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）9/9.pdf_大学文库

1 123 Hamann, M. T.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 5825 环肽 Kahalalide F 2000年在欧洲就已经投入了治疗非雄激素依赖型前列腺癌的I期临床研究,目前正在进行治疗前列腺癌II期临床研究。F具有与其他抗肿瘤药不同的作用机制, 它选择性地改变肿瘤细胞的溶酶体膜,干扰前列腺、结直肠和肺癌细胞系的溶酶体功能,通过非调亡机制的细胞死亡程序诱导细胞死亡,而不是阻滞细胞周期和降解DNA,以及在动物模型中显示对肺和乳腺癌有抗肿瘤活性。 H N O N H NH N O O NH HN NH O O O O HO N H O H2N HN O NH O NH N H HN O O O O O Sea hare Elysia rufescrens Algal diet Bryopsis sp. 124 In 2005, M. Hamman & R. Hill have reported two marine bacteria Vibrio sps. as producers of this compound 125 Anti-TB Activity Cyclic Depsipeptides K. A. El Sayed et al. Tetrahedron 2000, 56: 949–953 Massetolide-A and Viscosin are the first example of marine derived peptide having antimicrobacterial tuberculosis activity. Massetolide-A Viscosin Isolated from algae with anti-TB and progressed in clinic trial. Gerard, J et al.. J. Nat. Prod. 1997, 60, 223. Burke, T. Ret al. Tetrahedron Lett. 1989, 30, 519. HN HN NH OH O O NH O O O NH H N O N H O O H N O OH HN HO O O O R 1 R = Me 2 R = H 126 Jasplakinolide = Jaspamide Anti-fungal NH N NH O O O O O NH Br HO Fusetani N. Bioctive Sponge Peptides. Chem. Rev. 1993, 93:11793-1806. 伏谷伸宏 127 Discodermins A-D from Discodermia kiiensis. Matsunaga, S.; Fusetani, N.; Konosu, S. Tetrahedron Lett. 1984, 25, 5165. Matsunaga, S.; Fusetani, N.; Konosu, S. Tetrahedron Lett. 1985, 26, 855. N NH HN N H H N N H H N N O O R1 R2 O O NH O O HN O H HN O NH H2N NH O SO3 O HN O O NH2 HN H N O N O OH O O O CONH2 Discodermin A R1=R2=Me Discodermin B R1=H, R2=Me Discodermin C R1=Me, R2=H Discodermin D R1=R2=H 从海绵中分离得到的活性肽类化合物，discodermins是磷酸酯酶A2抑制剂(IC50为3.5-7.0´10–7 M)。A还具有抗炎和抑制肿瘤促进剂的活性。 128 Didemnins A-C were isolated from Trididemnum solidum, a Caribbean tunicate ( 加拉比海鞘 ). Didemnin-B has completed phase II human clinical trials against advanced adenocarcinoma of the kidney, advanced epithelial ovarian cancer, and metastatic breast cancer. Didemnin-B O O NH O NH N O O O OH N H3C O O OMe NH O N N O OH O O Didemnins 的來源

2 129 Dehydro-didemnin B O O NH O NH N O O O OH N H3C O O OMe NH O N N O O O O 一种环状多肽，可直接杀死癌细胞, 杀伤力是紫杉醇的80 倍。 Didemnin B was the first MNP enter clinic trial in USA. Dehydrodidemnin B was in the clinic II trial (20 times stronger than that of didemnin B), showed promise be accepted as a anticancer drug. 130 Didemnin B and Dehydrodidemnin • Didemnin B, a major component, was the first marinederived compound to undergo phase I clinical trials as an anticancer agent and was also the first to reach phase II testing for efficacy. The second-generation agent dehydrodidemnin B (also known as Aplidin), also arising from Professor Rinehart’s work, is 6-10 times more active, but lacks the cardiotoxicity of didemnin B. It is currently in phase II clinical trials against both solid tumors and hematological malignancies. Which has been approved in Europe for acute lymphocytic leukemia. 131 •Aplidin is a cyclic peptide, originally isolated from the marine tunicate Aplidium albicans, currently obtained by total synthesis. It induces apoptosis rapidly and persistently, inhibits VEGF secretion and blocks cell-cycle. It is currently in therapeutic exploratory clinical evaluation (phase II) in solid and haematological malignancies, including paediatrics. Approximately 400 patients have been treated. Aplidin has commenced Phase II clinical trials in both prostate and bladder cancers. News About Aplidin The precise mechanism of action of this agent is not yet known. NH O O NH O Me N O O Me Me O O Me Me OH O Me Me N H N Me Me O N Me Me O O N Me O O OCH3 132 从Leptolyngbya sp.中分离得到的全新多肽以全新的作用机制可以选择性地抑制癌细胞的繁殖，被NCI选为有价值的先导化合物。 Coibamide A 133 Ziconotide (PrialtTM, SNX-111) 从芋螺类海蜗牛的毒液中分离的一种神经毒素，称为芋螺毒素多肽。是一种N-型电压敏感的该通道阻断剂。美国Elan公司研制， 2004年 6月上市，是一非成瘾镇痛药。主要用于癌症和艾滋病患者。Ziconotide is an N-type calcium channel blocker that has been evaluated by Elan Pharmaceuticals as a potential treatment for patients suffering from chronic pain and is at the registration stage in both the US and Europe. 芋螺毒素 134 S N N O HN O O O NH O OR R2 1 Halipeptin A R1 = Me, R2 = CH2OH Halipeptin B R1 = H, R2 = CH2OH Halipeptin C R1 = H, R2 = H Halipeptin D R1 = Me, R2 = Me Halipeptins是意大利化学家L. Gomez-Paloma等人从Vanuatu 岛海水的海绵Haliclona sp.中分离得到的16元的大环酯肽，具有很强的抗炎活性。 Halipeptins

