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
西加毒素(Ciguatoxin) 聚醚梯：4.Maitotoxin MTX Polyether ladder刺尾鱼毒素 平间正博 1992,114 Maitotoxin MTX Maitotoxin .Na Maitotoxin MTX ofTwo World Records 0Mw-342 ith 99 sl of en le bond-there are 2-6.3
2 61 Hirama M. Science 2001, 294: 1904. 平间正博 PNAS, 2004,101, 12013–12018. 西加毒素 (Ciguatoxin) After a twelve-year struggle, the total synthesis of ciguatoxin CTX3C has been achieved. 62 4. Maitotoxin MTX 刺尾鱼毒素 Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto, T. J. Am. Chem. Soc. 1992, 114, 6594 C164H256O68S2Na2 32 ether rings 聚醚梯: Polyether ladder O O O O O O O O O O O O O OH O O O OH O O O O HO OH O OH S O O ONa HO OH OH OH OH OH O S O ONa HO OH O H H H H H H H HO H H H H H H H H OH OHH H H H H H OH H OH HO OH H H OH H H OH OH H H HO H H H H H O O O O O O O OH H H H H H H H H H HO H A B C D E F G H I J K L M N P Q R S T U V Y X W 51 52 O O O O O HO OH H H H H H H O Z A' B' D C' ' F E' ' 63 Maitotoxin MTX MTX 属于典型的钙通道激动剂 LD50 50 ng/Kg, 毒性高于岩沙海葵 毒素9倍，比河豚毒素强200倍。 Ca2+ ion channel activator MTX is the largest and most toxic of all non-peptidic secondary metabolites. Murata M. Yasumoto T. Nat. Prod. Rep. 2000, 17, 293-314. Murata M. Yasumoto T. Chem. Rev. 1993, 93, 1897-1909. 64 Maitotoxin 代表着现代鉴定技术NMR-MS在天然产物化学结构研究中的应用水平 C164H256O68S2Na2 村田 道雄 65 Maitotoxin MTX 5 μg/100 Kg 1 mg kill 1 million mice C164H256O68S2Na2 (MW = 3422) with 99 elements of stereochemistry-98 stereogenic centers and 1 trisubstituted double bond-there are 299=6.3 × 100 000 000000 000 000 000000 000 000 possible stereoisomers. Holder of Two World Records 66
Maitotoxin Extraction Maitotoxin Extraction [11 o5C年1m VK的络gg.na Structure Elucidation of Maitotoxin 梦罗 Degradation of maitoloxin (m 8*g the 特务 3
3 67 Maitotoxin Extraction Large-scale culture Were continued for Over ten years to yield around 10-20 mg of the pure sample From 4000 L of the Culture. 4000 L 村田 道雄 68 Maitotoxin Extraction 69 degradation reduction Structure Elucidation of Maitotoxin 70 Degradation of maitotoxin (Yasumoto, et al, 1992) [1] M. Murata, T. Iwashita, A. Yokoyama, M. Sasaki, T. Yasumoto, J. Am. Chem. Soc. 1992, 114, 6594. [2] a) M. Murata, H. Naoki, T. Iwashita, S. Matusunaga, M. Sasaki, A. Yokoyama, T. Yasumoto, J. Am. Chem. Soc. 1993, 115, 2060; b) M. Murata, H. Naoki, S. Matsunaga, M. Satake, T. Yasumoto, J. Am. Chem. Soc. 1994, 116, 7098; c) M. Satake, S. Ishida, T. Yasumoto, M. Murata, H. Utsumi, T. Hinomoto, J. Am. Chem. Soc. 1995, 117, 7019. 