Isolation and structure of brevetoxin B from the "red tide" dinoflagellate Ptychodiscus brevis (Gymnodinium breve)

Lin, Yong-Yeng; Risk, Martin; Ray, Sammy M.; Engen, D. Van; Clardy, Jon; Golik, Jerzy; James, John C.; Nakanishi, Koji

doi:10.1021/ja00412a053

Cited by 544 publications

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Section: Introductionmentioning

confidence: 99%

“…The most well-known bioactive compounds isolated from K. brevis are a family of neurotoxins called the brevetoxins (Figure 1), which consist of nine different toxins with two different structural backbones: brevetoxin-A (containing 10 fused cyclic ether rings, 5,8,6,7,9,8,8,6,6,6) 1-3 and brevetoxin-B (containing 11 fused cyclic ether rings, 6,6,6,7,7,6,6,8,6,6,6). [3][4][5][6][7][8] Brevetoxins bind with high affinity to site 5 of voltage sensitive sodium channels (VSSC) in neurons. 9,10 Binding of brevetoxins to tissues containing VSSC results in membrane depolarization, repetitive firing, and increased sodium currents.…”

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confidence: 99%

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A New Polyether Ladder Compound Produced by the Dinoflagellate Karenia b revis

et al. 2004

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A new ladder-frame polyether compound containing five fused ether rings was isolated from laboratory cultures of the marine dinoflagellate Karenia brevis. This compound, named brevenal, and its dimethyl acetal derivative both competitively displace brevetoxin from its binding site in rat brain synaptosomes. Significantly, these compounds are also nontoxic to fish and antagonize the toxic effects of brevetoxins in fish. The structure and biological activity of brevenal, as well as the dimethyl acetal derivative, are described in this paper.A number of bioactive polyether compounds have been isolated from the marine dinoflagellate Karenia brevis, the organism responsible for toxic red tides along Florida's Gulf Coast. The most well-known bioactive compounds isolated from K. brevis are a family of neurotoxins called the brevetoxins (Figure 1), which consist of nine different toxins with two different structural backbones: brevetoxin-A (containing 10 fused cyclic ether rings, 5,8,6,7,9,8,8,6,6,6) 1-3 and brevetoxin-B (containing 11 fused cyclic ether rings, 6,6,6,7,7,6,6,8,6,6,6). 3-8Brevetoxins bind with high affinity to site 5 of voltage sensitive sodium channels (VSSC) in neurons. 9,10 Binding of brevetoxins to tissues containing VSSC results in membrane depolarization, repetitive firing, and increased sodium currents. 11-14 Investigation of the effect of brevetoxins on excitable membranes using voltage clamp experiments indicates that brevetoxins activate VSSC by prolonging mean open time, inhibiting channel inactivation, and shifting the channel activation potential to more negative values. 12-14 During K. brevis red tides humans are most commonly affected by brevetoxins that have been aerosolized in sea spray or bioaccumulated in shellfish. Inhaled brevetoxins cause respiratory irritation and breathing difficulties in sensitive populations. 15-17 At sufficiently high concentrations ingested brevetoxins lead to a collection of symptoms commonly referred to as neurotoxic shellfish poisoning (NSP). 18,19 NSP in humans is characterized by sensory abnormalities, cranial nerve dysfunction, gastrointestinal symptoms, and sometimes respiratory failure. 19In 1989 Prasad and Shimizu 20 isolated and described another polyether ladder compound from K. brevis cultures that contained a different structural backbone and named it hemibrevetoxin-B. Hemibrevetoxin-B contains structural features similar to brevetoxin but is about half of the size and contains only four fused cyclic ether rings (6,6,7,7). Hemibrevetoxin-B (Figure 2) showed cytotoxicity in mouse neuroblastoma cells at concentrations of 5 μM, but no fish or In this report we describe the isolation, structural characterization, and biological activity of a new ladder-frame polyether aldehyde named brevenal (Figure 3a), isolated from cultures of K. brevis. Brevenal as well as its dimethyl acetal derivative ( Figure 3b) contain five fused cyclic ether rings, have low toxicity to fish, and have a structural backbone different from both brevetoxins and hemibre...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

A New Polyether Ladder Compound Produced by the Dinoflagellate Karenia b revis

et al. 2004

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“…During Florida red tides, dead fish are often associated with a bloom of the dinoflagellate Karenia brevis [= Gymnodinium breve (15)]. This organism produces a series of 10 polyether toxins (brevetoxins); the three most abundant forms are shown in Figure 1 (16)(17)(18)(19)(20). Brevetoxins bind with high affinity to site five of voltage-gated sodium channels in nerves, producing membrane depolarization (21,22).…”

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confidence: 99%

New fish-killing alga in coastal Delaware produces neurotoxins.

