河北医科大学：《天然药物化学》课程教学资源（课件讲稿）第十五章 海洋天然产物MARINE NATURAL PRODUCTS（2014）7/9

第十五章 天然药物化学 洋天然产物 .2 1习要点老试点 2.概念（名词解释，简答） 3.结构式（中文名称） RINE NATURAL PRODUC 醒类化合物 合物 分析比较 含物区别、 甾体及其苷 1.化学反应（化合物鉴定） 8.生物碱类化合物 8结构解析四谱推断结构 第一节概述 海洋天然产物 INTRODUCTION Purpose and Aim 一、海洋知多少How much do you learn? 1了解开展海祥天然产物哥究的现状和意义： 二、海洋生物的特点Characteristics of MNP 2了解海弹天然产物研究的主要对： 三、海洋天然产物的研究概况Outline of MNP 天内类的结构特 了解其生物活性 和 解其生物活性 四、海洋天然产物研究的意义Meaning of MNP 的 五、海洋天然产物研究的对象Objeets of MNP 结构龄点，了其生物活性 )了解C乙雕原类、衡体类、生物碱类化合物的结构转点) 第二节大环内酯类Macrolide 简单大环内酯 内面 一大类化合物，特别是在海洋微生物中。适常有抗叶富活性 二、简单大环内酯类化合物：不论环的大小如何，但环上只 从海绵 ,中分得的单大环内酯 有O州和R,一个内环，为长使脂防腰形成的内丽， 为合有2元环的多不和脂助酸内，对大 的作用机制，对耐药性的乳C7细康的抑制作用 IC为15M)比紫老(ICn为25nM)还强

1 1 第 十 五 章 MARINE NATURAL PRODUCTS 海洋天然产物 史 清 文 2014-5-27 2 天然药物化学 1. 总论 2. 糖和苷 苯丙素类 3. 醌类化合物 4. 黄酮类化合物 5. 萜和挥发油 6. 三萜及其苷 7. 甾体及其苷 8. 生物碱类化合物 1. 学习要点(考试重点) 2. 概念(名词解释，简答) 3. 结构式(中文名称） 4. 分析比较极性、酸碱性 5. 提取、分离流程 6. 化合物区别、鉴定 7. 化学反应(化合物鉴定) 8. 结构解析(四谱推断结构) 3 第一节 概 述 INTRODUCTION 一、海洋知多少 How much do you learn? 二、海洋生物的特点 Characteristics of MNP 三、海洋天然产物的研究概况 Outline of MNP 四、海洋天然产物研究的意义 Meaning of MNP 五、海洋天然产物研究的对象 Objects of MNP 4 Purpose and Aim 1 了解开展海洋天然产物研究的现状和意义； 2 了解海洋天然产物研究的主要对象; 3 掌握大环内酯类的结构特点、分类，了解其生物活性； 4 掌握聚醚类化合物的结构特点、分类，了解其生物活性； 5 了解肽类的结构特点、分类和生物活性； 6 掌握前列腺素类化合物结构特点；了解其生物活性； 7 了解C15乙酸原类、甾体类、生物碱类化合物的结构特点； 海 洋 天 然 产 物 5 一、特点 长链脂肪酸形成的内酯含内酯环 Macrocyclic lactones通常是指含八元以上的环内酯。大环内酯是海洋中常见的 一大类化合物，特别是在海洋微生物中。通常有抗肿瘤活性。 二、简单大环内酯类化合物:不论环的大小如何,但环上只 有-OH 和–R,一个内酯环，为长链脂肪酸形成的内酯。 第二节 大环内酯类 Macrolides Altmann KH, Gertsch J. Anticancer drugs from nature-natural products as a unique source of 6 new microtubule-stabilizing agents. Nat. Prod. Rep. 2007, 24, 327–357. 简单大环内酯 从海绵Spongia sp. 中分得的简单大环内酯dictyostatin (dictyostatin-1) 为含有22元环的多不饱和脂肪酸内酯，对大鼠 淋巴白血病P388细胞ED50为0.7 nM。Dictyostatin具有与紫杉醇 一样的作用机制，对耐药性的乳腺癌MCF-7细胞的抑制作用 （IC50为1.5 nM）比紫杉醇（IC50为2.5 nM）还强 。 OH O O HO OH OH 1 6 16

