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.The monomericnature of tetrodotoxin in solution had been ascertained through a carefulanalysis of its titration curve.99 About 1-2 g of crystalline precipitate(tetrodotoxin) was obtained from 100 kg of puffer ovaries by followingHirata s procedure.99 Total synthesis of tetrodoxin was reported in 2004.1002.4.2 Tetrodotoxin DerivativesDetection of tetrodotoxin (TTX) derivatives occurring in puffers, newts, anda frog was facilitated by a highly sensitive TTX analyzer, which separatesanalogues on a reversed phase column and detects fluorescent products formedupon heating with sodium hydroxide solution.114, 115 Yasumoto et al116 haveisolated tetrodotoxin (55), 4-epi-TTX (56), 6-epi-TTX (57), 11-deoxy-TTX(58) and 11-deoxy-4-epi-TTX (59) from newts collected in Okinawa, Japan,and assigned their structure mainly through NMR measurements.11-Nortetrodotoxin-6 (R)-ol, 6-epi TTX (57) and 11-deoxy TTX (58) have been123obtained from the puffers Fugu niphobles.117 Chiriquitoxin,118 an unusualanalogue of tetrodotoxin in which 11-CH2OH of TTX had been replaced bya CH(OH)CH(NH2)-CO2H group, had been isolated from the Costa Ricanfrog Atelopus chiriquiensis.118 The puffer Arothron nigropunctatus had Bioactive Marine Toxins 167Compound R1 R2 R3 R455, TTX H OH OH OH56, 4-epi-TTX OH H OH OH57, 6-epi-TTX H OH CH2OH OH58, 11-deoxy-TTX H OH OH CH359, 11-deoxy-4-epi OH H OH CH360, 11-oxo-TTX H OH OH CH2OHfurnished 11-oxotetradotoxin hydrate (60) TTX, 4-epi TTX, 6-epi TTX, 11-deoxy TTX, 11-nor TTX-6(R)-ol.115 Two epimers of 11-nor TTX are likelyto be decarboxylation products of a hypothetical 11-CO2H derivative.Those analogues found in puffers and newts were not found in a CostaRican frog, Atelops chiriquiensis which contained TTX and chiriquitoxin.Interestingly, l-oxo TTX (60) was more active than TTX in blocking sodiumchannels.124,125 Other analogues were less potent than TTX.A pocket shapedmodel has been proposed for binding site in the sodium channel protein.Thecharge groups in a clevis of channel protein supposedly act as anchoringpoints by interacting with the toxin s functional groups orienting in differentdirections.1252.4.3 Mechanism of Tetrodotoxin and Saxitoxin ActionTetrodotoxin (55) and saxitoxin (1) are the most widely studied marinetoxins by physiologists and pharmacologists.In spite of their structuraldissimilarities, both are known to inactivate the sodium channel in the skeletalmuscles and nerve tissues of various animals.The effect of these toxins isspecific as both selectively block the transient Na+ current without any effecton the steady state current by K+ ions.Owing to this specific action of thesetoxins, many investigators are using them as tools in the characterization ofion channels.These toxins have become an extremely useful and popularchemical tool for the study of neurophysiology and neuropharmacology.Tetrodotoxin binds to the entrance part of the Na+ channel and inhibits Na+channel and Na+ influx, and generates an active potential, thus, causing theblockade of nerve of muscle function.Narahashi126 has reviewed the mechanism 168 Bioactive Marine Natural Productsof tetrodotoxin and saxitoxin action.Tetrodotoxin is commercially availableand in carefully controlled doses is being used as muscle relaxant and painkiller in neurogenic leprosy and terminal cancer.3.Neurotoxic Shellfish PoisoningThe dinoflagellate Gymnodinium breve (Ptychodiscus brevis) often formsblooms along the Florida coast and this leads to mass mortality of fish.Largeblooms of this organism (red tide) can kill hundreds of tons of fish a day.Sometimes the blooms cause human irritation in eyes and throat in the coastalareas, and the contamination of shellfish occasionally result in humanintoxication.The symptoms of neurotoxic shellfish poisoning (NSP) aremild which generally subside within 36 hrs, and include tingling and numbnessin the mouth and digits, ataxias, hot cold reversal of temperature sensation,myadriasis, reduced pulse rate, diarrhea and vomiting.126 NSP is not a lethalhuman intoxication.3.1 BrevetoxinsSeveral toxins have been isolated from the toxic dinoflagellate, Gymnodiniumbreve127 and named brevetoxins.128-131 Brevetoxin-B (GB-2 