紫杉醇:具有里程碑意义的天然抗癌药物
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摘要
紫杉醇是从红豆杉树皮中分离得到的微量单体成分,作为世界上最优秀的植物抗癌药,紫杉醇及其衍生物是临床上常用的广谱抗癌药。自20世纪70年代发现紫杉醇后,科学家对此类化合物的构效关系、结构修饰、药理药效方面开展了大量研究,并开发出泰素、多西他赛、卡巴他赛、拉洛他赛、信立他赛、康莫他赛等抗癌药。直到40年后的今天,科学家对紫杉醇的研究依然活跃,对其生物合成、真菌培养、新剂型开发等方面也成为新的研究方向。作为源于天然的单体成分开发成新药的成功典范,紫杉醇类化合物的研发历程对当前开发天然新药提供有益的借鉴。本文对紫杉醇的研发及最新进展进行综述,回顾其开发历程及相关研究,以期为天然药物的开发带来新的思考。
As a most effective monomer composition from bark of Pacific Yew, paclitaxel and its derivatives are used in clinical practice as broad spectrum anticancer drugs. Since its discovery in the 1970 s, many researches had been carried out, mainly focusing on the modification, structure-activity relationship and pharmacological activity. The great successes pressed ahead the development of a series of taxol-like drugs, including taxol, docetaxel, cabazitaxel, larotaxel.Nowadays, studies of taxol are still the hotpots, which concentrated on the new source such as cultivation of tissue, fungus culture and new dosage forms. As the representative of drugs research from natural source, taxol is worth to be summarized of its history and ongoing development for looking forward to bring new innovation mentality in new drugs.
As a most effective monomer composition from bark of Pacific Yew, paclitaxel and its derivatives are used in clinical practice as broad spectrum anticancer drugs. Since its discovery in the 1970 s, many researches had been carried out, mainly focusing on the modification, structure-activity relationship and pharmacological activity. The great successes pressed ahead the development of a series of taxol-like drugs, including taxol, docetaxel, cabazitaxel, larotaxel.Nowadays, studies of taxol are still the hotpots, which concentrated on the new source such as cultivation of tissue, fungus culture and new dosage forms. As the representative of drugs research from natural source, taxol is worth to be summarized of its history and ongoing development for looking forward to bring new innovation mentality in new drugs.
引文
1 Ferlay J,Soerjomataram I,Dikshit R,et al.Cancer incidence and mortality worldwide:Sources,methods and major patterns in GLOBOCAN 2012.Int.J.Cancer,2015,136:E359–E386.
2 Tachibana Y,Zhu X K,Krishnan P,et al.Characterization of human lung cancer cells resistant to 4′-O-demethyl-4β-(2″-nitro-4″-fluoroanilino)-4-desoxypodophyllotoxin,a unique compound in the epipodophyllotoxin antitumor class.Anticancer Drugs,2000,11(1):19-28.
3 邓立新.抗癌新药紫杉醇简介.化学教学,2006,1:46-48.
4 周波,姜虎生.红豆杉及其产物紫杉醇研究概况.吉林师范大学学报(自然科学版),2001,1:78-81.
5 Wani M C,Taylor H L,Wall M E,et al.Plant antitumor agents.VI.The isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxusbrevifolia.J Am Chem Soc,1971,93(9):2325-2327.
6 Schiff P B,Fant J,Horwitz S B.Promotion of microtubule assembly in vitro by taxol.Nature,1979,277(5698):665-667.
7 Horwitz S B.Personal Recollections on the Early Development of Taxol.J Nat Prod,2004,67(2):136-138.
8 王莺.紫杉醇类抗癌药物的临床应用概述.海峡药学,2007,19(8):97-99.
9 Pronk L C,Stoter G,Verweij J.Docetaxel(Taxotere):single agent activity,development of combination treatment and reducing sideeffects.Cancer Treat Rev,1995,21(5):463-478.
10 张学玉,曲玮,梁敬钰.红豆杉属植物化学成分及药理作用研究进展.海峡药学,2011,23(6):5-9.
11 李春元,李梓.抗癌药紫杉烷类临床应用现况.世界临床药物,2001,22(3):140-141.
12 谢宝芬,潘柏良.紫杉醇的药理与临床研究进展.中国药业,2008,17(15):76-78.
13 Sunters A,Madureira P A,Pomeranz K M,et al.Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt.Cancer Res,2006,66(1):212-220.
14 张桂芝,方向群.紫杉醇参与逆转肺部肿瘤细胞免疫逃逸的机制研究.中国药业,2015,24(22):41-43.
