Structural Diversity Gymnorrhizol Structural Diversity aricin 氟代酸基 的第 pathee D Cm o7. Structural Diversity Ingenamine G Symmetric Marine Compounds Symmetric Marine Compounds Aerothionin
1 33 S S S S S NH2 OMe MeO Varicin was isolated from algae Lissoclinun vareau, 中分离 的第一个天然存在的环状多硫化合物，Varicin有十分显著的 抗肿瘤活性。在人肠癌试管混合实验时，其活性比已知的治 疗药物5-氟尿嘧啶细胞毒性高100倍。 Varicin Gymnorrhizol, an unusual macrocyclic polydisulfide possessing an unprecedented carbon skeleton, has been isolated from a mangrove Bruguiera gymnorrhiza (Guangxi). Guo YW, TL 2004, 45, 5533. Structural Diversity Gymnorrhizol 34 O OH Cl N Cl Cl Cl OH NaO3SO OH OH OSO2NHMe Faulkner D. J. J. Am. Chem. Soc. 1977, 99, 7367. Faulkner D. J. Tetrahedron. 1999, 55, 8323. Structural Diversity Marine Sponges Special residue 二氯代亚胺基 扩大了天然存在 的基团的概念 35 Structural Diversity The structure elucidation of Aplasmomycin A was performed by X-ray crystallographic methods. To the surprise, the molecule contained an unexpected Boron atom in the center of the complex. Nakamura, H.; et al. Antibiot. 1977, 30, 714. 36 Ingenamine G Ingenamine G was isolated from marine Sponge Pachychalina sp. Which displayed cytotoxic activity against HCT-8 (colon), B16 (leukemia), and MCF-7 (breast) cancer cell lines. Oliveira, J. H. H. L. et al. J. Nat. Prod. 2004, 67, 1685. 37 Cyclostellettamines G, H, I, K and L Cyclostellettamines G, H, I, K and L were also isolated from marine sponge Pachychalina sp. Symmetric Marine Compounds 38 Aerothionin The sponges Aplysia aerophoba and Verongia thiona have yielded the antibiotic substance, Aerothionin having a spiro cyclohexadienylisoxazole skeleton. Encarnacion, R. D.; Sandoval, E.; Christophersen, C. J. Nat. Prod. 2000, 63, 874. Symmetric Marine Compounds
HO. OH Bacteria of the gemus 0 S9adietabydrotrichodimcrol6a W.Lin,Q Gs.W.Zhe.C.Cui and G Fan L,2105.58.621 Lissoclibadin 1 三、海洋天然产物的研究概况 tine of 历史-Histor 海祥天然活性物质的研究已有100多年的历史，额观其发 展大致可分为四个阶段 96年代似前 camp c 期 一代以后 孕育期一1960年代以前 头孢菌素钠 1940s-1950s Emerson,Taft and Bergman (Sterol) 稀挥务高中》绿带带实霜 195年，意大利利学家
2 39 The red Antarctic alga Delisea pulchra has been found to elaborate three new dimeric halogenated furanones, pulchralides A–C. S. Ankisetty, et al. J. Nat. Prod., 2004, 67, 1295. Bacteria of the genus Nocardiopsis, found in deep-sea Pacific sediments (3000 m) contained a new cyclic tetrapeptide. J. Shin, et al. J. Nat. Prod., 2003, 66, 883. 40 Penicillium terrestre from marine sediment (Jiaozhou Bay, China) generated the bisorbicillinoids dihydrotrichodimerol 59 and tetrahydrotrichodimerol 60. W. Liu, Q. Gu,W. Zhu, C. Cui and G. Fan, J. Antibiot., 2005, 58, 621. 