环肽 Kahalalide F m 《人 3 Alternatives 一Total Chemica Synthesis Biotechnology/Fermentation Anti-TB Activity Cyclic Depsipeptides Jasplakinolide=Jaspamide Anti-fungal R:e Discodermins A-Dfrom Discodermia kiiensis Didemnin- 等 清美 al tria cancer,and metastatic breast caneer
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
Dehydro-didemnin B Didemnin B and Dehydrodidemnin News About Aplidin 29 Coibamide A retion and cell-eyce 含好 The pre Ziconotide(PrialtM,SNX-111) Halipeptins 試 主要用于 其水终大化事中语带的元物大贝 有很强的抗活性
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
第五节前列腺素类似物 Prostanoic Acid Prostaglandins or Prostanoids 为一族有二十碳的多不饱和脂肪酸衍生物。 of them is seven carbon atom 155-POA: 15-cp/PGAg 5member ring 案例 Prostaglandins(PGs) of the 灭的直捷因压下降休克教死时 冲的江管属植物 增加133倍。 Prostaglandins(PGs) Prostaglandins(PGs) aT enl e chai and C15. A.B.C.D.E and F depending aistry of the C9 hydroxy grou 3
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
前列腺素类似物分类 Prostaglandins(PGs) =以以 m-人人ew人人 人m人 女$年衣红这 华y然 Prostaglandins(PGs) The Nobel Prize in Physiology or Medicine 1982 PGA2 Sune K.Bergstrom Jan 10,1916.Sweden MD. Prostaglandin 物失代菌箱时立体化幸关系的暗无 2- 什么叫做科学和艺术的结合？ 飞din录多人 4
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
纹n 从日本款明Ca 血中分个前到列集素化合 adpotiloeopote 短胞的增殖有中等强度的抑制作用。 Clavulactone II 茉莉酸(Jasmonic Acid) Jasmoni acis (JA) 州生新在手质有夜 佐精理囊体有排制性致生长、两发、促进套老、某高抗
5 147 O CO2CH3 1 10 Clavulone II AcO H OAc ED50 = 0.3 µg/ml O CO2CH3 1 10 Claviridenone F AcO O CO2CH3 Claviridenone G AcO 148 O COOMe Cl O COOMe Cl O OH CO2Me Br O CO2Me I OH O COOMe HO Cl O COOMe Cl HO O OH CO2Me Br O OH CO2Me I Iodovulones I Chlorovulone IV Bromovulones I Chlorovulone III 从日本软珊瑚Clavularia viridis中分离出约50种新型的前列腺 素衍生物 ，10位含有卤素取代的前列腺素衍细胞增殖活性增强。 149 CO2Me AcO H H H O AcO H O H AcO H H CO2Me OAc 1 6 4 9 7 10 12 13 15 16 18 20 1 4 6 10 5 12 8 15 20 Tricycloclavulone Clavubicyclone 从日本软珊瑚Clavularia viridis中分得两个前列腺素化合 物tricycloclavulone 和clavubicyclone，后者 对乳腺癌MCF- 7 (IC50为2.7 μg/mL)和卵巢癌OVCAR-3 (IC50为4.5 μg/mL) 细胞的增殖有中等强度的抑制作用。 150 PGA2 was isolated from the Okinawan zoanthid, Palythoa kochii, PGA2 stimulated tubulin polymerization like taxol and epothilone A, Although less potently than taxol. Han CG et al. Biosci. Biotechnol. Biochem. 2006, 70: 706-711. O COOH OH 1 10 PGA2 151 Iguchi, K.; Iwashima, M.; Watanabe, K. Clavuloactone, New Marine Prostanoids with a - lactonic moiety in the R-Side-Chain from the Okinawan Soft Coral Clavularia Viridis. J. Nat. Prod. 1995, 58, 790. Clavulactone II O O O O O 152 COOH O Jasmoni acis (JA) 茉莉酸 (Jasmonic Jasmonic Acid) 茉莉酸(jasmonic acid，JA)及其甲酯：存在于所有高 等植物中的植物激素,是植物对病原性微生物和虫害防御反 应的关键激素,能调节高等植物的发育、应答外界刺激、调 节基因表达。有抑制植物生长、萌发、促进衰老、提高抗 性等生理作用。 O COOH OH 1 10 PGA2