15 徐律韵.紫杉醇对人肝癌细胞SMMC-7721黏附及侵袭转移潜能的影响.现代医药卫生,2014,30(5):655-657.
16 Meden H,Rath W,Kuhn W.Taxol-a new cytostatic drug for therapy of ovarian and breast cancer.Geburtshilfe Frauenheilk,1994,54(4):187-193.
17 宋沁馨,于立洁.多西他赛的临床应用进展.中国新药杂志,2001,10(12):900-903.
18 Tang P,Wang F.Recent Progresses in the Synthesis of Taxol.Chinese J Org Chem,2013,33(3):458.
19 冯双双,钞艳惠,何海冰,等.拉洛他赛共聚物脂质杂合纳米粒的制备及其性能评价.沈阳药科大学学报,2017,34(1):14-22.
20 Dong Y,Wang S,Wang C,et al.Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis.J Med Chem,2017,60(3):1219-1224.
21 陆红霞.紫杉醇剂型、临床用药方式及联合用药的研究进展.国外医学药学分册,2005,32(2):73-77.
22 Von Hoff DD,Ervin T,Arena F P,et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med,2013,369(18):1691-1703.
22 肖秀兰,任统伟.奈达铂联合紫杉醇同期放化疗治疗局部晚期鼻咽癌分析.中国医学工程,2012,20(10):52-53.
24 卢晨欣,孙警辉,伍春莲.白藜芦醇与紫杉醇联合用药对人喉癌Hep-2细胞凋亡机制的研究.中国中药杂志,2016,41(3):476-483.
25 Manju S,Sharma C P,Sreenivasan K.Targeted coadministration of sparingly soluble paclitaxel and curcumin into cancer cells by surface engineered magnetic nanoparticles.J Mater Chem,2011,21(39):15708.
26 蒲新霖.紫杉醇和姜黄素在肿瘤治疗中的联合应用.西南军医,2017,19(2):161-164.
27 杨孝来.紫杉醇与多烯紫杉醇.实用药物与临床,2010,13(4):281-283.
28 徐佳茗,夏学军,刘玉玲.紫杉醇新型制剂及临床研究进展.实用药物与临床,2016,19(4):510-517.
29 王懿娜,方红,张幸国,等.紫杉醇溶液外用治疗豚鼠耳部银屑病样病理改变的疗效观察.中华皮肤科杂志,2004,37(3):156-158.
30 冯健,童德兵,羊镇宇,等.紫杉醇预防心肌细胞线粒体缺血再灌注损伤的机制研究.中华全科医学,2014,12(11):1724-1726.
31 齐素华,巩娟娟,倪小宇.紫杉醇通过MLK_3/JNK_3信号通路对海马神经元损伤的保护作用.苏州大学学报:医学版,2012,32(1):1-5.
32 李弟贵,任莉.一种从人工种植南方红豆杉中全株提取紫杉醇的方法,中国:CN 1958580 A,2007-05-09.
33 唐培,王锋鹏.近年来紫杉醇的合成研究进展.有机化学,2013,33(3):458-468.
34 韩广甸,丁炬平,谢蓝.紫杉醇的合成进展.有机化学,1993,13(4):337-346.
35 Nicolaou K C,Yang Z,Liu J J,et al.Total synthesis of taxol.Nature,1994,367(6464):630-634.
36 Holton R A,Somoza C,Kim H B,et al.Chem Inform Abstract:First Total Synthesis of Taxol.Part 1.Functionalization of the B Ring.J Am Chem Soc,1994,116(4):1597-1598.
37 Holton R A,Kim H B,Somoza C,et al.Chem Inform Abstract:First Total Synthesis of Taxol.Part 2.Completion of the C and D Rings.Cheminform,1994,25(26):1599-1600.
38 Walsh C.Molecular mechanisms that confer antibacterial drug resistance.Nature,2000,406(6797):775-781.
39 陆怡,陈大明,熊燕.抗肿瘤药物的研发态势分析.生命科学,2012,24(6):535-542.
40 Osheroff N,Corbett A H,Robinson M J.Mechanism of Action of Topoisomerase II-Targeted Antineoplastic Drugs.Adv Pharmacol Academic Press,1994,9B:105-126.
41 Doi T,Fuse S,Miyamoto S,et al.A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer.Chem Asian J,2006,1(3):370-383.
42 Yang W,Sun J,Lu W,et al.Synthesis of kaempferol 3-O-(3″,6″-di-OE-p-coumaroyl)-β-D-glucopyranoside,efficient glycosylation of flavonol 3-OH with glycosyl O-alkynylbenzoates as donors.J Org Chem,2010,75(20):6879-6888.
