河北医科大学：《天然药物化学》课程教学资源（课件讲稿）第十章海洋药物 Marine Natural Medicine（MNM）4/4.pdf_大学文库

河北医科大学药学院天然药化教研室史清文教授 1 From micrograms to grams: scale-up synthesis of eribulin mesylate Melvin J. Yu, Wanjun Zheng and Boris M. Seletsky Nat. Prod. Rep., 2013,30, 1158-1164 Katrina L. Jackson, James A. Henderson, and Andrew J. Phillips. The Halichondrins and E7389. Chem. Rev. 2009, 109, 3044–3079. Angew. Chem., Int. Ed., 2015, 54, 5108 Better than Nature? Nor-halichondrine A O O O O O O O O O O O O O O H H H H H H H H H H H H H O O HO COOH H HO OH Uemura D Halicondrin B的结构为含60个碳的长链聚醚大环顺式连接的船式吡喃环。和Norhalichondrin A（59碳链）均有很强的细胞毒作用及抗B16黑色素瘤的活性，尤其是Halicondrin B对接种B16黑色素瘤细胞及P388白血病的小鼠，能延长寿命分别为244％和236％，比大田软海绵素 B少一个C Y. Kishi Spongistatins 含有氢化吡喃螺环的大环内酯环聚醚。 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 1. Isolated in the early 1990's by the Pettit, Fusetani, and Kitagawa. 2. Pettit’s attempted re-isolation delivered 35 mg of spongistatin 1 from 13 TONS of sponge! 3. Two spiroketals, two tetrahydropyrans, hemiketal, 42 membered macrolide 四、聚醚三萜  特点角鲨烯衍生的三萜,为红藻和一些海绵所产生。  结构新颖，含有多个手性中心，均有较好的生物活性。  如Sipholenol 海绵Siphonochalina siphonella O H OH 3 5 9 11 13 24 27 28 1 7 26 25 Sipholenol OH H H H 20 29 16 14 23 31 30 HO O O H OHAcO H OAc H O O O H O HO 3 5 9 11 13 15 23 24 25 28 29 1 7 17 26 27 30 31 Raspacionin Sodwanone E 聚醚三萜 O O O OH H H O 19 1 3 17 25 26 27 28 29 30 31 5 7 9 11 13 15 23 24 从海绵Axinella weltneri中分得的sodwanones是一组结构类似的聚醚三萜，其中Sodwanone M 对P388细胞有选择性毒性 IC50为1 μg/mL O H O 3 5 9 11 13 24 27 28 1 7 26 25 Sipholenone B OH H H H 20 29 16 14 23 31 30 HO O Fernandez J. J. et al. Marine polyehter triterpenes. Nat. Prod. Rep. 2000, 17, 235-246. 聚醚三萜 Total more than 65 O O HO OH H H Abudinol B Testudinariol B O O OH HO H H H H