41 Lissoclibadin 1 was isolated as a mildly antibacterial component of an Indonesian Lissoclinum cf. badium Lissoclibadin 1 H. Liu, S. B. Pratasik, T. Nishikawa, T. Shida, K. Tachibana, T. Fujiwara, H. Nagai, H. Kobayashi and M. Namikoshi, Tetrahedron Lett., 2004, 45, 7015. 42 三、海洋天然产物的研究概况 Outline of Marine Natural Products 历史-History History 海洋天然活性物质的研究已有100多年的历史，纵观其发 展大致可分为四个阶段： 孕育期——1960年代以前 形成期———1960~70年代 快速发展期———1980年代 成熟期———1990年代以后 43 孕育期— 1960年代以前 1940s –1950s Emerson, Taft and Bergman (Sterol) 44 1945年，意大利科学家Giuseppe Brotzu (1895-1976)从撒丁 岛 海 洋 污 泥 中 分 离 到 一 株 海 洋 真 菌 ( 顶 头 孢 霉 菌 ， Cephalosporium acremonium)。 O H N N S O HO O NH2 HO 头孢菌素钠 Cephalosporin
Cephalotin先锋霉素 Ara-C阿糖胞苷 8t=2 Cephalothin 阿糖胞苷(Cytarabine,Ara-C) 道 ，对哥性淋巴、中 ArH-C 同葡浪苷 Ara-A:Antivira 形成期一1960-70年代 形成期一196070年代 “Drug from5 d 。进 in 1973. 3
3 45 Modification of the side-chains resulted in the development of useful antibiotic agents, and the first agent cephalothin (cefalotin) was launched by Eli Lilly and Company in 1964. Cephalotin 先锋霉素 O H N N S O HO O O O S O H N N S O HO O NH2 HO Cephalosporin Cephalothin 46 Ara-C • Werner Bergmann在美国佛罗里达收集的海绵动物中发现了阿糖胞苷和 核黄素磷酸酯钠戊糖核苷（1951），最终这2个化合物的化学衍生物阿 糖腺苷Ara-A和阿糖胞苷Ara-C作为疗效显著的抗癌药应用于临床。 阿糖胞苷 N NH O O O HO OH HOH2C N NH O H2N O HO OH HOH2C Spongothymidine Ara-C Arabinosylcytosine Crytotethya crypta 47 阿糖胞苷（Cytarabine，Ara-C） Ara-C属于抗代谢抗肿瘤药 物，临床上主要用于治疗急性粒细 胞白血病，对恶性淋巴瘤、肺癌、 消化道癌、头颈部癌也有一定的疗 效。此外，Ara-C 还具有抗病毒 作用，对病毒性眼病、带状疱疹、 单纯疱疹性结膜炎有效。它是第一 个由海洋天然产物衍生而来并最终 成功上市的抗癌药物。 N NH O H2N O HO OH HOH2C Ara-C 48 O HO OH HOH2C Ara-A N N H2N N N Arabinosyladenine O OH HO HOH2C N N H2N N N MeO Spongosine Cryptotethya crypta Bergmann (1956) 阿糖腺苷 Natural Synthesized Ara-A: Antiviral 49 形成期—1960~70 1960~70年代 • 1957 年10月~1961年11月，在欧洲、亚洲、非洲、澳洲和南美洲被医生 大量处方给孕妇以治疗妊娠呕吐，“反应停” (Thalidomide-沙利多胺)成了 “孕妇的理想选择” 。仅仅四年时间，在全世界范围内诞生了1.2万多名 “海豹婴儿”。 •1960s “Return to the Nature” “Drug from Sea” 50 1. In 1967 the symposium entitled ‘Drugs from the Sea’ was held at the University of Rhode Island, Kingston. 2. Hugo D. Freudenthal, the editor, described ‘a great future in sight’ in development of drugs from marine organisms, in the proceedings published in 1968. 3. The discovery of a large amount of prostaglandin A2 methyl ester acetate in 1969 became an additional driving force to stimulate research activity of secondary metabolites in marine organisms. 4. Baslow’s ‘Marine Pharmacology’ published in 1969 promised a great future for marine-derived drugs. 5. Perhaps the term ‘marine natural products’ first appeared in CliVord Chan’s review papers in the Journal of Chemical Education in 1973. 形成期—1960~70 1960~70年代
河豚毒素(Tetrodotoxin,TTx) 前列腺素类似物 1964 Prostaglandins or Prostanoids 15R-PGA 前列腺素15R-PGA2 Unprecedented Molecules First Book of MNP Paul Scheuer ry af 快速发展期一1980年代 里程碑式的标志性工作 Ciguatoxin CTX 发装买 中西香尔 (Okadaic Acid OA)
