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.pdf

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

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

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

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

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-DesacetyiAltohyrtin 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

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

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