第六节生物碱及其它类 生物、和幽化合物指弹天就产物中三大 类主要的化学成分，其中生物酿类化合物种类多、结 多变、生物活性显，约占海天然产物的15%，类 化合物数量最多，的占海务 物的化学成分5 生物碱类Alkaloids Tetrodotoxin 货餐 i,TT是 博有毫的时装。Dae:22 上市 是近3年来准的第一个治疗软组帆肉的药物， Tetrodotoxin Analogues ng incidents in Japan tarm 236410332 6
6 153 154 第六节 生物碱及其它类 生物碱、萜类和甾醇类化合物是海洋天然产物中三大 类主要的化学成分，其中生物碱类化合物种类繁多、结构 多变、生物活性显著，约占海洋天然产物的15 %，萜类 化合物数量最多, 约占海洋天然产物的化学成分45 %。本 节对海洋生物中生物活性显著的或特有的生物碱、甾醇、 C15乙酸原类和萜类等化学成分作一介绍。 155 • Et 743 对晚期软组织癌症如直肠癌，乳腺癌，卵巢癌、肺癌，黑色素 瘤等有显著的疗效。 Date: 22/09/2007 上市 YondelisTM • In Europe Used to soft-tissue sarcoma (肉瘤) by Sep. 2007. • 是近30年来批准的第一个治疗软组织肉瘤的药物。 N N O O OAc Me HO OMe Me Me O NH MeO HO O H OH S 被囊动物红树海鞘 Ecteinascidia turbineta Yondelis (Trabectedin) 他比特定 曲贝替定 一、 生物碱类 Alkaloids 156 Tetrodotoxin 河豚毒素(Tetrodotoxin，TTX) 是一种电压敏感的Na+通道外口特异性阻滞 剂，其麻醉作用是Procaine的4000倍，可代替吗啡，杜冷丁起镇痛作用不成 瘾，并有解痉，降压，抗心律失常作用。 TTX因其毒性剧烈，性质稳定， 且国外已能人工化学合成，故引起国外军界的高度重视。美、前苏联军队 早已将其列入化学战计划。 Tetrodotoxin has been used extensively as a tool in the study of sodium channel pharmacology. N H N OO OH H NH HO OH HO OH H OH + 1 4 4a 8 10 11 6 157 Tetrodotoxin Analogues Analytical Biochemistry 2001, 290, 10-17. 158 Table 1. Pufferfish poisoning incidents in Japan
Total Synthesis of Tetrodotoxin Saxitoxin(STX）石房蛤毒素 in are involved in the Paraly g(sr ey are also produced by the r blue. Saxitoxin (STX) 一、生物碱类Alkaloids 气 安有个生次从西中 Manzamine A(万座毛碱) 生物碱类Alkaloids a类生大有 sosarain-1 imino等从海佛Remiera sarai中分得自然界见的生物碱， 7
7 159 Total Synthesis of Tetrodotoxin Yoshito Kishi Racemic Total synthesis in 1972 Asymmetric Total in 2003 N H N O O OH H NH HO OH HO OH H OH + 1 4 4a 8 10 11 6 160 Saxitoxin and Neosaxitoxin are involved in the Paralytic Shellfish Poisoning (PSP). They are also produced by the fresh water blue-green algae. Saxitoxin (STX) N N H N N H NH2 H2N O H OH OH H H + + 1 6 8 H H2N O N N H N N H NH2 H2N O H OH OH H H + + 1 6 8 HO H2N O 11 Saxitoxin Neoaxitoxin More than 30 STXs were isolated. Lyndon E. Llewellyn. Saxitoxin, a toxic marine natural product that targets a multitude of receptors. Nat. Prod. Rep., 2006, 23, 200-222. 石房蛤毒素 161 石房蛤毒素因中毒后产生麻痹性中毒效应，又称麻痹性 贝毒。它是海洋生物中毒性最强烈的麻痹性毒素之一， 0.5 mg即可使人毙命，其毒力与神经毒气沙林相同，STX在国际 条约中已被列为化学武器。作为潜在的化学生物战剂，长期 以来为国外军事研究单位所高度重视的主要的研究对象之 一。 Saxitoxin (STX) N N H N N H NH2 H2N O H OH OH H H + + 1 6 8 H H2N O 11 162 一、 生物碱类 Alkaloids N N N O Me OH Fragilamide H H 1983 年Kirkup 等首次从红藻Martensia fragilis 中 分得的第一个生物碱. 163 从十几种海绵中分离出数十种manzamine类生物碱，大多有抗癌 和抗虐活性，1986年首次从冲绳万座毛(manzamo)海域Halichona sp属 海绵中分离得到manzamine A 对P388肿瘤细胞的IC50值为0.7 µg/mL。 Manzamine A (万座毛碱) Activity: Demonstrated activity against malaria, tuberculosis, HIV et al. Status: Preclinical N N H N H H N H OH 164 生物碱类 Alkaloids Isosarain-1 N N O H H Cimino等从海绵Reniera sarai中分得自然界罕见的生物碱
