Tax0(警杉醇】 Worldwide Race For Taxol Synthesis The last line of defense in advanced cancer 0.2 Total Synthesis of Taxol Nature,An Excellent Synthetic Chemist 1971-Present e Tax L-地T SSSS 2008年Takabashi(高着1用了48步枚来0.070% Semi-synthesis of Taxol" Question Why so many compounds in nature have biological effects to humans? 1
1 Taxol® (紫杉醇®) The last line of defense in advanced cancer 红豆杉: 希望之树 CH3 H H3C CH3 HO O H O CH3 H O O O H OH O H 20 5 CH3 O O H3C O O HO H N O 1 15 13 H H H 10 Nature 1979, 277: 665-667 0.004% Worldwide Race For Worldwide Race For Taxol® Synthesis Synthesis Nature, 1994, 367: 630-634. K. C. Nicolaou R. A. Holton Total Synthesis of Taxol® 广藿香醇 黏酸 维兰德-米舍尔酮 蒎烯 合成构素 L-丝氨酸 O OH O Nicolaou (1994) 39 steps Wender (1997) 37 steps Me Holton (1994) 39 steps Kuwajima (1998) 60 steps O Danishefsky (1995) 49 steps Mukaiyama (1998) 60 steps O Me Me Me Me HO COOH H Me O O 4.3% 0.041% 0.63% 0.63% 0.17% 0.014% NH2 1971-Present 2008年Takahashi (高桥)用了48步收率0.0070% +16 Nature, An Excellent Synthetic Chemist 紫杉醇 Taxol Me Me HO Me AcO OBz H Me OAc OH O O O OH Ph NH O O 红豆杉 Yew Ұ750 Ұ1300 Nat. Prod. Chem. Nat. Prod. Chem. h CO2 + H2O $ $ $ $ $ $ $ $ Blockbuster Drug: 10 billion $ in 2000 Semi-synthesis of Taxol® R. A. Holton N Ph OPG O Ph O DAMP Pyridine 96% at 96% conversion HF, Pyridine 98-100% PG:Protecting Group HO HO OBz H OAc OH O O HO 10-Deacetyl-baccatin III + Taxol HO AcO OBz H OAc OH O O O OH Ph NH O O 13 13 30吨皮100g Taxol,150万美元 1988 J.N.Denis 0.1％ 1994年底 1985 Question Why so many compounds in nature have biological effects to humans?
Why Drinking Green Tea Could 从绿茶到Veregen:一片树叶的故率 Prevent Cancer? 茶多酸：第一个成为美国处方药的中草药 思 Keep Your Doctor Awa Why an apple a day keep the doctor away? Promising Se 热这 8 g9 近 8阳 a 天然产物在抗肿瘤治疗中起着重要作用 All available anticancer drugs.1940s-06/2006.by source (N 175 S￥2010,32132-3H 2
2 Why Drinking Green Tea Could Why Drinking Green Tea Could Prevent Cancer? Prevent Cancer? Jankum, H. et al. Why drinking green tea could prevent cancer. Nature 1997, 387, 561. HO O OH OH OH OH HO O OH O OH OH O OH OH HO O OH OH OH OH OH O OH O OH OH HO Polyphenols Keep Your Doctor Away 从绿茶到Veregen®：一片树叶的故事 茶多酚：第一个成为美国处方药的中草药 2006 年10 月30 日, FDA 批准从绿茶叶中提取的VeregenTM成为处方药 (21902)。这是自1964 年6 月美国颁布新的药品法以来, 第一个通过FDA 审 批的植物药。这一批准证明FDA不仅仅把植物作为食物补充剂，而同样可 作药物用。历史性的里程碑。这为一个新药行业的建立铺平了道路。 HO O OH OH OH OH 百药之药-茶叶 Why an apple a day keep the doctor away? Why an apple a day keep the doctor away? R2 HO R1 1 R1=OH, R2=CH3 2 R1=H, R2=CH3 3 R1=OH, R2=CH2OH R2 HO R1 4 R1=OH, R2=CH3 5 R1=H, R2=CH3 6 R1=OH, R2=CH2OH COOH RO HO OH 7 R= 8 R= C OH O C OH O CH2OH 9 HO RO OH O 10 R=H 11 R=CH3 HO O R2 O OH R1 12 R1=H, R2=OH 13 R1=OH, R2=H O O OH OH OH OH OH HO O 14 HO OH O O OH O HO O 15 16 HO OH OH OH HO O 17 HO O OH O OR OH OH 18 R=H 19 R=β-D-Gal 20 R=β-D-Glu 21 R=α-L-Ara O H OH OH HO OH OH 22 O H OH OH HO OH OH 23 H H H H Phlorizin 根皮苷 Thapsia garganica 毒胡萝卜素 Promising Sesquiterpenoids— Thapsigargin, Prostratin and Ingenol Thapsigargin: killing tumor cells by destroying their calcium balance Homalanthus nutans下垂澳杨 Prostratin 毒胡萝卜 Ingenol 巨大戟素 Anti-HIV 光化性角化病 2012 prostate cancer 30多年来在云南北部每年7-9月雨季都发生几十例甚至更多的不明 原因猝死。