toxin) (61),132-137brevetoxin-C (62),138 GB-3 toxin (63),139 GB-5-toxin (64),140 and GB-6 toxin(65),140 GB-7 toxin (67)127 had been isolated from G.breve.Of the isolatedtoxins, brevetoxin-A (GB-l toxin) (66)127 is the most potent toxin in theFlorida Red Tide organism G.breve (Ptychodiscus brevis).Brevetoxins,particularly brevetoxin B is associated with the red tide catastrophes thatoccurs along coastal areas around the world.It is highly poisonous to humanlife and cases death.141 The term red tide means seawater decoloration byvast blooms of phytoplankton, which constitute the base of the marines foodchain.The name tide derives from the red coloration of seawaterredduring this process, although red tide may be brown, green or even colorless.61, X = O, Y = CH2, R = H (Brevetoxin-B)62, X = HCl, Y = O, R = H (Brevetoxin-C)63, X = HOH, Y = CH2, R = H (GB-3)64, X = O, Y = CH2, R = H (GB-4)65, X = O, Y = CH2, R = Ac (GB-5) Bioactive Marine Toxins 169The story of brevetoxin B may be summarized as for a passage in the biblementions an event that some believe high have been the first recorded incidentof a .red tide .and the waters that were in the river were turned to blood.And the fish that werein the river died, and the river stank and the Egyptians could not drink the water of theriver. [Exodus 7:20-21, 1000 B.C]The toxin is of particular interest not only because it is the most potenttoxin of the family but also because it uniquely binds to sodium channels onexcited membrane.3.1.1 Brevetoxin-ABrevetoxin-A (66)142,143 was isolated from the cultured cells of G.breve bypartition and successive chromatographic separation.127 It forms fine prisms,m.p.197-199°C; 218-220°C (double-melting point) from acetonitrile.Highresolution FAB mass spectrometry gave the molecular formula C49H70O13.1 13The H and C NMR spectra of the toxin showed the presence of twosecondary and two tertiary methyl groups, one methylene, one aldehyde,two disubstituted cis double bonds, and a carbonyl group.The IR band at11790 cm suggested that nonaldehyde carbonyl group belongs to ±-lactone [ Pobierz caÅ‚ość w formacie PDF ]
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.The monomericnature of tetrodotoxin in solution had been ascertained through a carefulanalysis of its titration curve.99 About 1-2 g of crystalline precipitate(tetrodotoxin) was obtained from 100 kg of puffer ovaries by followingHirata s procedure.99 Total synthesis of tetrodoxin was reported in 2004.1002.4.2 Tetrodotoxin DerivativesDetection of tetrodotoxin (TTX) derivatives occurring in puffers, newts, anda frog was facilitated by a highly sensitive TTX analyzer, which separatesanalogues on a reversed phase column and detects fluorescent products formedupon heating with sodium hydroxide solution.114, 115 Yasumoto et al116 haveisolated tetrodotoxin (55), 4-epi-TTX (56), 6-epi-TTX (57), 11-deoxy-TTX(58) and 11-deoxy-4-epi-TTX (59) from newts collected in Okinawa, Japan,and assigned their structure mainly through NMR measurements.11-Nortetrodotoxin-6 (R)-ol, 6-epi TTX (57) and 11-deoxy TTX (58) have been123obtained from the puffers Fugu niphobles.117 Chiriquitoxin,118 an unusualanalogue of tetrodotoxin in which 11-CH2OH of TTX had been replaced bya CH(OH)CH(NH2)-CO2H group, had been isolated from the Costa Ricanfrog Atelopus chiriquiensis.118 The puffer Arothron nigropunctatus had Bioactive Marine Toxins 167Compound R1 R2 R3 R455, TTX H OH OH OH56, 4-epi-TTX OH H OH OH57, 6-epi-TTX H OH CH2OH OH58, 11-deoxy-TTX H OH OH CH359, 11-deoxy-4-epi OH H OH CH360, 11-oxo-TTX H OH OH CH2OHfurnished 11-oxotetradotoxin hydrate (60) TTX, 4-epi TTX, 6-epi TTX, 11-deoxy TTX, 11-nor TTX-6(R)-ol.115 Two epimers of 11-nor TTX are likelyto be decarboxylation products of a hypothetical 11-CO2H derivative.Those analogues found in puffers and newts were not found in a CostaRican frog, Atelops chiriquiensis which contained TTX and chiriquitoxin.Interestingly, l-oxo TTX (60) was more active than TTX in blocking sodiumchannels.124,125 Other analogues were less potent than TTX.A pocket shapedmodel has been proposed for binding site in the sodium channel protein.Thecharge groups in a clevis of channel protein supposedly act as anchoringpoints by interacting