43 Denis J N,Greene A E,Guenard D,et al.Highly efficient,practical approach to natural taxol.J Am Chem Soc,1988,110(17):5917-5919.
44 王九一,阎家麒.紫杉醇的半合成.中国药物化学杂志,1999,6(24):56-58.
45 Mangatal L,Adeline M T,Guenard D,et al.Application of the vicinal oxyamination reaction with asymmetric induction to the hemisynthesis of taxol and analogues.Tetrahedron,1989,45(13):4177-4190.
46 Rao K V.Semi-synthesis of paclitaxel from naturally occurring glycosidic precursors.J Heterocyclic Chem,2010,34(2):675-680.
47 王雪松,孙剑秋,臧威,等.从Strobel的发现看植物内生真菌研究的未来.生物学通报,2012,47(10):1-3.
48 段丽丽,陈鸿锐,陈杰鹏,等.选育紫杉醇高产菌种链格孢单孢变种.中国抗生素杂志,2008,33(11):650-652.
49 Soliman S S,Trobacher C P,Rong T,et al.A fungal endophyte induces transcription of genes encoding a redundant fungicide pathway in its host plant.Bmc Plant Biology,2013,13(1):93.
50 邱德有.紫杉醇生物合成研究历史、现状及展望.生物技术通报,2015,31(4):56-64.
51 Hampel D,Mau C J,Croteau R B.Taxol biosynthesis:Identification and characterization of two acetyl Co A:taxoid-O-acetyltransferases that divert pathway flux away from Taxol production.Arch Biochem Biophys,2009,487(2):91-97.
52 Chen S,Song J,Sun C,et al.Herbal genomics:Examining the biology of traditional medicines.Science,2015,347(6219):S27-S29.
53 Zefirova O N,Nurieva E V,Ryzhov A N,et al.Taxol:Synthesis,Bioactive Conformations,and Structure-Activity Relationships in Its Analogues.Russ J Org Chem,2005,41(3):315-351.
54 Chen S H,Farina V,Wei J M,et al.Chem Inform Abstract:StructureActivity Relationships of Taxol?:Synthesis and Biological Evaluation of C2 Taxol Analogues.Bioorg Med Chem Lett,1994,4(3):479-482.
55 Chen S H,Kant J,Mamber S W,et al.Taxol?;structure-activity relationships:synthesis and biological evaluation of taxol analogs modified at C-7.Bioorg Med Chem Lett,1994,4(18):2223-2228.
56 Greenwald R B,Pendri A,Bolikal D.Highly Water Soluble Taxol Derivatives:7-Polyethylene Glycol Carbamates and Carbonates.J Org Chem,1995,60(2):331-336.
57 Marder-Karsenti R,Dubois J,Bricard L,et al.Synthesis and Biological Evaluation of D-Ring-Modified Taxanes:15(20)-Azadocetaxel Analogs.Cheminform,1998,29(62).
58 Rapha?le M K,Jo?lle D,Laurent B,et al.Synthesis and Biological Evaluation of D-Ring-Modified Taxanes:5(20)-Azadocetaxel Analogs.J Org Chem,1997,62(19):6631-6637.
59 Dubois J,Guénard D,Guéritte-Voegelein F,et al.Conformation of Taxotere?,and analogues determined by NMR spectroscopy and molecular modeling studies.Tetrahedron,1993,49(30):6533-6544.
60 Ojima I,Inoue T,Chakravarty S.Chem Inform Abstract:Enantiopure Fluorine-Containing Taxoids:Potent Anticancer Agents and Versatile Probes for Biomedical Problems.Cheminform,1999,30(42):3-10.
61 Nicolaou K C,Dai W M,Guy M R K.Chemistry and Biology of Taxol.Angew Chem Int Edit,1994,33(106):15-44.
62 高锦明,傅建熙,张鞍灵.抗癌新药紫杉醇的构效关系.西北农林科技大学学报自然科学版,1997,25(5):96-99.
基于中药有效单体成分的新药研究系列讨论-Ⅵ。
世界卫生组织官方网站:http://www.who.int/mediacentre/factsheets/fs297/zh/。
2 Tachibana Y,Zhu X K,Krishnan P,et al.Characterization of human lung cancer cells resistant to 4′-O-demethyl-4β-(2″-nitro-4″-fluoroanilino)-4-desoxypodophyllotoxin,a unique compound in the epipodophyllotoxin antitumor class.Anticancer Drugs,2000,11(1):19-28.
3 邓立新.抗癌新药紫杉醇简介.化学教学,2006,1:46-48.
