracid-6, and Stability Studies

Kilcoyne

Keogh

Clancy

et al. 2012

J. Agric. Food Chem.

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Azaspiracids are a group of lipophilic polyether toxins produced by the small dinoflagellate Azadinium spinosum. They may accumulate in shellfish and can result in illnesses when consumed by humans. Research into analytical methods, chemistry, metabolism, and toxicology of azaspiracids has been severely constrained by the scarcity of high-purity azaspiracids. Consequently, since their discovery in 1995, considerable efforts have been made to develop methods for the isolation of azaspiracids in sufficient amounts and purities for toxicological studies, in addition to the preparation of standard reference materials. A seven-step procedure was improved for the isolation of azaspiracids-1−3 (1, 2, and 3) increasing recoveries 2-fold as compared to previous methods and leading to isolation of sufficiently purified azaspiracid-6 (6) for structural determination by NMR spectroscopy. The procedure, which involved a series of partitioning and column chromatography steps, was performed on 500 g of Mytilus edulis hepatopancreas tissue containing ∼14 mg of 1. Overall yields of 1 (52%), 2 (43%), 3 (43%), and 6 (38%) were good, and purities were confirmed by NMR spectroscopy. The structure of 6 was determined by one-and two-dimensional NMR spectroscopy and mass spectrometry. The stability of 6 relative to 1 was also assessed in three solvents in a short-term study that demonstrated the greatest stability in aqueous acetonitrile.

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Section: Journal Of Agricultural and Food Chemistrysupporting

confidence: 85%

Improved Isolation Procedure for Azaspiracids from Shellfish, Structural Elucidation of Azaspiracid-6, and Stability Studies

Kilcoyne

Keogh

Clancy

et al. 2012

J. Agric. Food Chem.

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“…AZA‐2 and azaspiracid‐2‐methyl ester were synthesized by K.C. Nicolaou and coworkers (2006c). Mouse monoclonal antibodies against phospho‐JNK [p‐JNK, dually phosphorylated SAPK/JNK (Thr183/Try185)] and pan JNK/SAPK1 were purchased from BD Biosciences (Madrid, Spain).…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic effect of azaspiracid‐2 and azaspiracid‐2‐methyl ester in cultured neurons: Involvement of the c‐Jun N‐terminal kinase

Vale

Wandscheer

Nicolaou

et al. 2008

J of Neuroscience Research

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Human poisoning by azaspiracids (AZAs) has emerged as an increasing problem in Europe in recent years. Azaspiracid-2 (AZA-2) is one of the most abundant azaspiracids in nature. Although AZA-2 was recently involved in several toxic episodes leading to human intoxications, there is no information available about its mechanism of action or its cytotoxic effect in cellular models. This paper reports on the neurotoxic effect of azaspiracid-2 and its potential cellular targets. We explore the cellular and cytotoxic effects of AZA-2 and AZA-2-methyl ester (where the carboxylic acid moiety of AZA-2 was converted to the corresponding methyl ester) in cerebellar neurons. Pharmacological tools were used to analyze the role of different signal transduction pathways in the toxicity of AZA-2. The neurotoxicity of AZA-2 and AZA-2-methyl ester was developmentally regulated, exhibiting a higher cytotoxicity in younger cells (2-3 div). After excluding several signal transduction pathways, we found that inhibition of the mitogen-activated protein kinase JNK completely prevented the cytotoxic effect of AZA-2 in neurons. Furthermore, neuronal exposure to AZA-2 or AZA-2-methyl ester caused an increase in the amount of total and phosphorylated JNK and produced nuclear accumulation of the protein. The results presented here point to a common target for AZA-1 and AZA-2 and constitute the first experimental approach to investigate the cytotoxicity of AZA-2 in vitro, establishing an initial approach to probe the mechanism of action of these group of natural toxins.

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“…Azaspiracids were first recognized in the 1990s following an outbreak of human illness in the Netherlands that was associated with ingestion of blue mussels cultivated in Killary Harbour, Ireland (McMahon and Silke, 1996). The polyether toxins found to be present in this shellfish batch were subsequently identified and named azaspiracids (Satake et al, 1998;Nicolaou et al, 2006). Since then, AZA contamination of mussels above the European Union's regulatory level of 0.16 mg AZA per kg mussel meat has been a recurrent and major problem in Ireland (Salas et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Azadinium poporum from the Argentine Continental Shelf, Southwestern Atlantic, produces azaspiracid-2 and azaspiracid-2 phosphate

et al. 2016

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Total Synthesis and Confirmation of the Revised Structures of Azaspiracid‐2 and Azaspiracid‐3

Cited by 21 publications

References 53 publications

Improved Isolation Procedure for Azaspiracids from Shellfish, Structural Elucidation of Azaspiracid-6, and Stability Studies

Improved Isolation Procedure for Azaspiracids from Shellfish, Structural Elucidation of Azaspiracid-6, and Stability Studies

Cytotoxic effect of azaspiracid‐2 and azaspiracid‐2‐methyl ester in cultured neurons: Involvement of the c‐Jun N‐terminal kinase

Azadinium poporum from the Argentine Continental Shelf, Southwestern Atlantic, produces azaspiracid-2 and azaspiracid-2 phosphate

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