Chartelline A 超难关天然物Palau'amine 有 sw 空 LCMIALUDC-NKEr-C Angewandte 东风螺毒素(Surugatoxin） 7年日丰折检生本中作，关死它赛 更贤深穿性徽了一中 骏河毒素(Surugatoxin,SGTX) Anti-osteoporotic Alkaloid Norzoanthamine CH. a
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
二、海洋甾体化合物 二、海洋甾体化合物 1皂苷类 o6g 海参皂苷 海星皂苷 wo. nakfanlktseandaccn a Marine Sterol Side-Chains(N-Nueleus) Unusual Marine Steroids yed 8 Unusual Marine Steroids 甾体化合物Sterols SO,NHMS 8 9
9 171 二、 海洋甾体化合物 A single general formula can describe most terrestrial sterols (1-3). 1 R = H, Cholesterol (1) 2 R = Me, 24-MethylCholesterol (2) 3 R = Et, 24-EthylCholesterol (3) HO 17 19 1 11 5 R 24 A B C D 172 二 、 海洋甾体化合物 1 皂苷类 海参皂苷 海星皂苷 1955年Yamanouchi首次从海参中分得海参素-B, 直到1978年Kitagawa测定出海参素-B的结构。 海参和海星是从动物中分离皂苷的第一资源 Minale. L. Chem.Rev. 1993, 93:1839-1895 Fattorusso E. Steroids from sponges: Recent reports. Steroids. 1999, 64:687-714. O O OH HO OO O O OH OH OH OH NaO3SO Echinoside B OH O-Xyl OH OH OH NaO3SO Aphelasteroside A 173 N17 24 23-Methyl-22,23-methyleneCholesterol (1) N17 24 Dihydrocalysterol (2) N17 24 Calysterol (3) N17 24 23H-Isocalysterol (4) N17 N 5 6 Marine Sterol Side Marine Sterol Side-Chains (N=Nucleus) Chains (N=Nucleus) 陆生植物产生的甾醇通常与b-谷甾醇密切相关，海洋生物中含有 大量异常的甾醇，大多是在侧链不同位置上烷基化，C-22 or 23. 174 Unusual Marine Steroids HO O O O HO H H O OH OH H H Nephthea chabrolii was the source of the 3-keto-steroids chabrolosteroids A and B and unusual spiro-steroid chabrolosteroid C. J.-H. Su, F.-Y. Lin, H.-C. Huang, C.-F. Dai, Y.-C. Wu, W.-P. Hu, C.-H. Hsu and J.-H. Sheu, Tetrahedron, 2007, 63, 703. 175 Unusual Marine Steroids 9,11-Seco-steroids 8,9-Seco-steroids Degraded Steroids HO 17 19 1 5 24 A B C D MeO 17 19 1 11 5 24 A B D HO H O 17 11 24 C D O O MeO 17 11 24 C D O O MeO 176 甾体化合物 Sterols Sterols Marine organisms have been found to be storehouses of sterols, particularly in terms of unique side-chain structures and unusual functionalization. • Sulfamate group in haplosamate A have only been found in nature as metabolite of marine sponges. Haplosamate A Faulkner D. J. Tetrahedron. 1999, 55, 8323. O OH NaO3SO OH OH OSO2NHMe
甾醇Sterols Squalamine 1970s Shark cartilage oil (squ nhibits angiogenes mie角 作为新生血管抑制剂类抗塘药物进入山有低床试验 nd ha 自白角Squabus的肝中分 出“n 甾体化合物Steroids -CH 0 ty aa】 A-C U-3 The 甾体化合物Steroids 甾醇二聚体生物碱 subapbo 10
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
