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
Total sy nthesis of PTX Palytoxin岩沙海葵毒素 沙海毒素的生物活性樱高，具有多种药理效应，它是量 水宿。试验结果表明，17只小白眼中16只（占94⅓）的所有墙细 惠被杀死，全部治意，引起了各方面科学寒的极大重视：令 素相及，地设对器 并用生物生产和人工合成 非常酒 Simultaneous Publications of Palytoxin Zooxanthellamide A ⊙ 191年，Moore发袭平面结构 I982年，Moore发表立体结构(MR) ,平田从沙海舞Pa时c中分箱 (合成 对* 主人，上村大（emura C-38脂肪酸多醚结构 大田软海绵酸(Okadaic AcidO) 人
6 85 沙海葵毒素的生物活性很高，具有多种药理效应，它是最 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，剂量84μg/kg时就能100％地抑制小鼠艾氏腹 水瘤。试验结果表明，17只小白鼠中16只(占94％)的所有癌细 胞被杀死，全部治愈，引起了各方面科学家的极大重视；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，包括它的性质、活性、用微生物生产和人工合成。 Palytoxin 岩沙海葵毒素 86 Armstrong R. W. Kishi et al. J. Am. Chem. Soc. 1989, 111: 7530. Totalsynthesis “珠穆朗玛峰的攀登” 64 C* & 7db 21 P-PhD and Dr. Students spend more than 8 years 岸 义人教授1937-，歧阜人，名大毕业，哈佛 教授载入美国化学会过去75最伟大的化学研究 Total Synthesis of PTX 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 杨玉荣 Carboxylic acid (C1-C115) in 1989, and that of palytoxin itself in 1994. 87 1971年， Scheuer从沙海葵 Palythoa toxica中分得。 1981年， Moore发表平面结构 1982年， Moore发表立体结构（NMR） 1974年，平田从沙海葵 Palythoa toxica中分得。 1981年，平田（Yoshimasa Hirata) 发表平面结构 1982年，平田义正 和岸义人 发表立体结构（合成） [主研人：上村 大埔 （Uemura Daisuke)] Simultaneous Publications of Palytoxin 88 Zooxanthellamide A K. Onodera, H. Nakamura, Y. Oba and M. Ojika, Tetrahedron, 2003, 59, 1067. From a cultured marine dinoflagellate Symbiodinium sp. 89 A Symbiodinium species, isolated in the free-living state from a Hawaiian tide pool, gave the polyhydroxy metabolite zooxanthellamide B 108, a dlactone analogue of zooxanthellamide A. Tetrahedron, 2003, 59, 1067. Zooxanthellamide B 90 C-38脂肪酸多醚结构 如 大田软海绵酸 (Okadaic Acid OA) Sigma 105 US$/0.025 mg ID50 = 1.7ug/L & 17ug/L to P388 & L1210 cell Tachibana, K. Structural Studies on Marine Toxins. 1980 Ph.D. Dissertation, University of Hawaii, Honolulu. Murakami, Y.; Oshima, Y.; Yasumoto, T. Bull. Jap. Sot. Sci. Fish. 1982,48,69-12. Murata, M.; Shimetani, M.; Sugitani, H.; Oshima, Y.; Yasumcto, T. Bull. Jap. Sot. Sci. Fish. 1982,48,549-552. Having 7 Analouges O O O O O O O HO O OH OH HO OH Tachibana K. Scheuer PJ. J. Am. Chem. Soc. 1981,103:2469
(Okadaic Acid OA) X 三、大环内酯聚醚 安元 iod1976-1982wer1000p kadaic acid. of DSP reported .195. Halichondrin B大田教海绵豪B Halichondrin B Halchondrin B及其天然类物目前 3内减 仅在5种海锦中被发现，它们是： agminata. 同以及L 发力 方公里的内，总存仅为29士料 nese sponge H s of the 才是必须的 海洋药物研究开发的制约因素—药源问题 Halicho HalavenTM e中味 中 是一种从色