2008年昆明植物所高等真菌化学专家刘吉开从云南一种新的 小白菌（Trogia sp.）中分离鉴定出了两个新的非蛋白质氨基酸: 2R-氨 基-4S-羟基-5-己炔酸，2R-氨基-5-己炔酸, 证明该菌是30多年来导致云南 不明原因猝死的罪魁祸首。 Science 2010, 329: 132-134 鹅膏毒素 -Amanitin “死亡天使” (Death Angel): 鹅膏毒素 摧毁人们的肝和肾 OH O OH NH2 OH O NH2 All available anticancer drugs, 1940s-06/2006, by source (N ) 175 A直接来源于天然产物的抗 肿瘤药物占14%；B 以天然 产物为先导进行全合成或半 合成而形成的抗肿瘤药物占 51%, 二者共占65%。 A B B B B C 天然产物在抗肿瘤治疗中起着重要作用 You need chemicals to fight cancer, and chemists have spent decades working on molecules they hope will fight everything from breast cancer to prostate cancer. But all the chemists in the world are no match for Mother Nature
"War on Cancer" 喜树碱Camptothecin ons Camptothecin Taxol Taxus brerifolia 1966 10 高格工1976合 1985年H准吧普禄道喜树城能够掉制与 10-Hydroxycamptothecin is used in DNA直制豪的 选一China to treat cancers of the liver and 1958车头国下C☐%250亿美无，两时20多年1958-1980)，对 视为喜树碱的研完创造丁新的爽放成。 stomach and also leukaemias. 【来潭】头物升植前喜树Camptotheca acuminata全林：蒿草料桂的 3500拿种植物中的11万多个授果物的花痛活性进行丁师选。 蛇根草phiorrh位mungos叶， 【希性】抗肿清。对DNA拓补异构酶有明显抑制作用。 “老南作用” Richard Nixon 1971 "National Cancer Act" Crm.Bkh204」2：1585-14 长春碱与长春新碱 Podophyllotoxin鬼白毒素 蒙长花属枝物(rosy periwinkle】 H.Co OH rted in 1951 小限属植物亮白 by Hartwell and Schrecker 白血病、重奇金淋巴肉痛 lonathon Hartwel cop pchan 2013FDA晚期乳 1972 Maytansine 天然产的-体向给黄 breast olated tymphomas.gastrie.small-cell lung) retiosum which is possibly ndophytie to the original plar 4 n.Chem.Sc.1980,1026613-15 3
3 “War on Cancer War on Cancer” Richard Nixon 1971 “National Cancer Act” N N O O O HO AcO OBz H OAc OH O O O OH Ph NH O O Taxol Taxus brevifolia Camptothecin Camptotheca acuminata 1958年美国NCI耗资250亿美元, 历时20多年(1958-1980年), 对 3500 余种植物中的11万多个提取物的抗癌活性进行了筛选。 喜树碱 Camptothecin 1958 l0-Hydroxycamptothecin is used in China to treat cancers of the liver and stomach and also leukaemias. • ［来源］珙桐科植物喜树Camptotheca acuminata全株；茜草科植物 蛇根草Ophiorrhiza mungos叶。 • ［活性］抗肿瘤。对DNA拓扑异构酶I有明显抑制作用。 • Craig J. et al. Bioorg. Med. Chem. 2004,12 : 1585–1604. “靶向作用” 1966 高怡生1976 合成 Dr. Wall & Wani 1985年Hsiang 等报道喜树碱能够抑制参与 DNA 复制和转录的topo, 这一确切机理发 现, 为喜树碱的研究创造了新的突破点。 Dr. Robert L. Noble William Lipscomb 白血病、霍奇金淋巴肉瘤 长春碱与长春新碱 紫长春花属植物（rosy periwinkle） Podophyllotoxin 鬼臼毒素 O O O O OH H3CO OCH3 OH H H Podophyllum emodi var. chinense 小檗属植物鬼臼 Structure reported in 1951 by Hartwell and Schrecker 1 Etoposide 2 Teniposide O O O O OH H3CO OCH3 O H H O O OH HO H3C O O O O OH H3CO OCH3 O H H O O OH S HO 1880 2013 FDA晚期乳腺癌 Maytansine Uni. Calif 天然产物-抗体-靶向给药 1972 J. Am. Chem. Soc., 1980, 102, 6613–15