老药新用一黄连素Berberine New Wine In Old Bottle Anticancer and Anti-diabetes Aspirin,A Wonder Medicine New Wine In Old Bottle Heart Attacks 光 ne was a Nicotine,the Wonder Drug? Artemisinin,A Wonder Anticancer? Nicotine is a friggin wonder drug 05
1 老药新用—黄连素 Berberine Berberine Anticancer and Anti-diabetes 臭名昭彰的镇定剂利多胺Thalidomide会导致孕妇的胎儿畸形，以致受 到禁用；但它也是治疗麻风病及AIDS的特效药物。 。 WHO于2002年宣布, 将重新启用DDT用于控制蚊子的繁殖以预防疟疾、 登革热、黄热病等在世界范围的卷土重来。 N O O OMe OMe Cl New Wine In Old Bottle New Wine In Old Bottle 桦木酸(Betulinic acid) Anti-HIV 与现有抗艾滋 药物作用靶点完全不同。 OH O OAc Acetylsalicyclic acid H H COOH HO H H Aspirin, A Wonder Medicine A Wonder Medicine 1988年阿司匹林与突发心脏病的研究 刊登在“新闻周刊”的封面上：“突发 心脏病你要知道些什么？” 左下角是 一片有心电图的阿司匹林药片。 1969阿波罗太空 New Wine In Old Bottle New Wine In Old Bottle Quinine approved by FDA in 2004 used for centuries for the treatment of malaria, fever, indigestion, mouth and throat diseases and cancer. In 1994, an oral formulation of pilocarpine was approved by the FDA to treat dry mouth (xerostomia口腔干燥 ). In 1998, the oral preparation was approved for the management of Sjogren's syndrome, an autoimmune disease that damages the salivary and lacrimal glands. O O N N CH3 N Pilocarpine O H N H H HO Quinine 口腔干燥 Nicotine, the Wonder Drug? Nicotine, the Wonder Drug? Nicotine is a Nicotine is a friggin wonder drug Study finds nicotine safe, helps in Alzheimer's, Parkinson's N N Cl 大麻毒品有望研发成新的糖尿病药物 Marijuana Ingredients Show Promise In Battling Cannabis sativa L 桑科 Superbugs O OH CH3 H3C H3C 四氢大麻酚 1964 Tetrahydrocannabinol Artemisinin, A Wonder Anticancer? A Wonder Anticancer? Artemisinin: The New Penicillin— That Could Save Your Life O O O CH3 CH3 CH3 O O 青蒿素
Ephedrine-highly potent in weight loss Marine:Unique Environment and Peculiar Organism Drugs From The Sea 鲨鱼中抗病毒活性成分：Squalamine 向海洋要药 Wonder drug from shark chemical 膜海销素Didemnins来自海洋的抗痛药物 Ziconotide (PrialtTM,SNX-111 夺 芋螺毒青 的内师 2
2 Ephedrine Ephedrine — highly potent in weight loss highly potent in weight loss H C H C HN CH3 OH CH3 Ephedrine Ephedrine 麻黄碱 陈克恢 Marine: Marine: Unique Environment and Peculiar Organism 海洋中有：1）丰富多样的生物物种，其品种是陆地上的两倍以上，无 论大小、软硬、抑或速度快慢，都能生存下来，这说明它们有天然自卫、抵 抗疾病的能力。特别是那些身上充满生物活性分子、利用化学方式保护自己 的海洋物种，很可能蕴含丰富的药物资源。2）特殊的生态环境。 Et-743 对晚期软组织癌症如直肠癌，乳腺癌，肺癌，黑色素瘤 等有显著的疗效。来源于被囊动物红树海鞘 Ecteinascidia turbinata. ET-743 2007年9月欧盟已批准该药(商品名Yondelis®)用于晚期软组织肿瘤的治疗， 成为第一个现代海洋药物。 N N O O OAc Me HO OMe Me Me O NH MeO HO O H OH S 曲贝替定 Drugs From The Sea Drugs From The Sea YondelisTM 向海洋要药 Dr. Michael A. Zasloff Georgetown University Medical Center 鲨鱼中抗病毒活性成分: Squalamine Squalamine 1993 角鲨胺 膜海鞘素(Didemnins)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即将推向市场。 膜海鞘素(Didemnins Didemnins)——来自海洋的抗癌药物 O O NH O NH N O O O OH N H3C O O OMe NH O N N O OH O O AplidineTM 伊利诺州立大学 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 Baldomero M. Olivera
Pseudopterosin A 天然产物化学促进有机化学的发展 20世气最伟大的化学拿 两*绿数 天然产物化学促进有机化学的发展 推动有机化学的发展 atural product s d Mark Wa 化料 天然产物化学促进有机化学的发展 天然产物化学促进有机化学的发展 Ceres-Wondward-Hattmaan rula✉9 A 积 上特大 3