河北医科大学药学院天然药化教研室史清文教授 2 O O O O + HN HO OH O COOH 1 O O O O + HN HO O H 2 OH COOO 1975至1981年间日本人因吃牡蛎Pinna pectinata而发生食物中毒的多达2500人，1995年上村大埔等从牡蛎P. pectinata中分离出4个毒性成分 pinnatoxins A-D，其中pinnatoxins A (1)和D (2)的结构已经确定，它们都是Ca2+通道激动剂。其他聚醚 Pinnatoxins A and D as a major cause of food poisoning. 上村大埔 pinnatoxin A pinnatoxin D Seafood Poison • Seafood poisoning is usually caused by ingestion of shellfish toxicated with one of six types of poisons 1. Paralytic shellfish poisons (PSP): Saxitoxin 2. Neurotoxic shellfish poisons (NSP): BTX 3. Diarrhetic shellfish poisons (DSP) : Okadaic Acid 4. Amnesic shellfish poisons (ASP) : Domoic Acid 遗忘症 5. Ciguatera Fish Poisoning (CFP): CTX, MTX 6. Puffer Fish Poisoning (PFP): TTX 河豚中毒 7. Hepatotoxic Shellfish Poisoning (HSP): YTXs Paralytic shellfish poisoning (PSP) is one of the most severe forms of food poisoning caused by ingestion of seafood. It is acute and often fatal. There is no effective way to destroy the toxins or to treat the patients. Therefore, it poses serious health problems. Deterring shellfish consumption causes economic problems. The history of the poisoning goes back to prehistoric days and the incidents due to the consumption of toxic shellfish are well documented. Paralytic shellfish poisoning (PSP) N N H N N H NH2 H2N O H OH OH H H + + 1 6 8 H H2N O 11 Saxitoxin石房蛤毒素 1957年美国阿拉斯加大石房蛤 Saxidomus giganteus 肌肉麻痹剂 The term ciguatera is used to food poisoning caused by ingestion of toxic coral reef fish. Ciguatera not only endangers public health. It is estimated that roughly 20,000 people suffer annually from such poisoning. Two groups of compounds implicated in the poisoning are ciguatoxin and maitotoxin. Both groups of toxins are produced by dinoflagellate Gambierdiscus toxicus and transferred to herbivorous fish and subsequently to carnivores through the food chain. Ciguatoxin is regarded as the principal toxin responsible for human illness. Ciguatera (Seafood Poisoning) Ciguatera Fish Poisoning (CFP, such as CTX and MTX) are also responsible for many of the massive fish kills which have been observed throughout history and around the world. O O O O O O O O O O O O O H H H H H HO H H H H OH H OH H H H H H H H H H H OH HO OH CTX O O O O O O O O OH HO HO Me Me Me H Me H H H H H H H H H H H Me Gambierol DSP is a major public health problem even though it is not lethal. The toxic symptoms are abdominal cramps (1 hr elapse time), nausea progressing to diarrhea (2-7 hr), and a “raw”, “burning” feeling in the stomach. Diarrhea is noted in 92% of all cases, nausea in 80%, vomiting in 79%, abdominal pain in 53%, and chills in 10%. DSP was first discovered in 1976, associated with eating bivalves such as mussels, scallops or clams which have accumulated dinoflagellate toxins. Causative toxins that have been identified are Okadaic acid and its analogs and pectenotoxins. Diarrheic Shellfish Poisoning (DSP)

河北医科大学药学院天然药化教研室史清文教授 3 Okadaic acid (OA) was first isolated independently from the sponges, Halichondria okadoi kadota and H. melonodocia. Subsequently, it was found in dinoflagellate, Prorocentrum lima and Dinophysis spp. O O O O O O O HO O OH OH HO OH Diarrheic Shellfish Poisoning (DSP) The first total synthesis of okadaic acid was achieved in 1984 by the Isobe group . Pectenotoxins 扇贝毒素 Pectenotoxin-l (PTX1) was isolated as one of the Diarrheic Shellfish Toxins from the digestive glands of the scallop, Patinopecten yessoensis found Northeastern Japan. Diarrheic Shellfish Poisoning (DSP) O O O O O O O R O O O O HO OH OH 7 10 PTX1 R=CH2OH R at C-7 PTX2 R=CH3 R at C-7 PTX3 R=CHO R at C-7 PTX4 R=CH2OH S at C-7 PTX5 R=COOH R at C-7 PTX6 R=COOH S at C-7 Pectenotoxins 1 5 41 47 33 42 43 44 45 46 H H 聚醚类化合物的特点  杂原子对碳原子的比例很高；  结构特殊，新颖，分子量大；  活性强，剧毒；目前尚无抗毒剂。  广谱药效，作用机制独特；  多数对神经系统或心血管系统具有高特异性作用。  海洋天然产物所特有。聚醚类毒素是海洋天然产物特有的一类化学结构, 如岩沙海葵毒素(PTX ) , 西加毒素(CTX ) , 刺尾鱼毒素(M TX) 等。其药理和毒理作用机制特殊, 常作用于控制生命过程的关键靶位, 如神经受体、离子通道、生物膜等, 已成为新药开发的特殊模式结构。岩沙海葵毒素以特殊的作用方式作用于细胞膜, 具有强抑癌活性。西加毒素具有高强心活性。海葵毒素已作为强心药物的重要先导化合物。多数海生毒素均有较强的神经毒性, 而且作用于神经离子通道, 对神经系统起重要作用。聚醚类毒素第四节肽类化合物 Peptides 海洋生物中一大类生物活性物质,来源于除海蛇以外进化程度较低的动物,如海绵,水母,海兔,海葵,芋螺等以及蓝绿藻。  由于海洋环境的特殊，组成海洋多肽类的氨基酸除了常见的氨基酸外，还有大量的特殊氨基酸。 COOH N H COOH COOH N H COOH COOH N H COOH HOOC H 47 allo-kainc acid 48 1' 5' 6' 7' 8' a-Kainic acid Domoic Acid a-红藻氨酸别-红藻氨酸软骨藻草酸 COOH N H COOH COOH N H COOH COOH N H COOH HOOC H 47 allo-kainc acid 48 1' 5' 6' 7' 8' a-红藻氨酸别-红藻氨酸软骨藻草酸 Domoic acid 1953年日本学者从日本海藻（Digenea simplex）中分离得到海人草酸（红藻氨酸，kainic acid）和别红藻氨酸（-allo-kainic acid）1955年用经典的化学降解反应和对降解片断的合成等方法研究了它们的结构，并最终用X-衍射确定了其立体结构. Domoic acid,软骨藻草酸 , act as insecticide and was found to be 14 times more active than DDT. a-Kainic acid

