河北医科大学药学院 链状肽Dolastatin10 Analogues 环肽(300)：海鞘，海兔，海绵和微藻 o 人 · 环肽 Kahalalide F 人 人 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 6 • 链状肽 Dolastatin 10 Analogues 环肽 (300) ：海鞘，海兔，海绵和微藻 Kahalalide F 是从一种夏威夷海生软体动物( Elysia rufescens) 分离得到抗肿瘤活性成分. From 216 g of the animal, 2.1 g of kahalalide-F was isolated, while 5 mg was isolated from 3 kg of the alga collected at same site. Kahalalide F 对结核杆菌 具有较高的抑制活性。 Sea slug-海牛 海牛 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。KF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. 海牛
河北医科大学药学院 Anti-TB Activity Cyclic Depsipeptides 】 2:y 人 Microcystin-LR微囊藻毒素 Jasplakinolide=Jaspamide Anti-fungal HO Discodermins A-D from Discodermia kiiensis Didemnin-B 风情分清得为人运康果精 便逢刺的落性， 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 7 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 Microcystin-LR 1996年在巴西造成100多名急性肝功能障碍，7个月内至少50人死于 藻毒素产生的急性效应，引起举世瞩目的关注。 微囊藻毒素 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 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 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3.5-7.010–7 M)。A还具有抗炎和抑制肿瘤 促进剂的活性。 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. 但因心脏 和神经毒性而被放弃。 Didemnin-B Trididemnum solidum 膜海鞘素B O O NH O NH N O O O OH N CH3 O O OMe NH O N N O OH O O
河北医科大学药学院 Dehydro-didemnin B 膜海鞘素Didemnins) 来自海洋的抗癌药物 去童莲海精意 a小. Didemnin B and Dehydrodidemnin CoibamideA wo. Halipeptins 锥形蜗牛毒液：开发新药之源 霜，有强的花活性。 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 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
河北医科大学药学院 Ziconotide(Prial0芋螺毒素 From Foe to Friend:Using Animal Toxins to Investigate Ion Channel Function 4,2004FD Venom of marine snails provide new drugs Ziconotide(Prialt)芋螺毒素 第五节C-15乙酸原化合物 1、直链C-15乙酸原化合物 冬结构特点：从EOAc成乙酰灿酶A生新合减，的 多分塞：1、直绿C15乙酸爱化合物 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 9 Cys-Lys-Gly-Lys-Gly-Ala-Lys-Cys-Ser-Arg-Leu-Met-Tyr-Asp-Cys-Cys-Thr-Gly-Ser-Cys-Arg-Ser-Gly-Lys-Cys-NH2 Ziconotide (Prialt) Ziconotide (Prialt) 芋螺毒素 Ziconotide is the first N-type calcium-channel blocker and it is also the first marine-derived peptide drug on the market. Ziconotide is 1000-times more potent than morphine and it does not produce tolerance, which is well known with opiatebased therapies. Baldomero M. Olivera J. Michael McIntosh 1979 Isolated, 2004 FDA From Foe to Friend: Using Animal Toxins to Investigate Ion Channel Function 鸡心螺(Cone Snail)又叫“芋螺”、锥蜗牛，主要生长于热带海域，一般多 生活在暖海，属于软体动物门。Pain therapeutics from cone snail venoms: From Ziconotide to novel nonopioid pathways. Venom of marine snails provide new drugs Ziconotide was developed into an artificially manufactured drug by Elan Corporation. It was approved for sale under the name Prialt by the U.S. FDA on December 28, 2004, and by the European Commission on February 22, 2005. Their venom - and the way they deliver it - is the most interesting thing HO O N H NH S O HN O H N O N H O OH H N O N H O H2N OH O NH O S O NH HN S S N H H2N O NH2 NH O OH N H NH NH HN O O H2N O O O N H O OH H N O N H OH O HN O OH N H H N O O HO N H O HN O N H O HN O HN S S S NH2 O NH2 NH NH2 Baldomero M. Olivera J. Michael Mcintosh Ziconotide (Prialt) 芋螺毒素 世界著名神经药理 学家和海洋药物新 药研发专家、美国 犹他大学精神病学 系主任 第五节 C-15 乙酸原化合物 结构特点：从EtOAc 或乙酰辅酶A生物合成的 十五个碳的非萜类化合物。 主要来源于红藻的凹顶藻属Laurencia sp 分类: 1、 直链C-15 乙酸原化合物 OH 直链型 OH OH OH Laurencenyne 1、 直链C-15 乙酸原化合物 直链型