4 周波,姜虎生.红豆杉及其产物紫杉醇研究概况.吉林师范大学学报(自然科学版),2001,1:78-81.
5 Wani M C,Taylor H L,Wall M E,et al.Plant antitumor agents.VI.The isolation and structure of taxol,a novel antileukemic and antitumor agent from Taxusbrevifolia.J Am Chem Soc,1971,93(9):2325-2327.
6 Schiff P B,Fant J,Horwitz S B.Promotion of microtubule assembly in vitro by taxol.Nature,1979,277(5698):665-667.
7 Horwitz S B.Personal Recollections on the Early Development of Taxol.J Nat Prod,2004,67(2):136-138.
8 王莺.紫杉醇类抗癌药物的临床应用概述.海峡药学,2007,19(8):97-99.
9 Pronk L C,Stoter G,Verweij J.Docetaxel(Taxotere):single agent activity,development of combination treatment and reducing sideeffects.Cancer Treat Rev,1995,21(5):463-478.
10 张学玉,曲玮,梁敬钰.红豆杉属植物化学成分及药理作用研究进展.海峡药学,2011,23(6):5-9.
11 李春元,李梓.抗癌药紫杉烷类临床应用现况.世界临床药物,2001,22(3):140-141.
12 谢宝芬,潘柏良.紫杉醇的药理与临床研究进展.中国药业,2008,17(15):76-78.
13 Sunters A,Madureira P A,Pomeranz K M,et al.Paclitaxel-induced nuclear translocation of FOXO3a in breast cancer cells is mediated by c-Jun NH2-terminal kinase and Akt.Cancer Res,2006,66(1):212-220.
14 张桂芝,方向群.紫杉醇参与逆转肺部肿瘤细胞免疫逃逸的机制研究.中国药业,2015,24(22):41-43.
15 徐律韵.紫杉醇对人肝癌细胞SMMC-7721黏附及侵袭转移潜能的影响.现代医药卫生,2014,30(5):655-657.
16 Meden H,Rath W,Kuhn W.Taxol-a new cytostatic drug for therapy of ovarian and breast cancer.Geburtshilfe Frauenheilk,1994,54(4):187-193.
17 宋沁馨,于立洁.多西他赛的临床应用进展.中国新药杂志,2001,10(12):900-903.
18 Tang P,Wang F.Recent Progresses in the Synthesis of Taxol.Chinese J Org Chem,2013,33(3):458.
19 冯双双,钞艳惠,何海冰,等.拉洛他赛共聚物脂质杂合纳米粒的制备及其性能评价.沈阳药科大学学报,2017,34(1):14-22.
20 Dong Y,Wang S,Wang C,et al.Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis.J Med Chem,2017,60(3):1219-1224.
21 陆红霞.紫杉醇剂型、临床用药方式及联合用药的研究进展.国外医学药学分册,2005,32(2):73-77.
22 Von Hoff DD,Ervin T,Arena F P,et al.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med,2013,369(18):1691-1703.
22 肖秀兰,任统伟.奈达铂联合紫杉醇同期放化疗治疗局部晚期鼻咽癌分析.中国医学工程,2012,20(10):52-53.
24 卢晨欣,孙警辉,伍春莲.白藜芦醇与紫杉醇联合用药对人喉癌Hep-2细胞凋亡机制的研究.中国中药杂志,2016,41(3):476-483.
25 Manju S,Sharma C P,Sreenivasan K.Targeted coadministration of sparingly soluble paclitaxel and curcumin into cancer cells by surface engineered magnetic nanoparticles.J Mater Chem,2011,21(39):15708.
26 蒲新霖.紫杉醇和姜黄素在肿瘤治疗中的联合应用.西南军医,2017,19(2):161-164.
27 杨孝来.紫杉醇与多烯紫杉醇.实用药物与临床,2010,13(4):281-283.
28 徐佳茗,夏学军,刘玉玲.紫杉醇新型制剂及临床研究进展.实用药物与临床,2016,19(4):510-517.
29 王懿娜,方红,张幸国,等.紫杉醇溶液外用治疗豚鼠耳部银屑病样病理改变的疗效观察.中华皮肤科杂志,2004,37(3):156-158.
30 冯健,童德兵,羊镇宇,等.紫杉醇预防心肌细胞线粒体缺血再灌注损伤的机制研究.中华全科医学,2014,12(11):1724-1726.
31 齐素华,巩娟娟,倪小宇.紫杉醇通过MLK_3/JNK_3信号通路对海马神经元损伤的保护作用.苏州大学学报:医学版,2012,32(1):1-5.
32 李弟贵,任莉.一种从人工种植南方红豆杉中全株提取紫杉醇的方法,中国:CN 1958580 A,2007-05-09.