3 Pseudopterosin A Anti-inflamatory (skin care lotions) Patented by U. California 1989. Pseudopterogorgia elisabethae 假蕨素A (pseudopterosin)是一种从 软珊瑚虫体内分离出来的抗炎成分 Fenical W. Proc. Nati. Acad. Sci. USA 1986, 83: 6238. O O OH HO HO OH W. Fenical 雅诗兰黛 N N N N NH2 O Co O NH2 NH2 O H2N O H H2N O NH O O O P O O O OH N N CN HO O NH2 Albter Eschenmoser 瑞士联邦理工学院 Swiss Federal Institute of Technology Angew. Chem. Inter. Edi. 2011, 50(52): 12412-12472. 天然产物化学促进有机化学的发展 Woodward VB12 20世纪最伟大的化学家 Woodward and Mark Wuonola on March 17, 1976, the day that the synthesis of Vitamin B12 was completed. Woodward 1965 and Hoffmann 1981 NP. Natural product synthesis has indeed been the impetus for many fundamental discoveries (Vitamin B12-----Pericyclic Reaction and Woodward-Hoffman Rule) 天然产物化学促进有机化学的发展 Roald Hoffmann Total synthesis is augmented by the discovery of new structures in nature 推动有机化学的发展 Leopold Ruzicka提出了萜类的生源异戊二烯规则 (biogenetic isoprene rule); Woodward通过VB12的全合成和 Hoffman一起提出了轨道对称守恒定律； Barton对甾体的研 究提出环构象及其反应机理， 先后获得了诺贝尔化学奖。 Barton (UK) 1969年Nobel 化学奖获得者 Woodward (USA) 1965年Nobel 化学奖获得者 Leopold Ruzicka (Swiss) 1939年Nobel 化学奖获得者 Retro-synthetic Analysis 1990 天然产物化学促进有机化学的发展 Prostaglandins E. J. Corey COOH HO OH OH O O O O HO O O HO O OH H OH H H Ginkgolide C Corey–Woodward–Hoffmann rules? 将计算机图形处理技术引入 有机化学信息系统管理 ChemDraw、SciFinder 2004普利斯特里奖Priestley Medal Longifolene 天然产物化学促进有机化学的发展 岩沙海葵毒素 PTX Yoshito Kishi 岸 義人 O OH OH OH HO O OH OH O HO OH OH OH OH O OH HO OH OH OH OH O O O OH NH2 HO OH O O O OH OH OH HO OH OH OH HO HN O NH OH O OH OH OH OH OH HO OH OH OH OH OH OH OH 21 P-PhD and PhD Students spend more than 8 years in 1992 上村 大輔 最强的冠脉收缩剂，比血管紧张素Ⅱ强100倍
What can organic chemist Do with np? What Can Organic Chemist Do With NP? First Bio-mimic Synthesis C-E-a 6195 netic total synthesis of tropinone (Robinson.1917 Mimic Synthesis inspiration for Nature Examples of Structure Elucidation 65 高 天然产物化学促进生命科学的发展 Natural products as chemical probes 漫有天然产物就没有分子生物学的今天：
4 Biomimetic total synthesis of tropinone (Robinson, 1917) (1) Robinson, R. J. Chem. Soc., Trans. 1917, 762. (2) Robinson, R. J. Chem. Soc., Trans. 1917, 762. (3) See also: Birch,A. J. Notes Records Royal Soc. London 1993, 47, 277. First Bio-mimic Synthesis mimic Synthesis 1886-1975 1947年Nobel Prize R. Robinson CHO CHO + H2NMe + COOH COOH O Aqua N O Me What Can Organic Chemist Do With NP? What Can Organic Chemist Do With NP? What Can Organic Chemist Do With NP? What Can Organic Chemist Do With NP? 英国Nottingham 大学的Gerald Pattenden发明了用一步反应合成甾体化 合物四个环和7个手性中心的简易巧妙方法。 Gerald Pattenden Nature, 2008, 445, 323-332. Natural products as inspiration for the development of asymmetric catalysis SePh CH3 CH3 CH3 H CH3 H O O n-Bu2SnH, AlBN Heat Redical cascade H CHO OHC HN i) CH3NH2 ii) AcOH 65% C.H. Heathcock see PNAS 1996, 63, 14323 Methyl Homosecodaphniphyllate Daphniphyllum macropodum 虎皮楠 C.H. Heathcock Science, 1990, 248, 1532-1534. Mimic Synthesis Mimic Synthesis inspiration for Nature Examples of Structure Elucidation O HO NCH3 H HO H N O H H H H O H N Morphine 118 Years! Strychnine 127 Years! Robert Robinson published 54 paper for structure elucidation And determined it in 1946 and got Nobel Prize in 1947. Robert B. Woodward Total Syn. In 1954. Robert Robinson 1925 (1886-1975) 1952 Total Syn By Gates 高怡生 曾广方 天然产物作为化学和生物学之间一个天然的通道，是大自然经过漫 长的筛选和进化选择出来的。生命科学的发展急需应用新的小分子作为 分子探针去帮助研究已知的生物反应机理，去发现尚未被阐明的生物作 用机理，去验证全新的生物药物靶点，和去解决重大的医学难题。天然 产物作为化学小分子探针做出了其他生物技术方法无法企及的特殊贡 献，并此催生了一门新的学科——(天然产物)化学生物学。 天然产物化学促进生命科学的发展 Erin E. Carlson. Natural Products as Chemical Probes. ACS Chem. Biol. 2010, 5, 639-653. Stuart L. Schreiber, Harvard Uni. Natural Products as Chemical Probes Natural Products as Chemical Probes 没有天然产物就没有分子生物学的今天?