4 51 N N HO OH HO H O H O O- OH H OH NH - 河豚毒素（Tetrodotoxin，TTX） 1964 Yoshimasa Hirata It is about 1200 times more toxic to humans than cyanide and it has no known antidote. 52 1969年美国科学家Weinheimer和Spraggins从加勒比海 柳珊瑚Plexaura homomalla中分离得到了含量高达1.4%的 前列腺素15R-PGA2 COOH O H H 1 8 10 15R-PGA2 OH 前列腺素类似物 Prostaglandins or Prostanoids 53 The structures of entirely new chemical entities, which challenged accepted biosynthetic understanding, were published at an impressive rate. These pioneering chemical researchers found that marine animals possessed a rich new chemistry that had never been seen before. It then became clear that the oceans were indeed a new and exciting resource of NP. O Br Cl Br HO O Prepacifrnol Unprecedented Molecules 54 Sesquiterpenes is less than 40 and only 4 diterpenoids in this Book published in 1973 by Paul Scheuer. First Book of MNP Paul Scheuer 55 快速发展期— 1980年代 O O O O O O O O O O O CH3 O HO CH3 CH3 CH3 CH3 H3C CH3 H H H H H H H H H H H H H H H H O Brevetoxin BTX-B 短裸甲藻毒素 中西香尔 Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773. 里程碑式的标志性工作 形成“赤潮”的涡鞭毛藻Gymnodinium brevis 第一个梯状聚醚类海洋神经性毒素 Neurotoxic Shellfish Poisoning (NSP) 56 O O O O O O O HO O OH OH HO OH 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 Ciguatoxin CTX (Okadaic Acid OA)
Palytoxin:岩沙海簧毒素 PALYTOXIN Manoalide 分高得到的线数二 类 Microorganisms 成熟期一1990年代以后 1990s Golden Age the a at the 5 限组装 * ” 女 件分条 。 5
5 57 Palytoxin 岩沙海葵毒素 58 Manoalide 1980年从海绵（Luffariella variabilis）中分离得到的线型二倍半萜类化 合物Manoalide是第一个具有选择性作用于磷酯酶A2(PLA2)及对磷脂酶C、 鸟氨酸脱羧酶、醛糖还原酶等多种酶具有抑制作用的活性化合物，其对细 胞膜上Ca2+通道也有阻滞作用，现已成为研究阻断PLA2的常规工具药。 Anti-inflammatory : IC50 = 0.05 µM De Silva ED, Scheuer PJ. Manoalide, an antibiotic sesterterpenoid from the marine sponge Luffariella variabilis (Polejaeff). Tetrahedron Lett., 1980, 21: 1611-1614. Paul Scheuer O O HO O HO 59 Microorganisms • Also dating back to the 1980s was the move towards the study of marine microorganisms. A continuing leader in this field is William Fenical. Initially, Fenical and his group focused on bacteria, especially those colonising the surfaces of marine algae and invertebrates, but in time changed their emphasis more towards marine fungi. Scripps Institution of Oceanography, USA University of California 60 成熟期—1990年代以后 • 1990s Golden Age Collection, isolation and structure elucidation is no problem. Past achievement can leave no doubt that the oceans have the ability to offer new pharmaceuticals, particularly for the treatment of cancer. 61 62 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 H OH H H H H H H H H HO H A O O O O HO OH H H H H H H O 安元 健