河北医科大学药学院 Better than Nature? Nor-halichondrine A ms:scale-up sya The Halic Spongistatins 四、聚醚三萜 。特点角生的三花，为藻和一业产生 ◆陆构断瓶，有多个性中心，有枝好的生物活性 聚醚三萜 聚醚三萜 c Abudinol B Total more than 65 1C为1e/ml 天然药化教研室史清文教授
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 其他聚醚 0 Seafood Poison Seafood poisoning is usually caused by ingestion of shellfish 女 toxicated with one of six types of poisons 1.Paralytis shellfish poisons (PSP]Saxitoxin 2.Neurotoxic shellfish poisons (NSP):BTX &Diarrhetic shellfish poisons(DSP):Okadais Asid .Amnesie shellfish poisons (ASP:Domeic Acida 中 s(HSP):YTXs Paralytic shellfish poisoning(PSP) Ciguatera(Seafood Poisoning) Paralytic shellfish po ing (PSP)is one of the nost severe forms of food poisoning caused by ingesti The term ciguater is used to food poisoning caused by ng n of toxie coral reef fish.Ciguat ra not only endanger Ther oses serious health pr ated in the po and umption causes eco ic problems.The history of the 吧goes back和pre and Terred to he ouhthe food chain.Cg Ciguatera Fish Poisoning (CFP.such as CTX and Diarrheic Shellfish Poisoning(DSP) ve been observed throughout history and aroun blem even though it i are abd ans (1 h (2-7 hr),and 9 92%of all sase in809 ring in 79%abd 6 s which have ac 天然药化教研室史清文教授
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 Diarrheic Shellfish Poisoning(DSP) Pectenotoxins扇贝毒素 Diarrheis Shellfish Pois ing (DSP) mie-l (PTXIw 聚醚类化合物的特点 聚醚类毒素 来熊奏奉素是海泽天格产物特有的一类化学地物，知老 ◆杂原子对碳原子的比例很高： 沙海素PTN).面如素CT),剂业0MT四普 ·结构特珠，新颗，分子量大： ◆活性强，刷泰：司前尚无杭春剂， 特珠提式站构。 ◆广清药效，作用机制独特： 岩沙海婆春素以排球的作用方式作用于如胞疏、具有得 ◆多敷对神经系统戴心血管系统具有高补异性作用 种活性。◆素具有高强心活性，海串素已作为强心 ◆降洋天然产物所特有。 第四节肽类化合物Peptides 装指u1 款装半酸 )中分高得人手 he 14 times more active than DDl 天然药化教研室史清文教授 3
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 软骨藻草酸Domoie Acid Historical timeline of domoic acid Amnesie Stelifis Pooning ASP时a者周表中专 History of worldwide events associated with Chemical Structures of Domoic Acid and lomoic acid di gpumpioaad its Analogues 生 堂芝 y=- Transmission of Domoic Acid at Various 软骨藻草酸Domoic Acid Levels of Biotrophs s 有言作用。 天然药化教研室史清文教授
河北医科大学药学院 天然药化教研室史清文教授 4 软骨藻草酸 Domoic Acid 1987年在加拿大东部的爱德华王子岛人们因误食了污染的海鲜食品贻贝 Mytilus edulis发生了一起食品中毒事件，造成153人中毒，中毒症状是腹痛、 拉痢、呕吐且同时记忆丧失, 意识障害, 重症者处于昏睡状态, 两周内3人死亡。 Amnesic Shellfish Poisoning (ASPs) 遗忘贝类中毒 Historical timeline of domoic acid COOH N H COOH HOOC H 1' 5' 6' 7' 8' The timeline shows discovery, isolation and numerous domoic acid events across the global waters in various countries. JPN: Japan, USA: United States, CAN: Canada, NZL: New Zealand, IRL: Ireland, FRA: France, PRT: Portugal, TUR: Turkey, ITA: Italy, SCO: Scotland, AUS: Australia, and MYS: Malaysia. History of worldwide events associated with domoic acid discovery, overconsumption and poisoning episodes COOH N H COOH HOOC H 1' 5' 6' 7' 8' Chemical Structures of Domoic Acid and its Analogues Transmission of Domoic Acid at Various Levels of Biotrophs Domoic acid is produced significantly by various species of the genus Pseudo-nitzschia that intoxicate marine animals and humans after overconsumption. COOH N H COOH HOOC H 1' 5' 6' 7' 8' Mechanism of domoic-acid-induced neurotoxicity in nerve cells 软骨藻酸(domoic acid) 与L-海人草酸和L-谷氨酸一样为脑神经系统 中的主要传递物质，是一种兴奋性氨基酸。该物质最初从红藻类Chondria armata中分离出来，与海人草酸一样都具有驱虫作用。 1991年美国西海岸加利福尼亚的蒙特里湾发现鹈及鹈形目的鸟类大 量死亡，从鸟吃的鳀等鱼类肉中检出软骨藻草酸180 mg/kg，内脏中检出 2300 mg/kg。 软骨藻草酸 Domoic Acid COOH N H COOH HOOC H 1' 5' 6' 7' 8
河北医科大学药学院 第四节肽类化合物Peptides Dolastatin 10 多社可他行 心用前所完校多的是芋娜奉素C0not0 (CT,芋奉素 300种。国此格计芽城◆素可达5万种。 主要有：直链肤和环秋。 降儿◆常 直链肽一Dolastatin10 Adce体治行淋巴海 dotin) 平8 克oA6 of the m 抗体药物偶联物(Antibody Drug Conjugate) ,链状肽Dolastatin 10 Analogues 种新型的抗体药物 盈 天然药化教研室史清文教授
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