71 ? ? In 2006, the assigned structure of maitotoxin came under close scrutiny by Gallimore and Spencer on the basis of biosynthetic considerations, which suggested the opposite configuration at the two stereocenters of the JK junction (C-51, C-52). O O O O O O O O O O O O O OH O O O OH O O O O HO OH O OH S O O ONa HO OH OH OH OH OH O S O ONa HO OH O H H H H H H H HO H H H H H H H H OH OHH H H H H H OH H OH HO OH H H OH H H OH OH H H HO H H H H H O O O O O O O OH H H H H H H H H H HO H A B C D E F G H I J K L M N P Q R S T U V Y X W 51 52 O O O O O HO OH H H H H H H O Z A' B' D C' ' F E' ' 72
istry of Mairotosin Gymnocin-A a性 岸义人 安元健 h华 of from Japanese water 驾司鸟 Gambieric Acid A Yessotoxin (YTX) 从受毫的夏的消化中分海 y mt1987 虾夷南贝毒素 og(HSP): d eids A-D (GA-A-GA-D)wen 2n oo8 Yessotoxin(YTX) Yessotoxin(YTX) Ctt-yoe y es of YTX hay e beem id 4
4 73 岸 义人 74 Gymnocin-A A new cytotoxic polyether, Gymnicin-A, consists of 14 contiguous ether rings, isolated from a culture of the Red Tide dinoflagellate Gymnodinium mikimotoi from Japanese waters. M. Satake, M. Shoji, Y. Oshima, H. Naoki, T. Fujita and T. Yasumoto, Tetrahedron Lett., 2002, 43, 5829. O O O H O Me H H H H H OH H H O O O O O O O O O O O OH OH Me H H H H H H H Me H H H H Me H H H H H H H 佐竹 真幸 安元 健 75 Gambieric Acid A Gambieric acids A–D (GA-A–GA-D) were isolated in 1992 by Nagai and co-workers from a strain of the epiphytic marine dinoflagellate, Gambierdiscus toxicus, which is well-known as the causative organism responsible for ciguatera seafood poisoning and which showed strong antifungus activity. O O O O O O O O O HO HO O HO O OR2 OH R1 H H H H H H H H H H H H H Gambieric acid A: R1=R2=H Gambieric acid B: R1=CH3, R2=H Gambieric acid C: R1=H, R2= Gambieric acid D: R1=CH3, R2= O COOH O COOH H H 76 Yessotoxin YTX 从受毒的扇贝的消化腺中分得 Patinopecten yessoensis 1987 虾夷扇贝毒素 O O O O O O O O O O O A B C D E F G H I J K HO3SO HO3SO H H H H H H H H H H H H H H H H H H H OH OH 1 50 49 51 52 53 54 55 47 48 Murata, M.; Masanori, K.; Lee, J.S.; Yasumoto, T. Isolation and structure of Yessotoxin, a novel polyether compound implicated in diarrhetic shellfish poisoning. Tetrahedron Lett. 1987, 28, 5869-5872. Yessotoxin (YTX) Hepatotoxic Shellfish Poisoning (HSP): 77 O O O O O O O O O O O A B C D E F G H I J K HO3SO HO3SO H H H H H H H H H H H H H H H H H H H OH OH 1 50 49 51 52 53 54 55 47 48 Carboxy-Yessotoxin COOH O O O O O O O O O O O A B C D E F G H I J K HO3SO HO3SO H H H H H H H H H H H H H H H H H H H OH OH 1 50 49 51 52 53 54 55 47 48 45-OH Carboxy-Yessotoxin COOH OH Yessotoxin (YTX) Currently 36 natural derivatives of YTX have been identified. 78 O O O O O O O O O O O A B C D E F G H I J K HO3SO HO3SO H H H H H H H H H H H H H H H H H H H OH OH 1 50 49 51 52 53 54 55 47 48 45-OH Homo-Yessotoxin OH 45 O O O O O O O O O O O A B C D E F G H I J K HO3SO HO3SO H H H H H H H H H H H H H H H H H H H OH OH 1 50 49 51 52 53 54 55 47 48 CarboxyHomo-Yessotoxin OH 45 COOH Yessotoxin (YTX)