3 135 第五节前列腺素类似物为一族有二十碳的多不饱和脂肪酸衍生物. Prostaglandins or Prostanoids O H OH CO2H 1 8 10 O H OH CO2H 1 8 10 15S-PGA2 15-epi-PGA2 15S 15R Weinheimer, A.J.; Spraggins, R.L. Tetrahedron Lett. 1969, 5185-5188. The first PGs compounds isolated from Florida Coral by Weinheimer in 1969. 136 Chemically Prostaglandins are C20 carboxylic acids consisting of a five member ring with two side chains. One of them is seven carbon atoms and the other of eight carbon atoms. All prostaglandins may be regarded as derivative of Prostanoic Acid, a trivial name. 7 carbon side chain 5 member ring 8 carbon side chain Prostanoic Acid 2 COOH 3 4 5 6 7 8 9 10 11 12 13 14 15 1 16 17 18 19 20 137 1993年 10月日本横滨发生一起食江篱属(Gracilaria verrucosa)海洋植物中毒的事件，中毒2 人，死亡1人。迄今在日本已知的江篱属植物中毒已有3起，死3人。几起中毒的共同特点是：(1)采集不久即生吃，(2)主要症状为呕吐、嗳气、腹泻等，死亡的直接原因是血压下降导致休克，致死时间一般在十几小时，(3)死者均为女性。同期从神奈川县野岛冲的江篱属植物中检出前列腺素(PGE2)，含量最高达78.6 mg/kg。同时发现，当在该植物中加入花生四烯酸(Na盐)时，其PGE2的含量会在数分钟后增加1.3~3倍。极微量PGE2即可引起子宫收缩，短时间内大量生成的PGE2会对女性产生极强的作用，这可能是该物质主要导致女性中毒的重要原因。案例 138 Prostaglandins and related molecules are called eicosanoids as a class. The term eicosanoid is derived from “eicosa” meaning “twenty”, referring to the 20 carbons in most of the molecules. The eicosanoids are used as signaling molecules. They generally act locally, either affecting cell that makes them or nearby cells; in most cases, eicosanoids are not systemic hormones, because of their short half-lives. Most prostaglandins are synthesized from arachidonic acid (20:4△5,8,11,14). These are called “Series 2” products, because most have two double bonds. However, the triene fatty acid 20:3 △8,11,14 can also be used; the products have one fewer double bond than the arachidonic acid derivatives and are called Series 1 products. Prostaglandins (PGs) 139 Prostaglandins are a family of important chemicals involved in a variety of biological regulatory functions and are found in most biological tissues. The name is derived from the fact that the original members of the series were derived from the prostate gland (in sheep). Structurally, they are a C20 system containing a cyclopentane unit, a carboxylic acid functional group and -OH groups at C11 and C15. They are divided into series A, B, C, D, E and F depending on the cyclopentane substituents. They are biosynthesised is from C20 fatty acids, such as arachidonic acid, which in turn are formed from linoleic acid. Prostaglandins (PGs) 140 The stereochemistry of substituents on 5-member cyclopentane ring could be a or b. The configuration of C-15 hydroxyl function is 15(S). Naturally occurring prostaglandins could be divided into nine groups (A-I) based on the substitution pattern on the cyclopentane ring. Individual member of each group is distinguished by the number of double bonds in the side chain which are denoted by the subscript 1, 2, 3. In the F-series, a further subscript is added to define the stereochemistry of the C9 hydroxy group. Prostaglandins (PGs) CO2H O H H 1 8 10 HO PGE1 15