7 91 Okadaic acid is a polyether fatty acid first isolated in 1981 from the marine sponges Halichondria okadaii. During the period 1976-1982 over 1000 people suffered diarrhetic shellfish poisoning (DSP) was shown to be caused by okadaic acid. Numerous cases of DSP were reported in countries such as Mexico, Spain, Netherlands, Scandinavia, France and South America. OA was used for studies of cellular regulation. The lethal potency of okadaic acid is 192 μg /kg. (Okadaic Acid OA) O O O O O O O HO O OH OH HO OH 92 三、大环内酯聚醚 有的聚醚类化合物可以首尾相连或局部成环形成大环内酯。大环内酯聚醚 大多来自扇贝，海绵，甲藻和苔藓虫。 扇贝毒素 Yasumota T, Murada M, Oshima Y, et al. Diarrhetic shellfish toxins. Tetrahedron, 1985, 41: 10l9-1025. O O O O O O O R O O O O OHOH OH 7 10 1 PTX1 R=CH2OH R at C-7 2 PTX2 R=CH3 R at C-7 3 PTX3 R=CHO R at C-7 4 PTX4 R=CH2OH S at C-7 5 PTX5 R=COOH R at C-7 6 PTX6 R=COOH S at C-7 Pectenotoxins 1 5 41 47 33 42 43 44 45 46 H H 安元 健 93 Halichondrin B (12.5 mg) is one of a series of compounds originally isolated and reported in 1985 from the 600 Kg Japanese sponge Halichondria okadai. Subsequently, a number of sponges from other areas of the Pacific and Indian Oceans were reported to contain one or more of these macrolides. Halichondrin B is being tested for melanoma and leukemia. . H O O O O O O O O O O O O O O H H H H H H H H H H H H O H H O H HO OH OH H H 44 Halichondrin B 上村 大埔 大田软海绵素 B 94 Halichondrin B • Halchondrin B 及其天然类似物目前 仅在5 种海绵中被发现，它们是： Halichondria okadai，Axinella sp， Raspalia agminata, Phakellia carteri 以 及 Lissodendoryxn. sp。其中Lissodendoryxn. sp 是最具开发潜力的海绵品种。 该海绵主要分布在日本Kaikoura 半岛附近海域水下约5 平 方公里的范围内，总存量仅为289 ± 90 t，而每吨该种海绵 中仅含有约310 mg halchondrin B。构效关系研究表明 halchondrin B 分子中的38元大环内酯片段对其抗肿瘤活性 才是必须的. • Aicher TD，Buszek KR，Fang FG，et al . J Am Chem Soc. 1992,114: 3162. Total Synthesis. Sipkema D, Osinga R, Schatton W, et al. Bioch. 2005, 90, 201-222. 95 Halichondrin B 全合成 每年需要 5 kg 需要 5000 吨Halichondria okadai 地球上仅有 289±90 吨 120 ×步 H O O O O O O O O O O O O O O H H H H H H H H H H H H O H H O H HO OH OH H H 44 （商业化） ？ 43个 进入临床和 临床前 20,000个 新化合物 海洋生物资源有限，难以大量采集; 化学结构复杂，难以人工合成。 海洋动物是游动的，难以再次采集； 海洋药物研究开发的制约因素——药源问题 96 Halaven是一种从黑色软海绵(Halichondria okadai)中提取的一种有化 疗活性Halchondrin B的衍生合成制剂。该注射药是一种非紫杉烷类微管 抑制剂，能抑制癌细胞生长。 2010年11月15日美国食品药品管理局(FDA) 宣布，Halaven (甲磺酸艾日布林)已获准用于治疗转移性乳腺癌患者。 Eribulin has been previously known as E7389 and ER-086526. Eribulin H O O O O O O O H H H H O H H H H O MeO H2N OH 大田软海绵素 Halichondrin B Halichondrin B and E-7389 = HalavenTM H O O O O O O O O O O O O O O H H H H H H H H H H H H O H H O H HO HO HO H H 44
Better than Nature? Better than Nature? ribulin-Synthesis ”中变的化 armgh idR4p,2050115g116M Spongistatins Nor-halichondrine A 四、聚醚三萜 聚醚三萜 特点角蛇烯生的三范，为灯薄和一些海所产生 ◆结构新瓶，含有多个手性中心，均有较好的生物活性， 女如Siphale nol C为ml
