天然产物化学促进分析化学的发展 器 天然产物化学诺贝尔奖候选人 The Ginkgo Tree's Chemical Charms 980 Wanderine Natural produets chemist-Nakanishi koi tture determination of Ginkgolide 100 MHz 1966 What Can Organic Chemist Do With NP? First Bio-mimie Synthesis c-- metic total synthesis of (Robinson,1917) 1g,2m
1 Dorothy Crowfoot Hodgkin 因用X射线衍射方法研究青霉素 和维生素B12等的分子结构成功， 英国科学家霍奇金在1964年获得 诺贝尔化学奖。 天然产物化学促进分析化学的发展 Richard R. Ernst (瑞士)因发明了 傅立叶变换核磁共振分光法和二维 核磁共振技术在1991年获得诺贝尔 化学奖 。 Dorothy C. Hodgkin—— 霍奇金中国人民的老朋友 2005-7-1《细胞》 唐有祺院士 饶子和 院士 廖鸿英 天然产物化学诺贝尔奖候选人 IR, CD,NOE, NMR 800 papers, 9 books 达纳康 550 Students (Tanakan®) O O O O O O O O O O O CH3 O HO CH3 CH3 CH3 CH3 H3C CH3 H H H H H H H H H H H H H H H H O OH HO HO CH3 O CH3 OH OH O O O O HO O O HO O OH H OH H H A Wandering Natural Products Chemist A Wandering Natural Products Chemist-Nakanishi Koji Nakanishi Koji A Master of Chemistry and Magic 秦国伟 ACS MEETING NEWS The Ginkgo Tree's Chemical Charms The Ginkgo Tree's Chemical Charms Aesthetically pleasing and medically useful, ginkgolides Aesthetically pleasing and medically useful, ginkgolides fascinate Koji Nakanishi “We followed the bitter taste with our tongues” Bilobalide O O O O O O OH HO 最早的生物活 性指导分离： Structure Determination of Structure Determination of Ginkgolide 100 MHz 1966 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? Mimic Synthesis 8 虎皮 Bio-Synthesis 天然产物化学促进生命科学的发展 无脑产物作为化和生之一十天通，是大自过 的医 人人 Natural Products as Chemical Probes 没有天然产物没有分子生物学的今天 ra六
2 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 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 HOOC O OH O O O O O O O O O O CHO HO H O O O O O O O H H O O O O O O O O O O O Me O HO Me Me Me Me Me Me H H H H H H H H H H H H H H H CHO Epoxide-opening Ring closure Cascade Epoxidation Bio-Synthesis Synthesis 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 “Dear Monroe: Can you help this poor girl?” 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 Tools for Neuroscience Natural Products as Modulators of Bio-molecular Function Natural Products as modulators of Natural Pro Bio-molecular Function 灯 人 是 X属于新型的纳罐道功有是引复人类中毒分布广的一种毒素26万人年 Natural Products as Pharmacologic Tools Natural Produets as Chemical Probes to Study Signaling Pathway 帕等素可以让我们活过00岁 8 1率在南上有。年在中国上市 影d2m:水6365
3 N NH O O OCH3 O OCH3 OCH3 OCH3 H3CO OCH3 H O H H O O O O OH OH OH OH H N H3C O OH OH H Morphine Δ9-tetrahydrocannabinol Forskolin Reserpine Natural Products as Tools for Neuroscience Natural Products as Tools for Neuroscience 毛喉素：腺苷酸环化酶激活剂 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. 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。 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 西加毒素(Ciguatoxin, CTX)是电压依赖性Na+通道激动剂，可作为 研究兴奋细胞膜结构与功能以及局麻药作用机理的分子探针。 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 属于新型的钠通道激动剂,是引起人类中毒分布最广的一种毒素2-6万人/年 Natural Products as Natural Products as Pharmacologic Tools Pharmacologic Tools to Explore to Explore Bio-molecular Function Brefeldin A is a fungal metabolite used as a biological research tool for studying protein transport. 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
喜树碱Camptothecin Protein Synthesis Inhibition 拓扑异构抑制剂—向药物 ☆ 4
4 Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins. Bioorganic & Medicinal Chemistry 2013, 21: 6920-6928. 喜 树 碱 Camptothecin Camptothecin 拓扑异构酶I抑制剂——靶向药物 O N H O OH N Trichostatin A Trichostatin A have proven useful in the exploration of HDAC function in gene regulation as well as differentiation processes. Reveromycin A O O OH COOH O O COOH HOOC H H O O O O H2N N S N Pateamine A Protein Synthesis Inhibition Myriaporone OH O OH O OH O OH OH OH OH O O O OH