简单大环内酯 Macrolactin A 人人久 令又知)-macrolactinA+macrolactin E Caylobolide 必人人见 BmA,36-国 rcell (HCT-1 人Nmd2012.795-961 三、内酯环含有氧环的大环内酯类 Bryostatins苔藓虫素 ed a large-scale collection of t 总合草苔虫

2 7 v又如(-)-macrolactin A (+)-macrolactin E O O OH HO HO O O OH HO O 简单大环内酯 简单大环内酯类化合物:不论环的大小如何, 但环上只有-OH 和–R, 一个内酯环，为长链脂肪酸形成的酯。 8 O O OH HO HO 7 13 15 1 Macrolactin A Macrolactin A is a 24-membered polyene macrolide isolated from a taxonomically undefined deep sea bacterium. This compound exhibits antiviral activity against Herpes Simplex I and II and against HIV. 1. Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc. 1989, 111, 7519-7524. 2．Rychnovsky, S. D.; Skalitzky, D. J.; Pathirana, C.; Jensen, P. R.; Fenical, W. J. Am. Chem. Soc. 1992, 114, 671-677. 9 Caylobolide A 36-membered macrolactone from Lyngbya majuscula which displayed Cytotoxicity against human colon (结肠) tumour cell (HCT-116) in vitro. J. B. MacMillan and T. F. Molinski, Org. Lett., 2002, 4, 1535. O HO OH OH OH OH O HO OH OH OH 10 Bahamaolide A, a new 36-membered macrocyclic lactone,was isolated from the culture of the marine actinomycete Streptomyces sp. Which bearing a hexaenone and nine consecutive skipped hydroxy groups. Bahamaolide A displayed significant inhibitory antifungal activity against various pathogenic fungi. J. Nat. Prod. 2012, 75, 959−967. 11 三、内酯环含有氧环的大环内酯类 新颖的作用机制：作用于蛋白激酶C (PKC) v例：Bryostatin-1 (苔藓虫素 In Phase-II trials) 总合草苔虫为海洋底栖动物. 大环内酯类化合物由于在环的结构上含有双键，羟基等， 在次生代谢过程中发生氧化，脱水等化学反应，形成各种含氧 环 3, 5 or 6-membered epoxide rings. 苔藓虫素 O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H G. R. Pettit, et al. J. Am. Chem. Soc., 1982, 104, 6846. 12 Bryostatins • In 1968, NCI commissioned a large-scale collection of the bryozoan Bugula neritina by Gulf Specimen Company off the west coast of Florida that was sent to Pettit’s group for chemical workup. The aqueous 2-propanol extract was subsequently tested by NCI for its intrinsic activity as an antitumor agent in the then current P-388 and L- 1210 murine leukemia in vivo models. O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H 苔藓虫素 总合草苔虫 苔藓虫素

Bryostatins苔藓虫素 Total Synthesis Bryostatins 2 新坦福大学化学系Paul A.Wender教授 X-ray P -2 and 3 (500 Kg mterial Y Bryostatin Analogue Bryostatin--l苔薛虫素Bryostatin-l0 wing to the therapeutic p tial of the molecule,the gemeration of bryostatin-1 2 化学型r基因 Ste Vnl C 不含链 Bryostatin-1 News about Bryostatin 讨论知何 类的 工程 的背童 可以在直 主生产 过当中雕丁会产 分片度 大的医药需家 新颜的作用机制：作用于蛋白激路C(Protein KinaseC.PKC少 3