河北医科大学药学院天然药化教研室史清文教授 5  目前研究较多的是芋螺毒素 Conotoxins (CTX)，芋螺毒素是一类具有神经药理活性的多肽，一般含有 7-41 个氨基酸。种类繁多，一种芋螺可含不同序列结构的芋螺毒素达100- 300种。因此估计芋螺毒素可达5万种。 主要有：直链肽和环肽。第四节肽类化合物 Peptides Abel Aneiros, Anoland Garateix. Bioactive peptides from marine sources: pharmacological properties and isolation procedures. Journal of Chromatography B, 2004, 803, 41–53. 在20世纪70年代，亚利桑那州立大学的癌症研究所所长G. R. Pettit 等开始对印度洋无壳软体动物截尾海兔(Dolabella auricularia)中抗肿瘤活性成分的研究，发现海兔提取物可以延长P388白血病小鼠的寿命。Pettit等1981年从2吨的印度洋海兔dollabela中分离到18种具有抗瘤作用的肽类化合物，其中dolastatins 1和15的活性最好，都比长春花碱的生物活性好，而dolastatin 10的是15的9倍。Dolastatin 10是迄今发现活性最强的天然产物之一。 Dolastatin 10 G. R. Pettit N O H N O N O N O N H O S N O H 多拉司他汀软体动物截尾海兔亚利桑那州立大学的癌症研究所所长海兔毒素 In 1972, it was discovered that extracts of the sea hare Dolabella auricularia showed pronounced antineoplastic activity. Due to the vanishingly small amounts of active substances in the slug, it was not until 1987 that the structure of the most potent compound in this extract, dolastatin 10, could be elucidated: 1 ton of mollusk biomass was collected from the wild to isolate just 29 mg of dolastatin 10 (structure below)! But honor to whom honor is due – it has later been found that the dolastatins are in fact produced by the cyanobacteria蓝细菌Symploca hydnoides and Lyngbya majuscula, which are part of the sea hare’s diet. N O H N O N O N O N H O S N O H 直链肽—Dolastatin 10 软体动物截尾海兔 Adcetris 治疗淋巴瘤 (brentuximab vedotin) FDA 2011年8月19日批准Adcetris (brentuximab vedotin)治疗霍杰金淋巴瘤(HL)和一种罕见淋巴瘤被称为系统性间变性大细胞淋巴瘤(ALCL). 淋巴瘤是淋巴系统癌症。Adcetris是一种抗体药物结合物，结合抗体和药物，允许抗体指引药物至淋巴瘤细胞上被称为D30靶点。 Adcetris是自1977年第一个被FDA-批准治疗霍杰金淋巴瘤和第一个专门适用于治疗大细胞淋巴瘤(ALCL)的新药。 O N O H N O N O O O N O H N O OH N H O H N NH H2N O N H O O N O O S cAC10 H It took nearly 40 years from the initial bioactive extract to the approved drug. 抗体药物偶联物(Antibody Drug Conjugate) 一种新型的抗体药物 O N O H N O N O O O N O H N O OH N H O H N NH H2N O N H O O N O O H S Monomethyl Auriststin E (MMAE) Valine citruline linker Maleimido caproyl spacer O N O H N O N O O O N O H N O OH N H O H N NH H2N O N H O O N O O H S Monomethyl Auriststin E (MMAE) Valine citruline linker Maleimido caproyl spacer 2012年11月20日电 ——日本最大的制药公司—武田（Takeda）宣布，在英国推出抗体偶联药物Adcetris（brentuximab vedotin），该药是近 30多年来首个获批用于复发性或难治性CD30阳性霍奇金淋巴瘤的靶向性治疗药物。 ADC是通过一个化学链接将具有生物活性的小分子药物连接到单抗上，单抗作为载体将小分子药物靶向运输到目标细胞中。 Cematodin (LU-103793) • 链状肽 Dolastatin 10 Analogues Pettit小组最早对海兔抗肿瘤活性多肽展开研究，从中分得18个肽类化合物 Dolastatins 1-18, 具有强烈抑制肿瘤细胞生长的作用。 Pettit小组对 Dolastatins 10，15进行了全合成，结构修饰，SAR研究，LU-103793, TZT- 1027, Auristain PE 进入I期临床。 Me N O Me Me N H O Me Me N Me Me Me N O N H Me O NH O H H H H 1600 Kg sea hare Dolabella auricularia produce 10 mg dolastatin 10