Bourdelais

Tomas

Naar

et al. 2002

Environ Health Perspect

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Ten fish mortality events, involving primarily Atlantic menhaden, occurred from early July through September 2000 in several bays and creeks in Delaware, USA. Two events involved large mortalities estimated at 1-2.5 million fish in Bald Eagle Creek, Rehoboth Bay. Samples from Indian Inlet (Bethany Beach), open to the Atlantic, as well as from an enclosed area of massive fish kills at nearby Bald Eagle Creek and Torque Canal were collected and sent to our laboratory for analysis. Microscopic examination of samples from the fish kill site revealed the presence of a single-cell Raphidophyte alga Chattonella cf. verruculosa at a maximum density of 1.04 x 10(7) cells/L. Naturally occurring brevetoxins were also detected in the bloom samples. Besides the Chattonella species, no other known brevetoxin-producing phytoplankton were present. Chromatographic, immunochemical, and spectroscopic analyses confirmed the presence of brevetoxin PbTx-2, and PbTx-3 and -9 were confirmed by chromatographic and immunochemical analyses. This is the first confirmed report in the United States of brevetoxins associated with an indigenous bloom in temperate Atlantic estuarine waters and of C. cf. verruculosa as a resident toxic organism implicated in fish kills in this area. The bloom of Chattonella continued throughout September and eventually declined in October. By the end of October C. cf. verruculosa was no longer seen, nor was toxin measurable in the surface waters. The results affirm that to avoid deleterious impacts on human and ecosystem health, increased monitoring is needed for brevetoxins and organism(s) producing them, even in areas previously thought to be unaffected.

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“…As shown in Fig. 4, we undertook our goal of constructing the actual nanometer-scale ring system of 1, starting from the ABCDE ring and the HIJKLM ring segments (7,11). First, the terminal olefin of 11 was oxidatively cleaved to produce aldehyde 12.…”

Section: Resultsmentioning

confidence: 99%

“…injection into mice are much greater than the structurally related red-tide toxins, brevetoxins (LD 50 Ͼ 100 g͞kg) (11)(12)(13)(14)(15). Orally, an amount as small as 70 ng of CTX 4 can induce intoxication symptoms in humans (16).…”

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confidence: 99%

First- and second-generation total synthesis of ciguatoxin CTX3C

Inoue

Miyazaki

Uehara

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

116

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More than 20,000 people suffer annually from ciguatera seafood poisoning in subtropical and tropical regions. The extremely low content of the causative neurotoxins, designated as ciguatoxins, in fish has hampered isolation, detailed biological studies, and preparation of anti-ciguatoxin antibodies for detecting these toxins. Furthermore, the large (3 nm in length) and complex molecular structure of ciguatoxins has impeded chemists from completing their total synthesis. In this article, the full details of studies leading to the total synthesis of ciguatoxin CTX3C are provided. The key elements of the first-generation approach include O,O-acetal formation from the right and left wing fragments, conversion from O,O-acetal to O,S-acetal, a radical reaction to cyclize the G ring, a ring-closing metathesis reaction to close the F ring, and final removal of the 2-naphtylmethyl protective groups. Subsequent studies provided a second-generation total synthesis, which is more concise and results in a higher yield. Second-generation synthesis was accomplished by using a direct method of constructing the key intermediate O,S-acetal from ␣-chlorosulfide and a secondary alcohol. These syntheses ensure a practical supply of ciguatoxin for biological applications.ciguatera ͉ polyether ͉ convergent strategy C iguatera is a human intoxication caused by the ingestion of certain reef fish (1). More than 20,000 people suffer annually from ciguatera, making it one of the most common forms of nonbacterial food poisoning. Ingestion of affected fish leads to neurological, gastrointestinal, and cardiovascular disorders, which may last up to a month or more. The most prominent symptom is a disorder of temperature sensation. Specifically, touching cold water can induce pain similar to that of an electric shock. Other symptoms include diarrhea, vomiting, muscle pain and itching, whereas paralysis, coma, and even death may occur in severe cases.Yasumoto et al. (2) identified an epiphytic dinoflagellate, Gambierdiscus toxicus, as the causative organism and demonstrated that dinoflagellate-derived toxins are transferred by the food chain to various fish. About 100 species of fish cause ciguatera, and ciguateric fish look, taste, and smell like normal uncontaminated fish. In addition, the occurrence of poisoning is completely unpredictable. Current difficulties in predicting, detecting, and treating ciguatera have had an adverse socioeconomic impact, in particular, in developing countries.Ciguatoxins are regarded as the principal causative toxins of ciguatera seafood poisoning (Fig. 1) (3, 4). In 1989, the Yasumoto group successfully elucidated the structures of ciguatoxin (CTX) (4) and CTX4B (3) (5, 6), which were found to be large polycyclic ethers having molecular lengths Ͼ3 nm. They subsequently isolated other congeners including CTX3C (1) (7) and 51-hydroxyCTX3C (2) (8). To date, the structures of Ͼ20 congeners of ciguatoxins have been determined (9, 10).The lethal potencies of ciguatoxins (LD 50 ϭ 0.25-4 g͞kg) by i.p. injection into mic...

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Isolation and structure of brevetoxin B from the "red tide" dinoflagellate Ptychodiscus brevis (Gymnodinium breve)

Cited by 544 publications

References 0 publications

A New Polyether Ladder Compound Produced by the Dinoflagellate Karenia b revis

A New Polyether Ladder Compound Produced by the Dinoflagellate Karenia b revis

New fish-killing alga in coastal Delaware produces neurotoxins.

First- and second-generation total synthesis of ciguatoxin CTX3C

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