3 13 Bryostatins Bryostatins 苔藓虫素 v1968年发现总合草苔虫有抗癌活性，1982 年以釜野德明(Y. Kamano)为中心的Pettit Group从采集于加利福尼亚太平洋蒙 特内海湾的总合草苔虫Bugula nertina分得第一个具有抗癌活 性的大环内酯类并用X-ray 确定了结构。 v1982 年Bryostatin-1 v1983 年Bryostatin-2 and 3 (500 Kg material) v1984 年Bryostatin-4 v1985 年Bryostatin-5-8 v1986 年Bryostatin-9-11 v1987 年Bryostatin-12-13 (1000 Kg) v1994-6 年Bryostatin-14-18 vTotal 20. Bryostatin-1 and 3 in clinic trial. 苔藓虫素 O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H 14 Paul A. Wender 斯坦福大学化学系Paul A. Wender教授 Total Synthesis Bryostatins O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H Me Me HO Me AcO OBz H Me OAc OH O O O OH Ph NH O O Fourteen tons of Bugula neritina harvested from waters off the coast of California yielded a paltry 18 grams of bryostatin. 15 Bryostatin Analogue Owing to the therapeutic potential of the molecule, the generation of bryostatin-1 analogues is an area of intensive research. Scientists at Stanford Uni. have synthesized a series of such analogues, some of which were two to three orders of magnitude more potent against tumour cell lines. Neristatin-1, a biologically active yet structurally simpler biosynthetic precursor of bryostatin-1, was obtained at Arizona State Uni. Cancer Research Institute. 16 Bryostatin-1 Bryostatin-10 7 11 26 B A C O O O O O H3CO O OH H OH HO O O OCH3 OH O H H H H 7 11 26 B A C O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H 化学O型 or基因D型: 含2,4-二烯辛酸酯链 化学M型 or基因S型: 不含酯链 两种化学型的线粒体COI序列有约8%的差异。 基因D型分布在深水区，基因S型分布在浅水区。 苔藓虫素 苔藓虫素 17 Bryostatin-1 O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H Bryostatin-1 用于治疗白血病，肾癌，宫颈癌，黑色瘤 等。此类化合物不同于以前所有的化疗药物，它除了直接杀死 癌细胞外还能促进造血功能，是一类极有希望的抗癌药物。 新颖的作用机制：作用于蛋白激酶C (Protein Kinase C, PKC) 苔藓虫素 The £ 26100(UK)/5 mg bryozoan Bugula neritina. 18 • Haygood与她在Scripps海洋学院(University California)以及密西根大 学的研究团队一起讨论如何让bryostatins这类的化合物能成为商业化生 产。研究人员分析了两种不同种类的苔藓虫（一个是生长在深海中，另一 种则生长在较浅层的海中）身上的细菌株，然后从中筛选分离出相关的基 因组，透过基因工程的方式诱导其生成bryostatins的前驱物，目前取得的 bryostatins前驱物已超过20种以上，并将这些前驱物称为bryostatin 0。 Haygood表示，下一个步骤就是将来自细菌的基因转移到宿主之中， 这样就可以在实验室中让宿主生产bryostatins，过程当中除了会产生 bryostatins外，也会产生bryostatins的部分片段， 或是生产全新的bryostatins相关化合物。最后希 望能够透过工业生产的方式大量制备，以供应未 来广大的医药需求。 News about Bryostatin

Bryostatin-1 g 20 bei 海洋苔动物俗称苔有虫，海席子，假及苔虫。 Total Chemical S Mariculture 离是采用活性迫的方法， 活性部分 ) Biotechnology Amphidinolides B-C 含有氧环的大环内酯 有 环的 酯 四、多聚内酯类 多聚内酯类 人人义哭 Wo- - m&89 4

4 19 Bryostatin-1 v 海洋苔藓动物俗称苔藓虫，海席子，假珊瑚及苔虫。属 于真体腔动物, 是海底栖息动物的重要组成之一。约4000多 种，最常见的是 总合草苔虫(Bugula neritina Linnaeus). Bryostatin类化合物的分离是采用活性追踪的方法，将非 活性部分除去，Pettit小组经过长期的努力，摸索出一套行之 有效提取分离的方法： O O O O O H3CO O OH H OH HO O O OCH3 O OH O O H H H H B A C Bryostatin 1 has been in more than 80 human clinical trials, with more than 20 being completed at both the Phase I and Phase II levels. And currently bryostatin 3 Phase I and bryostatin 7 Phase II trials are ongoing in a variety of centers and protocols. 20 0.5 m2 panel (1,5 Kg) B. neritina After 5 months growing in the sea 21 Amphidinolides B-C T. Kubota, M. Tsuda and J. Kobayashi, J. Org. Chem., 2002, 67,1651. J. Kobayashi, K. Shimbo, M. Sato and M. Tsuda, J. Org. Chem., 2002, 67, 6585. J. Kobayashi and M. Tsuda, Nat. Prod. Rep., 2004, 21, 77 含 有 氧 环 的 大 环 内 酯 O O O HO OH OH OH O O OH O OH OH O O O H O H OH H H 日本北海道大学的小林淳一研究小组从Amphidinium属不同的 菌株培养液中分离得到45个从12元环到26元环不等的大环内酯 (amphidinolides), 很多具有很强的细胞毒性，对L1210和KB细胞 的 IC50 最 低 分 别 可 达 到 0.14 ng/mL 和 0.06 ng/mL 。 如 amphidinolides B, C 22 Laulimalide (1) and Isolaulimalide (2) are another group of active microtubule-stabilizing natural products isolated from a lipophilic extract of the marine sponge Cacospongia mycofijiensis. These compounds are also reported in other sponge genera, 含有氧环的大环内酯 O O O OH O H O HO H H H H O O O O O H OH HO H H H 1 2 23 四、多聚内酯类 v特点：两个或两个以上的酯键 Polyesters v例如： O O O O O O O O O O OH OH HO OH OH O O O O O O O O OH HO O O OH OH O O O O O O O OH HO OH OH HO OH O O O O 1 O 2 3 1 5 7 21 23 27 31 1 海洋微生物Hypoxylon oceanicum (LL-15G256)分得的15G256a-1 (1), 15G256b (2) 和15G256w (3)都具有一定的抗真菌活性 24 多 聚 内 酯 类 Swinholides A and B from the Red Sea sponge Theonella swinhoei (Isao Kitagawa et al., 1990). Both show potent in vitro cytotoxic activity against murine leukemia L1210 and KB human epidermoid carcinoma cell lines. J. Am. Chem. Soc. 1990, 112, 3710-3712. 44 membered ring with 30 Chiral C K. C. Nicolaou Total Syn. O HO R O O OH OH MeO O OMe HO HO OH O O O OMe HO MeO O OH Swinholide A R = CH3 Swinholide B R = H

