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

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

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