Microtubule-stabilizing Agents from Nature Natural Products as Modulators of w1w我护A6 Bio- cular Function hecd oos 8o of the warld's me Natural Products as modulators of Bio-molecular Function Colchicine秋水仙碱 灯 从海博中会痛的出山 Natural Products as Pharmacologic Tools Natural Produets as Chemical Probes to Study Signaling Pathway 袖素可以让们活过1岁？ 60 01:7非634 5
5 Microtubule Microtubule-stabilizing Agents from Nature stabilizing Agents from Nature Nature 1979, 277: 665-667 Her landmark research would help turn the molecule into one of the world’s most effective anti-cancer blockbuster drugs. O OH OH H O HO OH O NH2 O Discodermolide OH O O HO OH OH 1 6 16 Dictyostatin O O HO R O O N S OH Epothilone A R=H Epothilone B R=CH3 O O Me O H H N N Me OMe Eleutherobin O O OH AcO OH O O HO OH H H H O H FR182877 O O O H H OH H O H O H HO Laulimalide O OH HO OMe O O OH OMe OH Me Me HO Peloruside A MeO O O Me O COOMe H H N N Me OH Sarcodictyin A Natural Products as Modulators of Natural Products as Modulators of Bio-molecular Function N H N O O OH H NH HO OH HO OH H OH + 1 4 4a 8 10 11 6 Tetrodotoxin has been used extensively as a tool in the study of sodium channel pharmacology. 河豚毒素已经成为神经生 理学和肌肉生理研究的非常有用的工具。 O O O O O O O HO O OH OH HO OH 大田软海绵酸(Okadaic Acid) 是一种肿瘤促进剂，能抑制由钙激活 的磷脂依赖的蛋白激酶，是一种特殊的蛋白质磷酸酯酶1、2A和2B的抑 制剂，作为研究细胞调控的工具药。 Paul J. Scheuer Natural Products as Modulators of Natural Products as Modulators of Bio-molecular Function O O HO O HO 从海绵中分离的Manoalide是第 一个具有选择性作用于磷酯酶A2 （PLA2），现已成为研究阻断 PLA2的常规工具药。 Eleutherobin 从软珊瑚中分离的 二萜苷，具有紫杉烷一样的抗癌机 制，对乳腺、肾、卵巢及肺癌细胞有 极高的选择性，是未来几年有希望发 展为抗癌剂的候选化合物。 O O O N N O O OH OH OAc OMe O MeO OMe MeO OMe HN Ac Colchicine Colchicine Colchicine 秋水仙碱 秋水仙碱是从秋水仙（Colchicum autumnale）和丽江山慈菇（Iphigenia indica ) 中提取的一种生物碱，于1933年被发现，曾用于乳腺癌、宫颈癌等肿瘤的治疗， 因其骨髓抑制、神经毒性等副作用大，在肿瘤治疗中的应用被后来发现的长春碱 类抗微管微丝药替代。秋水仙碱能有效地抑制微管的聚合，因此被广泛地作为实 验工具药用于多种细胞骨架的特性研究；同时由于秋水仙碱的选择性神经毒性， 又被用于导致Alzheimer’s病和癫痫病的动物模型。 Brefeldin A is a fungal metabolite used as a biological research tool for studying protein transport. 布雷非德菌素A (蛋白转运抑制剂) Natural Products as Natural Products as Pharmacologic Tools Pharmacologic Tools to Study Signaling Pathway to Study Signaling Pathway Trapoxin A是组蛋白去乙酰化 酶(histone deacetylases)抑制剂 Trapoxin cause cell cycle arrest in mammalian cells and inhibit histone deacetylation. N S O O OH O OH O Epothilone B Epothilone B has similar modes of action to Taxol and is derived from the fermentation of Sorangium cellulosum. O H OH HO H O Brefeldin A NH N HN HN O O O O O O Trapoxin A Natural Products as Chemical Probes Natural Products as Chemical Probes Rapamycin and its derivatives have played important roles in the clarification of several cellular processes including cell growth, proliferation, and survival as well as protein synthesis and transcription. O O OH O N O O O H OMe O HO H MeO MeO HO ACS Chem Biol. 2010; 5(7): 639-653. 雷帕霉素靶点 mTOR信号途径 雷帕霉素可以让我们活过100岁？ 1999年在美国和欧洲上市，2003年底在中国上市 Dr. Suren N. Sehgal