Hemi-brevetoxin B 个26 半短裸甲藻毒素 CHO Prasad A.V.K.Shimim V.J.Am Chom. 聚醚梯结构的特点 个 ◆2分子青梨具有相可的立体化半特征莉环间以反式构型 相连，相悠酵环上的氧原子交普位于环的上塘成下端： ◆3.分子的两明大多为唇聊脂硫殿图务基等级性基团。 Ca 140 Marine Polyethers 二、线性聚醚（脂链聚醚） Palytoxin岩沙海葵毒素 ◆含高度氧化的碳链，但仅部分形成避环，多最羟蒸测 高，于水溶性聚， 之
5 79 Hemi-brevetoxin B HBTX- A, B, C-Three Rings 4, 9/9/6/6 半短裸甲藻毒素 Me O O O O CHO OH H H H Me H OH H H Prasad A.V.K., Shimizu Y. J. Am. Chem. Soc. 1989, 111: 6476. YUZURU SHIMIZU 80 Prymnesium parvum The structure is characterized by the presence of carbon–carbon triple bonds, chlorine atoms and cyclic ethers. An amino functionality in the molecule is another outstanding feature since amino groups are relatively rare among microalgal polyketide metabolites. J. Am. Chem. Soc., 1996, 118, 479. O O O NH2 Cl O O O O O O O O O O O HO H H H H H H H HH OH Cl H OH H H OH OH HO HO HO H H H H H H Me H H H H OH H H H H H O H OH O OH O OH OH Cl O HO HO OH OH O OH OH OH O OH OH H HO HO R HO O OH OH OH OH OH OH Cl O HO HO OH R 2 Prymnesin-2 1 Prymnesin-1 81 聚醚梯结构的特点 u 1.聚醚梯的分子骨架是由一系列含氧五元至九元醚环邻接 稠合而成,形成一种陡坡式的梯形线状分子( Polyether ladder); u 2.分子骨架具有相同的立体化学特征,稠环间以反式构型 相连,相邻醚环上的氧原子交替位于环的上端或下端; u 3.分子的两端大多为醛酮酯硫酸酯羟基等极性基团. Ca 140 Marine Polyethers 82 O O Me Me Me H H H n n Syn Syn Trans Syn Syn Trans A characteristic feature of these toxins is the syn/trans stereochemistry of the ring junctions (Fig. 1). Examination of all known polyether ladders demonstrates that this feature is conserved across the family. Figure 1. Common structural features of ladder polyether ring junctions. 83 二、线性聚醚（脂链聚醚） v含高度氧化的碳链，但仅部分形成醚环，多数羟基游 离，属于水溶性聚醚。 Moore, R. E.; Scheuer, P. J. Science 1971.172, 495-498. 如 Palytoxin 岩沙海葵毒素 Uemura D. Ueda K. Hirata Y. Tetrahedron Lett. 1981, 22: 1909. Uemura D. Ueda K. Hirata Y. Tetrahedron Lett. 1981, 22: 2781-2784. Moore R. E. Bertolini G. J. Am. Chem. Soc. 1981, 103: 2491. LD50 = 0.15ug/Kg O OH OH OH HO O OH OH O HO OH OH OH OH O OH HO OH OH OH OH O O O OH NH2 HO OH O O O OH OH OH HO OH OH HO OH HN O NH OH O OH OH OH OH OH HO OH OH OH OH OH OH OH Super-carbon-chain compounds (SCC) 84 沙海葵毒素是最强的冠脉收缩剂，比血管紧张素Ⅱ起码强100倍。该毒素还有强 的抗癌活性，令人感兴趣的另一个事实是，它对离子通透性的作用与河豚毒素相 反，能使Na+通道开放。目前对沙海葵毒素的研究非常活跃-微生物生产和人工合成。 Palytoxin 岩沙海葵毒素 O OH OH OH HO O OH OH O HO OH OH OH OH O OH HO OH OH OH OH O O O OH NH2 HO OH O O O OH OH OH HO OH OH HO OH HN O NH OH O OH OH OH OH OH HO OH OH OH OH OH OH OH 1 115 平田义正