8 97 Better than Nature? H O O O O O O O O O O O O O O H H H H H H H H H H H H O H H O H HO HO HO H H 44 Halaven是一种从黑色软海绵(Halichondria okadai)中提取的一种有化 疗活性Halchondrin B的衍生合成制剂。该注射药是一种非紫杉烷类微管 抑制剂，能抑制癌细胞生长。 2010年11月15日美国食品药品管理局(FDA) 宣布，Halaven (甲磺酸艾日布林)已获准用于治疗转移性乳腺癌患者。 甲磺酸艾日布林 Eribulin-Synthesis Halchondrin Nature 98 From micrograms to grams: scale-up synthesis of eribulin mesylate Melvin J. Yu,*a Wanjun Zhenga and Boris M. Seletskya Nat. Prod. Rep., 2013,30, 1158-1164 Better than Nature? 99 Spongistatins v含有氢化吡喃螺环 的大环内酯环聚醚。 O O O Me OH O O O OR2 HO O O HO Me O HO H R HO R1O HO OMe H H H HO H H H H Spongistatin-1 R=Cl, R1=COMe, R2=COMe Spongistatin-2 R=H, R1=COMe, R2=COMe Spongistatin-3 R=Cl, R1=H, R2=COMe Spongistatin-4 R=Cl, R1=COMe, R2=H Spongistatin-6 R=H, R1=COMe, R2=H 1. Isolated in the early 1990's by the Pettit, Fusetani, and Kitagawa. 2. Pettit’s attempted re-isolation delivered 35 mg of spongistatin 1 from 13 TONS of sponge! 3. Two spiroketals, two tetrahydropyrans, hemiketal, 42 membered macrolide 100 Nor-halichondrine A Uemura D, Takahashi K, Yamamoto T, Katayama C, Tanaka J, Okumura Y and Hirata Y. Norhalichondrin A: an antitumor polyether macrolide from a marine sponge Halichondria okadai. J Am Chem Soc 1985, 107: 4796-4798. O O O O O O O O O O O O O O H H H H H H H H H H H H H O O HO COOH H HO OH Uemura D 101 四、聚醚三萜 v 特点 角鲨烯衍生的三萜,为红藻和一些海绵所产生。 v 结构新颖，含有多个手性中心，均有较好的生物活性。 v 如Sipholenol 海绵Siphonochalina siphonella O H OH 3 5 9 11 13 24 27 28 1 7 26 25 Sipholenol OH H H H 20 29 16 14 23 31 30 HO O O H OHAcO H OAc H O O O H O HO 3 5 9 11 13 15 23 24 25 28 29 1 7 17 26 27 30 31 Raspacionin Sodwanone E 102 聚 醚 三 萜 O O O OH H H O 19 1 3 17 25 26 27 28 29 30 31 5 7 9 11 13 15 23 24 从海绵Axinella weltneri中分得的sodwanones是一组结构类 似的聚醚三萜， 其中Sodwanone M 对P388细胞有选择性毒性 IC50为1 μg/mL O H O 3 5 9 11 13 24 27 28 1 7 26 25 Sipholenone B OH H H H 20 29 16 14 23 31 30 HO O
聚醚三萜 其他聚醚 AbudinolB Total more than6经 Seafood Poison Paralytie shellfish poisoning (PSP)is one of the ing caued by inges oxicated with one of four types of poisons Paralytic shellfish poisons (PSP):Saxitoxin 2.Neurotexic shelish poisom (NSP):BTX it poses serious health problems.Deterring shellfish 0 mption causes ccon 3.Diarrheticshefis pis(DSP):Okadaic Acid ic problems The history of the 4.Amnesic selfish poisons(ASP):Domoic Acid 5.Ciguatera Fish Poisoning (CFP):CTX.MTX 6.Paffer Fish Poisoning (PFP):TTX 7.Hepatotoxic Shellfish Poisoning (HSP):YTXs Ciguatera(Seafood Poisoning) Cieuatera Fish Poiso MTX)are alse re The term to food poisoning caused by health Itise ed tha ally from such po ng Two groups of comp duced by s and tran rred to herh orous fish and rded as the nri cantd 9