with the toxin s functional groups orienting in differentdirections.1252.4.3 Mechanism of Tetrodotoxin and Saxitoxin ActionTetrodotoxin (55) and saxitoxin (1) are the most widely studied marinetoxins by physiologists and pharmacologists.In spite of their structuraldissimilarities, both are known to inactivate the sodium channel in the skeletalmuscles and nerve tissues of various animals.The effect of these toxins isspecific as both selectively block the transient Na+ current without any effecton the steady state current by K+ ions.Owing to this specific action of thesetoxins, many investigators are using them as tools in the characterization ofion channels.These toxins have become an extremely useful and popularchemical tool for the study of neurophysiology and neuropharmacology.Tetrodotoxin binds to the entrance part of the Na+ channel and inhibits Na+channel and Na+ influx, and generates an active potential, thus, causing theblockade of nerve of muscle function.Narahashi126 has reviewed the mechanism 168 Bioactive Marine Natural Productsof tetrodotoxin and saxitoxin action.Tetrodotoxin is commercially availableand in carefully controlled doses is being used as muscle relaxant and painkiller in neurogenic leprosy and terminal cancer.3.Neurotoxic Shellfish PoisoningThe dinoflagellate Gymnodinium breve (Ptychodiscus brevis) often formsblooms along the Florida coast and this leads to mass mortality of fish.Largeblooms of this organism (red tide) can kill hundreds of tons of fish a day.Sometimes the blooms cause human irritation in eyes and throat in the coastalareas, and the contamination of shellfish occasionally result in humanintoxication.The symptoms of neurotoxic shellfish poisoning (NSP) aremild which generally subside within 36 hrs, and include tingling and numbnessin the mouth and digits, ataxias, hot cold reversal of temperature sensation,myadriasis, reduced pulse rate, diarrhea and vomiting.126 NSP is not a lethalhuman intoxication.3.1 BrevetoxinsSeveral toxins have been isolated from the toxic dinoflagellate, Gymnodiniumbreve127 and named brevetoxins.128-131 Brevetoxin-B (GB-2 toxin) (61),132-137brevetoxin-C (62),138 GB-3 toxin (63),139 GB-5-toxin (64),140 and GB-6 toxin(65),140 GB-7 toxin (67)127 had been isolated from G.breve.Of the isolatedtoxins, brevetoxin-A (GB-l toxin) (66)127 is the most potent toxin in theFlorida Red Tide organism G.breve (Ptychodiscus brevis).Brevetoxins,particularly brevetoxin B is associated with the red tide catastrophes thatoccurs along coastal areas around the world.It is highly poisonous to humanlife and cases death.141 The term red tide means seawater decoloration byvast blooms of phytoplankton, which constitute the base of the marines foodchain.The name tide derives from the red coloration of seawaterredduring this process, although red tide may be brown, green or even colorless.61, X = O, Y = CH2, R = H (Brevetoxin-B)62, X = HCl, Y = O, R = H (Brevetoxin-C)63, X = HOH, Y = CH2, R = H (GB-3)64, X = O, Y = CH2, R = H (GB-4)65, X = O, Y = CH2, R = Ac (GB-5) Bioactive Marine Toxins 169The story of brevetoxin B may be summarized as for a passage in the biblementions an event that some believe high have been the first recorded incidentof a .red tide .and the waters that were in the river were turned to blood.And the fish that werein the river died, and the river stank and the Egyptians could not drink the water of theriver. [Exodus 7:20-21, 1000 B.C]The toxin is of particular interest not only because it is the most potenttoxin of the family but also because it uniquely binds to sodium channels onexcited membrane.3.1.1 Brevetoxin-ABrevetoxin-A (66)142,143 was isolated from the cultured cells of G.breve bypartition and successive chromatographic separation.127 It forms fine prisms,m.p.197-199°C; 218-220°C (double-melting point) from acetonitrile.Highresolution FAB mass spectrometry gave the molecular formula C49H70O13.1 13The H and C NMR spectra of the toxin showed the presence of twosecondary and two tertiary methyl groups, one methylene, one aldehyde,two disubstituted cis double bonds, and a carbonyl group.The IR band at11790 cm suggested that nonaldehyde carbonyl group belongs to ±-lactone [ Pobierz caÅ‚ość w formacie PDF ]