33 唐培,王锋鹏.近年来紫杉醇的合成研究进展.有机化学,2013,33(3):458-468.
34 韩广甸,丁炬平,谢蓝.紫杉醇的合成进展.有机化学,1993,13(4):337-346.
35 Nicolaou K C,Yang Z,Liu J J,et al.Total synthesis of taxol.Nature,1994,367(6464):630-634.
36 Holton R A,Somoza C,Kim H B,et al.Chem Inform Abstract:First Total Synthesis of Taxol.Part 1.Functionalization of the B Ring.J Am Chem Soc,1994,116(4):1597-1598.
37 Holton R A,Kim H B,Somoza C,et al.Chem Inform Abstract:First Total Synthesis of Taxol.Part 2.Completion of the C and D Rings.Cheminform,1994,25(26):1599-1600.
38 Walsh C.Molecular mechanisms that confer antibacterial drug resistance.Nature,2000,406(6797):775-781.
39 陆怡,陈大明,熊燕.抗肿瘤药物的研发态势分析.生命科学,2012,24(6):535-542.
40 Osheroff N,Corbett A H,Robinson M J.Mechanism of Action of Topoisomerase II-Targeted Antineoplastic Drugs.Adv Pharmacol Academic Press,1994,9B:105-126.
41 Doi T,Fuse S,Miyamoto S,et al.A Formal Total Synthesis of Taxol Aided by an Automated Synthesizer.Chem Asian J,2006,1(3):370-383.
42 Yang W,Sun J,Lu W,et al.Synthesis of kaempferol 3-O-(3″,6″-di-OE-p-coumaroyl)-β-D-glucopyranoside,efficient glycosylation of flavonol 3-OH with glycosyl O-alkynylbenzoates as donors.J Org Chem,2010,75(20):6879-6888.
43 Denis J N,Greene A E,Guenard D,et al.Highly efficient,practical approach to natural taxol.J Am Chem Soc,1988,110(17):5917-5919.
44 王九一,阎家麒.紫杉醇的半合成.中国药物化学杂志,1999,6(24):56-58.
45 Mangatal L,Adeline M T,Guenard D,et al.Application of the vicinal oxyamination reaction with asymmetric induction to the hemisynthesis of taxol and analogues.Tetrahedron,1989,45(13):4177-4190.
46 Rao K V.Semi-synthesis of paclitaxel from naturally occurring glycosidic precursors.J Heterocyclic Chem,2010,34(2):675-680.
47 王雪松,孙剑秋,臧威,等.从Strobel的发现看植物内生真菌研究的未来.生物学通报,2012,47(10):1-3.
48 段丽丽,陈鸿锐,陈杰鹏,等.选育紫杉醇高产菌种链格孢单孢变种.中国抗生素杂志,2008,33(11):650-652.
49 Soliman S S,Trobacher C P,Rong T,et al.A fungal endophyte induces transcription of genes encoding a redundant fungicide pathway in its host plant.Bmc Plant Biology,2013,13(1):93.
50 邱德有.紫杉醇生物合成研究历史、现状及展望.生物技术通报,2015,31(4):56-64.
51 Hampel D,Mau C J,Croteau R B.Taxol biosynthesis:Identification and characterization of two acetyl Co A:taxoid-O-acetyltransferases that divert pathway flux away from Taxol production.Arch Biochem Biophys,2009,487(2):91-97.
52 Chen S,Song J,Sun C,et al.Herbal genomics:Examining the biology of traditional medicines.Science,2015,347(6219):S27-S29.
53 Zefirova O N,Nurieva E V,Ryzhov A N,et al.Taxol:Synthesis,Bioactive Conformations,and Structure-Activity Relationships in Its Analogues.Russ J Org Chem,2005,41(3):315-351.
54 Chen S H,Farina V,Wei J M,et al.Chem Inform Abstract:StructureActivity Relationships of Taxol?:Synthesis and Biological Evaluation of C2 Taxol Analogues.Bioorg Med Chem Lett,1994,4(3):479-482.
55 Chen S H,Kant J,Mamber S W,et al.Taxol?;structure-activity relationships:synthesis and biological evaluation of taxol analogs modified at C-7.Bioorg Med Chem Lett,1994,4(18):2223-2228.
56 Greenwald R B,Pendri A,Bolikal D.Highly Water Soluble Taxol Derivatives:7-Polyethylene Glycol Carbamates and Carbonates.J Org Chem,1995,60(2):331-336.
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世界卫生组织官方网站:http://www.who.int/mediacentre/factsheets/fs297/zh/。