4 141 前列腺素类似物分类 2 COOH 3 4 5 6 7 8 9 10 11 12 13 14 15 1 16 17 18 19 20 Prostanoic acid 1-Seties 2-Seties 3-Seties 2 COOH 3 4 5 6 7 1 19 18 17 16 15 14 20 R1 R2 OH 13 19 18 17 16 15 14 20 OH 13 19 18 17 16 15 14 20 OH 13 3 COOH 4 6 5 7 1 2 3 COOH 4 6 5 7 1 2 8 9 10 11 12 R1 R2 O PGA 8 9 10 11 12 R1 R2 O PGB 8 9 10 11 12 R1 R2 O PGC 8 9 10 11 12 R1 R2 HO PGD 8 9 10 11 12 R1 R2 O PGE 8 9 10 11 12 R1 R2 HO PGF O HO HO 8 R1 9 10 11 12 13 14 15 16 17 18 19 20 OOH O O 8 R1 9 10 11 12 O O R2 PGG PGH O COOH OH R2 PGI 1 7 142 15(S) 15(S) Prostaglandins (PGs) O COOMe AcO OAc O OH CO2Me Cl clavulactones IV chlorovulone I CO2H O H H 1 8 10 PGF2 OH 20 HO CO2H HO H H 1 8 10 PGE1 OH 20 HO 143 Prostaglandins (PGs) CO2H O H H 1 8 10 PGA2 CO2H O 1 8 10 PGB2 OH OH CO2H O H H 1 8 10 PGA1 CO2H O 1 8 10 PGB1 OH OH 15 20 144 Sune K. Bergström Bengt I. Samuelsson The Nobel Prize in Physiology or Medicine 1982 John R. Vane Jan. 10th, 1916, Sweden 145 In the early and mid-1930s, Ulf S. von Euler, MD, of Sweden (also a Nobel laureate) and other investigators reported that human semen and extracts of sheep seminal vesicular glands had peculiar properties. Both substances caused contraction of smooth muscle in vitro and sharp decreases of BP in experimental animals. Because of the origin of these substances, von Euler inferred that the active agents were made mainly in the prostate gland, so he named them prostaglandins (PGs). Unfortunately, further identification of the responsible materials was extremely difficult because of the small amounts made in the body. Not only does an adult human produce only about 0.1 mg/day of the two most active prostaglandins—dinoprostone (PGE2) and dinoprost tromethamine (PGF2a). Finally, in 1957, Bergstrom and colleagues isolated pure crystals of two prostaglandins, alprostadil (PGE1) and PGFla, which cause contraction of smooth muscle. In 1962, they reported the chemical characterization of these two substances. 146 PGF3a Corey 醛 Elias James Corey 前列腺素：乙烯酮替代物2-氯丙烯腈的发明；用狄尔斯-阿尔德反应构筑五元环及控制环上取代基相对立体化学关系的策略尤为令人称道。 Prostaglandin O COOH HO OH OBzP OH CHO BnO O O 什么叫做科学和艺术的结合? Named reaction最多的人李丁-中山大学李卫东-南开

8 165 Chartelline A, a unique β-lactam indole alkaloid, which exhibits cytotoxicity in vitro against KB, and PS cell lines, has been isolated from a marine bryozoan Chartella papyracea collected in North Britanny waters. Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org. Chem. 1987, 52, 4709. Chartelline A N N O H Cl Br Br Br N H N Me Me Br 166 超难关天然物 Palau'amine Phil S. Baran Scheuer published the structure of the hexacyclic alkaloid palau’amine in 1993 from the marine sponge Stylotella aurantium. Which exhibits antifungal, antitumor and immunosuppressive activities. N N N H NH N H H N NH2 NH2 H H Cl O OH NH2 H Ian B. Seiple, Shun Su, Ian S. Young, Chad A. Lewis, Junichiro Yamaguchi, Phil S. 167 Baran. Angew Chem Int Ed Engl. 2010, 49(17): 2972-2974. Phil用一个又一个你见都没见过想都不敢想的试剂和方法做了一个又一个无数前人做了十几年或者几十年都做不出来的分子. 168 东风螺毒素 (Surugatoxin ) 1957年日本新渴县寺泊发生东风螺中毒事件，并造成死亡，1965年和 1967年静罔县沼津市产的东风螺分别造成26人和9人中毒，1971年岛乡产的该螺又使3人中毒。当初从该螺中分离出surugatoxin，后又分离出毒性更强的neosurugatoxin和毒性稍弱的prosurugatoxin，毒素主要存在于该螺的肠腺中。人食该螺后3~18h即可出现中毒症状，中毒者表现有视力减退、瞳孔散大、口渴、腹胀、便秘、血压下降等，以上症状可持续数日。 169 Surugatoxin is a type of venom found in the Japanese ivory mollusk (Babylonia japonia). It functions as a ganglionic blocker of nicotinic acetylcholine receptors . SGTX具有特异的扩瞳作用及自律的神经阻断作用，并有杀癌细胞的作用。后又分高得其衍生物新骏河毒素，其生物活性比SGTX的作用强100倍骏河毒素 (Surugatoxin, SGTX) 170 Norzoanthamine R=H Zoanthamine R=CH3 Anti-osteoporotic Alkaloid Norzoanthamine N O O O O O CH3 H3C CH3 R CH3 CH3 H H H H Norzoanthamine by Uemura D. Heterocycl. Commun. 1995, 1, 207-214. Zoanthamine by Faulkner D J. J. Am. Chem. Soc. 1984, 106, 7983-7984