Anti-fungus Polyester 五、其他大环内酯类 心含有氢化吡哺博环的大环内酯环化合物。 含有氢化吡喃螺环的大环内酯聚壁 含有氢化吡哺螺环的大环内酯 d aL)from ns A-( Spongistatins Altohyrtins 之m

5 25 Anti-fungus Polyester Cultures of the marine fungus Hypoxylon oceanicum from mangrove wood from Shenzen, China, yielded the macrocyclic polyesters. G. Schlingmann, L. Milne and G. T. Carter, Tetrahedron, 2002, 58, 6825. 多 聚 内 酯 类 O O O O O O O O O O O O HO OH OH HO OH OH 26 五、其他大环内酯类 v含有氢化吡喃螺环的大环内酯环化合物。 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 1 R=Cl, R1=COMe, R2=COMe 2 R=H, R1=COMe, R2=COMe 3 R=Cl, R1=H, R2=COMe 4 R=Cl, R1=COMe, R2=H 5 R=H, R1=COMe, R2=H 1993年从东印度洋海绵Spongia sp中分离得到了Spongistatin 1 (1)而后又 从同种海绵中分得Spongistatin 2 (2)和3 (3)，1对多种肿瘤模型表现出强烈的 细胞毒性，其中对大鼠白血病细胞L-1210 的IC50平均值为20 pmol/L，是目 前已进入抗肿瘤临床Ⅰ期试验的dolastatin 10活性的12 倍。 27 含有氢化吡喃螺环的大环内酯(聚醚) Spirastrellolides A and B, two unique polyketide, isolated from the sponge Spirastrella coccinea,were disclosed in 2003 and 2007. 1． Williams, D. E.; Andersen, R. J. J. Am. Chem. Soc. 2003, 125, 5296. UBC, Canada 2． Warabi, K.; Andersen, R. J. J. Am. Chem. Soc. 2007, 129, 508. O O O O HO O O O HO O Me OMe OH Me Cl OMe Me O HO HO OH O O O O HO O O HO O O OH Me OMe OH Me OMe Me O HO HO 1 3 7 9 11 13 17 21 23 27 35 28 38 1 46 Spirastrellolide A Spirastrellolide B 28 • In 1993 three independant research groups reported a new class of remarkably cytotoxic marine macrolides, the spongipyrans, from marine sponges for the first time. • The research was guided by bioassays and led to the identification and structure determination of spongistatins 1-9 (Pettit et al.) from Spongia sp. and Spirastrella spinispirulifera, cinachyrolide A (Fusetani et al.) from Cinachyra, and altohyrtins A-C as well as 5- desacetylaltohyrtin A (Kitagawa et al.) from Hyrtios. 含有氢化吡喃螺环的大环内酯 29 G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald, M. R. Boyd, J. M. Schmidt, J. N. A. Hooper, J. Org. Chem. 1993, 58, 1302-1304。 Spongistatins Pettit Group 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 30 M. Kobayashi, S. Aoki, H. Sakai, K. Kawazoe, N. Kihara, T. Sasaki, I. Kitagawa, Tetrahedron Lett. 1993, 34, 2795 -2798. First total syntheses from Evans et al. (Altohyrtin C) and Kishi et al. (Altohyrtin A) Both from Harvard University after 4 years work. Y. Kishi, Angew. Chem. 1998, 110, 198-202; Angew. Chem. Int. Ed. 1998, 37, 187-190; D. A. Evans, et al, Angew. Chem. 1997, 109, 2951-2954; Angew. Chem. Int. Ed. Engl. 1997, 36, 2737-2741. Kitagawa Group O O O Me OH O O O OAc HO O O HO Me O HO H OH R1O HO OMe H H H HO H H H Altohyrtin A R1=COMe, R2=Cl Altohyrtin B R1=COMe, R2=Br Altohyrtin C R1=COMe, R2=H 5-Desacetyi￾Altohyrtin A R1=OH, R2=Cl R2 3 2 4 5 6 7 8 9 10 11 15 17 19 21 25 27 33 35 37 41 43 47 51 1 Altohyrtins

