2.Brevetoxin BTX-A Brevetoxins 黄自 西加鱼中毒事件 3.Ciguatoxin CTX 被多各、维尔京群岛、夏夷、 CH 美国197 198 中毒人数 (LD 0.25-4) g 因食用一种实紫科室鱼导教5侧人中毒，98人死亡，这是立 今报导的最严重的一起西加中毒 History of CTX History of CTX 40 Daring 1975-76.T.Yasumoto was retained by the WHOt 7 He di ied Gau 0 kg.viscera 125 kg) e(r n th (1.I mg)the totl planar stracture of Cwas achieved. 1 1 55 2. Brevetoxin BTX-A The structures of both PBTX-A & B were determined by X-ray crystallography • Shimizu, Y.; Chou, H. N.; Bando, J.; Van Duane, T.; Clardy, J. J. Am. Chem. SOC. 1986, 108: 514. Yuzuru Shimizu. Microalgal Metabolites. Chem. Rev. 1993. 93. 1885-1698. Jan Pawlak, Koji Nakanishi, Takashi Iwashita,t Michael L. Gross,! and Kenneth B. Tomer! Structure of Brevetoxin A as Constructed from NMR and MS Data. J. Am. Chem. SOC. 1987, 109, 1144-1150. • Nicolaou Group total synthesized BTX A after 10 years’ work, in 1998 10 rings with 22 chiral centers O O O O HO H Me H H H H Me H O O O O Me H H H Me H H H H O O O H H Me OHC 56 Brevetoxins O O O O O O O O O O O Me O RO Me Me Me Me Me Me H H H H H H H H H H H H H H H CH Y X Brevetoxin-B X=O, Y=CH2, R=H Brevetoxin-C X=HCl, Y=O, R=H GB-3 X=OH, Y=CH2, R=H GB-4 X=O, Y=CH2, R=H GB-5 X=O, Y=CH2, R=Ac 57 西加中毒多发生在热带及亚热带地区，以珊瑚礁鱼为 通常食用鱼的地区尤为多见。加勒比海周围，佛罗里达、 波多黎各、维尔京群岛、夏威夷、法属波利尼西亚群岛、 日本冲绳等地经常发生，印度洋地区也有报道。全世界每 年此类中毒者估计达数万人。 美国1977～1981年共发生西加中毒事件70起，中毒人数 367人。日本自1965～1986年的22年间共发生28起，300人 中毒。据Habermehl等报道，1993年11月在马达加斯加岛， 因食用一种真鲨科鲨鱼导致500人中毒，98人死亡，这是迄 今报导的最严重的一起西加中毒。 西加鱼中毒事件 58 3. Ciguatoxin CTX CTX 属于新型的钠通道激动剂,是引起人类中毒分布最广的一种毒素2-6万人/年 a C55 fatty acid coiled into one terminal spiro and twelve contiguous transfused ether rings ranging in size from oxolane to oxonane. The remaining structural features were unremarkable-five olefins, five methyls, and six hydroxyls, two as a terminal vicinal diol. O O O O O O O O O O O O O H H H H H HO H H H H OH H OH H H H H H H H H H H OH HO OH (LD50 0.25–4 μg/kg) To date, the structures of 20 congeners of ciguatoxins have been determined. 59 From 75 kg of toxic viscera, representing ca 1,100 kg of eels isolated 1.3 mg of HPLC pure CTX in 1967. But the results were spectacular: by 1980 a mass spectral molecular weight (1111.7 Da) and a 600 MHz 1H-NMR spectrum of ciguatoxin recorded. Next attempt to obtain sophisticated NMR data in an east coast Lab., ended in disaster. Their entire sample (1.3 mg) of CTX was destroyed when a pyridine solution of the toxin was transferred from a glass to a plastic tube. Attempted recovery of the toxin from a matrix of depolymerized plastic proved fruitless. Once again, a molecular structure of CTX became an elusive goal. More than 10 years work become fruitless. History of CTX Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science, 1967, 155, 1267-1268. 60 During 1975-76, T. Yasumoto was retained by the WHO to investigate “biotoxins in marine food fish” in French Polynesia. He discoveried Gambierdiscus toxicus and got partially purified toxin from moray eels (ca. 4000 kg, viscera 125 kg). With the same 0.35 mg of toxin that produced the correct molecular formula. Finally, by pooling all available supplies (1.1 mg) the total planar structure of CTX was achieved. History of CTX Murata, M.; Legrand, A. M.; Yasumoto, T. Tetrahedron Lett. l989, 30, 3793-3796. Murata, M.; Legrand, A. M.; Yasumoto, T. J. Am. Chem. Sot. 1989, 111, 8929-8932. Murata, M.; Legrand, A. M.; Yasumoto, T. J. Am Chem Sot. 1990, 112, 438-4386. Murata, M.; Legrand, A.-M.; Scheuer, P. J.; Yasumoto, T. Tetrahedron Lett. 1992, 33, 525-526