河北医科大学药学院天然药化教研室史清文教授 8 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。而且毒性较弱，已经进入临床开发。 Didemnin B was the first MNP enter clinic trial in USA.因心脏和神经毒性而被放弃 Dehydrodidemnin B was in the clinic II trial (20 times stronger than that of didemnin B), showed promise be accepted as a anticancer drug. 去氢膜海鞘素B 膜海鞘素是一组从加勒比海被囊动物Trididemnum solidum中分离出来的抗病毒和细胞毒活性的肽类化合物。Didemnin B 的体内筛选结果表明它具有强烈的抗P388白血病和B16黑色素瘤活性,可诱导HL-60肿瘤细胞的迅速完全凋亡以及许多转化细胞的凋亡，但对静息的正常外周血单核细胞不起作用，是第一个在美国进入临床研究的海洋天然产物，作为一种新型抗肿瘤尤其是抗乳腺癌药物失败了，但Dehydrodidemnin B 很有希望。膜海鞘素(Didemnins)——来自海洋的抗癌药物 AplidineTM O O NH O NH N O O O OH N CH3 O O OMe NH O N N O OH O O 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. 从Leptolyngbya sp.（巴拿马海洋蓝藻）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 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 瓦努阿图共和国 the Republic of Vanuatu 为位于南太平洋西部锥形蜗牛毒液：开发新药之源科学家从这种蜗牛的毒液里提炼出止痛药，效力是阿片类止痛药的1000倍。锥形蜗牛的毒性是非常显著的，仅是一滴毒液便足以杀死20人,可作杀虫剂

河北医科大学：《天然药物化学》课程教学资源（课件讲稿）第十章 海洋药物 Marine Natural Medicine（MNM）4/4

河北医科大学：《天然药物化学》课程教学资源（课件讲稿）第十章海洋药物 Marine Natural Medicine（MNM）4/4