Cinachyrolide A Cytotoxic Marine Macrolides yrtin A (Spongistain-4) ⊙ The)of tent.pb ally active comp Ecteinascidin 743 y 肉瘤5p2007,T74

6 31 N. Fusetani, K. Shinoda, S. Matsunaga, J. Am. Chem. Soc. 1993, 115, 3977-3981. Fusetani Group O O O Me OH O O O OH HO O O HO Me O HO H OH AcO HO OMe H H H HO H H H Cl 3 2 4 5 6 7 8 9 10 11 15 17 19 21 25 27 33 35 37 41 43 47 51 1 Cinachyrtin A (Spongistatin-4) Cinachyrolide A 32 Cytotoxic Marine Macrolides 33 The achievement (1993) of the three groups is especially noteworthy, since only trace amounts (0.5-13.8 mg) of these extremely potent, physiologically active compounds could be isolated for extensive NMR experiments after laborious extractions and multiple chromatographic purifications. Evans D.N. Tetrahedron 1999, 55, 8671-8726. 34 35 v含有N原子的大环内酯环 v如 ET-743 and PT-650 In phase II & III v被囊动物红树海鞘 Ecteinascidia turbineta N NH N S O O H3C O O H3C H H OH HO CH3 O O O HO O H3C H3C CH3 H Rinehart K L Antitumor activity from the Ascidian (Tunicate) Ecteinascidia turbinata (被囊动物红树海鞘 ) had been reported as early as 1969 by Sigel et al., but it was not until 1990 that the structures of the active components were published simultaneously by Rinehart et al. and Wright et al. 36 Ecteinascidin 743 • Et 743 对晚期软组织癌症如直肠癌，乳腺癌，肺癌，黑色素瘤等有显 著的疗效。Eur & USA II & III • In Europe Used to soft-tissue sarcoma (肉瘤) by Sep. 2007. ET-743 represents the first active agent against sarcomas developed in the past 25 years and has demonstrated a therapeutic potential in pretreated ovarian cancer. 1969 Found Activity 1990 Structure Deter In Illinois Uni. 1996 Total Syn. In Harvard Uni. Corey N NH N S O O H3C O O H3C H H OH HO CH3 O O O HO O H3C H3C CH3 H

Semi-Synthesis of Et-743 Ph tar chemist dn egant semis Aquaculture of tunicate Ecteinascidia turbinate Total Synthesis of Et-743 in sea farms of Formentera. yield from nd d both Et-743 采用了镇仿生物合成化合物的机理 Cribrostatin 4 The Supply of MNP Case Study:Yondelis ral pr hy 7