10 177 甾醇 Sterols Sterols Squalamine 角鲨胺作为新生血管抑制剂类抗癌药物进入II期临床试验自白斑角鲨 Squalus acanthias的肝中分离 Squalamine is an essential ingredient which may be derived from various sources in nature. One known source of squalamine is predominantly found in the liver tissue (not the "liver oil") of the deep water shark. N H OH OSO3 - N H H2N H H H H 178 Squalamine, isolated from the common dogfish shark, Squalus acanthias collected off the New England coast, was originally reported by Zasloff’s group and collaborators from the University of Pennsylvania in 1993, and was shown to be a fairly simple aminosterol with broad spectrum antibiotic activity. The compound was licensed to Genaera and it entered Phase I, and has progressed into Phase II clinical trials for non-responding solid tumors. Moore, K.S.; Wehrli, S.; Roder, H.; Rogers, M.; Forrest Jr, J.N.; McCrimmon, D.; Zasloff, M. Proc. Natl. Acad. Sci. USA, 1993, 90, 1354. N H OH OSO3 - N H H2N H H H H Squalamine 1970s. Shark cartilage oil (squalamine) inhibits angiogenesis 179 Halistanol from Halichondria mooriei and a hydroxy sterol with unusual features is isolated from Dysidea species. Fusetani, N.; Matsunaga, S.; Konosu, S. Tetrahedron Lett. 1981, 22, 1985. Gunasekera, S. P.; Schmitz, F. J. J. Org. Chem. 1983, 48, 5157. NaO3SO H H H H OSO3Na NaO3SO HO HO H OAc HO O 甾体化合物 Steroids Steroids 180 The deep-water sea star Styracaster caroli, collected at a depth of 2000 m off the coast of New Caledonia, was found to contain three polyhydroxycholanic acid derivatives, designated carolisterol A–C (1–3). These polyhydroxysteroids (PHSs) are unique because they contain a polyhydroxycholanic acid moiety connected to D-cysteinolic acid via an amide linkage. F. De Riccardis, L.Minale, R. Riccio, M. Iorizzi,C. Debitus,D. Duhetand C. Monniot, Tetrahedron Lett., 1993, 34, 4381. NaO3SO H H R H R1 OH OH O SO3Na OH 1 R = OH, R1 = b-OH 2 R = OH, R1 = ketone 3 R = H, R1 = a-OH 181 The sea star Lethasterias nanimensis chelifera collected in the Sea of Okhotsk yielded a variety of sulfated alkaloidosteroid group in which a sulfate group bears an alkaloidal counter ion. O - O3SO H H H OH 17 1 17b, Counter ion : A 2 17a, Counter ion : Na+ 3 17a, Counter ion : B 4 17a, Counter ion : A NH HO HO NH3 HO Counter ion A B 甾体化合物 Steroids Steroids 182 N N O O O O OH H H O H H HO HO OH H H H OH N N O O OH O H H H H H H OH OH O OH OH 1 2 从印度洋蠕虫Cephalodiscus gilchristi和海鞘Ritterella tokiokal 中得到30 余个甾醇二聚体生物碱，对多种肿瘤细胞株都具有很强的抑制活性, 并且作用机制独特。其中 ritterazine A (1)对 P388肿瘤细胞的 IC50值为 0.018 ng/mL。cephalostatin 1 (2)是NCI筛选的抗癌活性最强的天然产物之一。甾醇二聚体生物碱

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）9/9

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）9/9