9 103 Fernandez J. J. et al. Marine polyehter triterpenes. Nat. Prod. Rep. 2000, 17, 235-246. 聚 醚 三 萜 Total more than 65 O O HO OH H H Abudinol B Testudinariol B O O OH HO H H H H 104 O O O O + HN HO OH O COOH 1 O O O O + HN HO O H 2 OH COOO 1975至1981年间日本人因吃牡蛎Pinna pectinata而发生食物中毒的多达 2500人，1995年上村大埔等从牡蛎P. pectinata中分离出4个毒性成分 pinnatoxins A-D，其中pinnatoxins A (1)和D (2)的结构已经确定，它们都 是Ca2+通道激动剂。 1. Uemura, D., Chou, T., Haino, T., Nagatsu, A., Fukuzawa, S., Zheng, S., Chen, H-S., Pinnatoxin, A., 1995. A toxic amphoteric macrocycle from the Okinawan bivalve Pinna muricata. J. Am. Chem. Soc. 117, 1155-1156. 其 他 聚 醚 Pinnatoxins A and D as a major cause of food poisoning. 105 Seafood Poison • Seafood poisoning is usually caused by ingestion of shellfish toxicated with one of four types of poisons 1. Paralytic shellfish poisons (PSP): Saxitoxin 2. Neurotoxic shellfish poisons (NSP): BTX 3. Diarrhetic shellfish poisons (DSP) : Okadaic Acid 4. Amnesic shellfish poisons (ASP) : Domoic Acid 5. Ciguatera Fish Poisoning (CFP): CTX, MTX 6. Puffer Fish Poisoning (PFP): TTX 7. Hepatotoxic Shellfish Poisoning (HSP): YTXs 106 Paralytic shellfish poisoning (PSP) is one of the most severe forms of food poisoning caused by ingestion of seafood. It is acute and often fatal. There is no effective way to destroy the toxins or to treat the patients. Therefore, it poses serious health problems. Deterring shellfish consumption causes economic problems. The history of the poisoning goes back to prehistoric days and the incidents due to the consumption of toxic shellfish are well documented. 107 The term ciguatera is used to food poisoning caused by ingestion of toxic coral reef fish. Ciguatera not only endangers public health. It is estimated that roughly 20,000 people suffer annually from such poisoning. Two groups of compounds implicated in the poisoning are ciguatoxin and maitotoxin. Both groups of toxins are produced by dinoflagellate Gambierdiscus toxicus and transferred to herbivorous fish and subsequently to carnivores through the food chain. Ciguatoxin is regarded as the principal toxin responsible for human illness. Ciguatera (Seafood Poisoning) 108 Ciguatera Fish Poisoning (CFP, such as CTX and MTX) are also responsible for many of the massive fish kills which have been observed throughout history and around the world. 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 CTX O O O O O O O O OH HO HO Me Me Me H Me H H H H H H H H H H H Me Gambierol