7 37 1929-2005 Ecteinascidins与didemnins (YondelisTM与AplidineTM) 38 Semi-Synthesis of Et-743 • PharmaMar chemists performed an elegant semisynthesis from the marine Pseudomonas fluorescens metabolite Cyanosafracin B that provided cGMP grade Et-743 from a 14-21-step synthetic process on a scale large enough to provide enough material for clinical trials. This was feasible despite a low overall yield of 1.4% because the starting material could be obtained on a large scale (in Kg-scale) by fermentation. N NH N S O O H3C O O H3C H H OH HO CH3 O O O HO O H3C H3C CH3 H Cyanosafracin B 1.4% 14-21-step 39 Aquaculture of tunicate Ecteinascidia turbinata in sea farms of Formentera. Carmen Cuevas and Andre´s Francesch. Development of Yondelis (trabectedin, ET-743). A semisynthetic process solves the supply problem. Nat. Prod. Rep., 2009, 26, 322-337. 40 Total Synthesis of Et-743 • The yield from natural sources was very low, and in order to provide enough material to perform basic studies, the compound was synthesized by Corey in 1996. Subsequently (2000), he improved the synthetic schema and developed a refined process that produced both Et-743 and phthalascidin (Pt-650) at much higher yields. . Corey, E. J.; et al. J. Am. Chem. Soc. 1996, 118, 9202-9203. Org. Lett. 2000, 2, 2545-2548 采用了模仿生物合成化合物的机理 福山 透 41 Cribrostatin 4 was isolated by Pettit et al. in 2000 from the blue sponge Cribrochalina. Cribrostatin 4 (1) belongs to a large family of complex tetrahydroisoquinoline natural products, which includes Et 743, Et 597, and cyanosafracin. Danishefsky described the first total synthesis of cribrostatin 4 (1) in 2005, Zhu JP. Angew. Chem. Int. Ed. 2007, 46, 3962-3965. Danishefsky, J. Am. Chem. Soc. 2005, 127, 4596-4598 Cribrostatin 4 Samuel Danishefsky 42 The Supply of MNP Case Study: YondelisTM

The Supply of MNP Case Study:Yondelis Halichondramide Mariculture 含恶唑环的大环 Hemi-synthesis →品 ocyclic ring Salarins C and A CpualideA (12).LabiramideA ( Zooxanthellatoxins Lyngbyabellins A and C 含噻唑环的内酯类 Lyargbra sp.from Palau vielded the dichlorinated thiazo coaiaigototkmeroikaebbearAnaC ”之

8 43 The Supply of MNP Case Study: YondelisTM 1.4% 21 steps 44 Halichondramide 含 恶 唑 环 的 大 环 内 酯 类 Halichondramide was a 25-membered macrolide, which accommodates an unusual system of three contiguous oxazole rings in the macrocyclic ring was isolated from sponge Halichondria sp Kernan, M. R.; Faulkner, D. J. Halichondramide, an antifungal macrolide from the sponge Halichondria sp. Tetrahedron Lett. 1987, 28, 2809-2812. N H O OMe O OMe Me O O N O N O N O HO O OMe 19 1 4 5 Ulapualide A (12), 45 kabiramide A (2) Three contiguous oxazole rings, linked between positions 2 and 4, form part of the macrocyclic ring. They also possess a functionalized lipid-like side chain that terminates in an N-methyl-N-alkenylformamide group. N H O MeO O OAc Me O O N O N O N O HO O 19 1 4 5 N H O MeO O OMe Me O O N O N O N O O O OMe 19 1 4 5 OMe HO OMe H2N O 46 Salarin C O O O O O Me N O H O Me O H N O Me Me O 6 27 1' 7 9 12 16 22 1 25 26 3 23 Salarin A O O O O O Me N O H O Me O H O 6 27 1' 12 16 22 1 25 9 3 23 N O Me O O Me 8' Tetrahedron 2010, 66: 4339-4345. Nitrogenous macrolides, designated salarins C (oxazole rings) and A have been isolated from the Madagascar Fascaplysinopsis sp. sponge. Salarins C and A 47 Lyngbyabellins A and C Lyngbya sp. from Palau yielded the dichlorinated thiazole containing cytotoxic macrolide lyngbyabellins A and C. H. Luesch, W. Y. Yoshida, R. E. Moore and V. J. Paul, Tetrahedron, 2002, 58, 7959. 含 噻 唑 环 的 内 酯 类 O O HO S N O S N HN HN O H O O Cl Cl O O HO S N O S N O Cl Cl O OH O 1 3 6 8 9 10 12 13 15 16 18 19 23 24 48 Zooxanthellatoxins Nakamura H. Tetrahedron Lett. 1995, 36: 7255. H HO N OH OH OH OH OH OH O O HO OH HO O O OH OH OH OH OH OH OH O(H) O(H) O(H) O(H) HO3SO OH HO OH OH OH OH O O OH OH HO OH O H N OH O OH OH OSO3H OH OH H HO 34' 37' 39' 1 lactonised at 34' 2 lactonised at 35' 3 lactonised at 36' 4 lactonised at 37' 5 lactonised at 39' A 62-membered macrolide. Relative stereochemistry among the ring portions is not known. It acts by favouring the permeability of Ca2+ across cell membrances

第三节聚醚类化合物Polyether 一、 聚醚梯Polyether Ladder Brevetoxin BTX-B 聚睡类化合物是海洋中一大类毒性成分，是“海洋毒素”的一种 一、聚酿（脂溶性聚藏，Ladder--like Polyether) 短裸甲藻毒素 心特点：5-9元藤环以相同的反式构型调合在一起，两增常有极 11 rings with 23 chiral centers 性基团。 Karenia brevis 二、线性录睫（雕链聚醚，Linear polyether) 特点：含高度氧化的碳链，但仅部分形成睡环，多数羟基游高， 属于水溶性章酸。 。个。不个个公人4 大环内酯聚壁：Macrolide Polyether 员，兰转：PolveterTriterpd 50 L Culture 5 mg BTX-B 0.8 mg BTX-A 0.4 mg BTX-C A Twelve-Year Synthetic Comprehensive Odyssey in Organic Synthesis Natural Products Chemistry 中西香眉和年前成功把银杏的活 H o- D 性成分进行分离，被誉为格天然 VOLUME B 产物彻底政变的科学家.中西香 丽博士不单备受业内人士推巢， 亦是多位现今世界顶尖科学享的 短领甲食 启蒙老师。1999年，这群科学家 BTX-B 夏联合出版了The Biology- Chemistry Interface:A Tribute K.C.Nicelaou.Total Synthesis of Brevetoxin B.A Twelve-Year Synthetic to Koji Nakanishi. Odyssey in Organic Synthesis.Angew.Chem.Int.Ed.Engl.1996.35,589-607. 51 Nicolaou Group total synthesized BTX-B after 12 years'work,in 1995 Crystals of synthetic brevetoxin B Nakanishi's proposed biosynthetic hypothesis for brevetoxin B. Polyene-epoxide mechanism of polyeyclic ether formatio in BTX biosynthesis. 53 9

9 49 第三节 聚醚类化合物 Polyether Polyether 聚醚类化合物是海洋中一大类毒性成分,是“海洋毒素”的一种 一、聚醚梯（脂溶性聚醚，Ladder-like Polyether) v特点：5-9元醚环以相同的反式构型稠合在一起，两端常有极 性基团。 二、线性聚醚（脂链聚醚， Linear polyether） v特点：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。 三、大环内酯聚醚: Macrolide Polyether 四、聚醚三萜: Polyether Triterpenoids 50 1. Brevetoxin BTX-B 短裸甲藻毒素 • 11 rings with 23 chiral centers 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 一、聚醚梯 Polyether Ladder 50 L Culture 5 mg BTX-B 0.8 mg BTX-A 0.4 mg BTX-C 51 中西香爾40年前成功把银杏的活 性成分进行分离，被誉为将天然 产物彻底改变的科学家．中西香 爾博士不单备受业内人士推崇， 亦是多位现今世界顶尖科学家的 启蒙老师。1999 年，这群科学家 更 联 合 出 版 了 The Biology￾Chemistry Interface：A Tribute to Koji Nakanishi。 52 Nicolaou Group total synthesized BTX-B after 12 years’ work, in 1995 BTX-B 短裸甲藻毒素 短裸甲藻毒素 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 K.C. Nicolaou. Total Synthesis of Brevetoxin B. A Twelve-Year Synthetic Odyssey in Organic Synthesis. Angew. Chem. Int. Ed. Engl. 1996, 35, 589-607. A Twelve-Year Synthetic Odyssey in Organic Synthesis 53 Crystals of synthetic brevetoxin B 54 Nakanishi’s proposed biosynthetic hypothesis for brevetoxin B. Polyene-epoxide mechanism of polycyclic ether formation in BTX biosynthesis. HOOC O OH O O O O O O O O O O CHO HO Epoxidation H O O O O O O O H H O O O O O O O O O O O Me O HO Me Me Me Me Me Me H H H H H H H H H H H H H H H CHO Ring closure Epoxide-opening Cascade [1] K. Nakanishi, Toxicon 1985, 23, 473; [2] M. S. Lee, G.-W. Qin, K. Nakanishi, M. G. Zagorski, J. Am. Chem. Soc. 1989, 111, 6234