Diarrheic Shellfish Poisoning(DSP) Diarrheic Shellfish Poisoning(DSP) hr elapse timel nau ea (2.7 hr). and a"raw feeli red in 1976,asso ed wi eatified are Okadaic acid and its analogs and Dimopky本pp Pectenotoxins扇贝毒素 聚醚类化合物的特点 Diarrheic Shellfish Poisoning (DSP) ◆杂原子对碳原子的比例很高： ◆结构特殊。新题，分子量大 ◆活性强，刷毒：目前尚无扰毒剂 ◆广谱药效，作用机制装特： ◆多数对神经系统或心血管系统具有高特异性作用 ·海洋天然产物所特有。 聚醚类毒素 第四节肽类化合物Peptides 案能类毒家是海祥天然产物特有的一类化学结构如岩 女性 发的特森式结构。 级类7 岩沙海英毒素以符珠的作用方式作用于细胞膜具有强 经系作用 :别-红集藏 10
10 109 DSP is a major public health problem even though it is not lethal. The toxic symptoms are abdominal cramps (1 hr elapse time), nausea progressing to diarrhea (2-7 hr), and a “raw”, “burning” feeling in the stomach. Diarrhea is noted in 92% of all cases, nausea in 80%, vomiting in 79%, abdominal pain in 53%, and chills in 10%. DSP was first discovered in 1976, associated with eating bivalves such as mussels, scallops or clams which have accumulated dinoflagellate toxins. Causative toxins that have been identified are Okadaic acid and its analogs and pectenotoxins. Diarrheic Shellfish Poisoning (DSP) 110 Okadaic acid (OA) was first isolated independently from the sponges, Halichondria okadoi kadota and H. melonodocia. Subsequently, it was found in dinoflagellate, Prorocentrum lima and Dinophysis spp. O O O O O O O HO O OH OH HO OH Diarrheic Shellfish Poisoning (DSP) The first total synthesis of okadaic acid was achieved in 1984 by the Isobe group . 111 Pectenotoxins 扇贝毒素 Pectenotoxin-l (PTX1) was isolated as one of the Diarrheic Shellfish Toxins from the digestive glands of the scallop, Patinopecten yessoensis found Northeastern Japan. Diarrheic Shellfish Poisoning (DSP) O O O O O O O R O O O O HO OH OH 7 10 PTX1 R=CH2OH R at C-7 PTX2 R=CH3 R at C-7 PTX3 R=CHO R at C-7 PTX4 R=CH2OH S at C-7 PTX5 R=COOH R at C-7 PTX6 R=COOH S at C-7 Pectenotoxins 1 5 41 47 33 42 43 44 45 46 H H 112 聚醚类化合物的特点 u 杂原子对碳原子的比例很高； u 结构特殊，新颖，分子量大； u 活性强，剧毒；目前尚无抗毒剂。 u 广谱药效，作用机制独特； u 多数对神经系统或心血管系统具有高特异性作用。 u 海洋天然产物所特有。 113 聚醚类毒素是海洋天然产物特有的一类化学结构, 如岩 沙海葵毒素(PTX ) , 西加毒素(CTX ) , 刺尾鱼毒素(M TX) 等。其药理和毒理作用机制特殊, 常作用于控制生命过程的 关键靶位, 如神经受体、离子通道、生物膜等, 已成为新药开 发的特殊模式结构。 岩沙海葵毒素以特殊的作用方式作用于细胞膜, 具有强 抑癌活性。西加毒素具有高强心活性。海葵毒素已作为强心 药物的重要先导化合物。多数海生毒素均有较强的神经毒性, 而且作用于神经离子通道, 对神经系统起重要作用。 聚醚类毒素 114 第四节 肽类化合物 Peptides u海洋生物中一大类生物活性物质,来源于除海蛇以外进化程度 较低的动物,如海绵,水母,海兔,海葵,芋螺等以及蓝绿藻。 u 由于海洋环境的特殊，组成海洋多肽类的氨基酸除了常见的 氨基酸外，还有大量的特殊氨基酸， COOH N H COOH COOH N H COOH COOH N H COOH HOOC H 47 allo-kainc acid 48 1' 5' 6' 7' 8' a-Kainic acid Domoic Acid a-红藻氨酸 别-红藻氨酸 软骨藻草酸