齐墩果酸衍生物的合成与表征及其抑菌活性的研究
|
摘要
齐墩果酸(Oleanolic Acid, OA)是一种齐墩果烷型五环三萜类化合物,是多种天然产物的主要功能成分,在自然界中分布广泛,如在青叶胆全草、白花蛇舌草、女贞果实等植物中以游离形式存在或与糖结合成苷存在。显示出多种生物活性：如抗炎、抗肿瘤、降血糖、抗高血脂等药理作用。OA是治疗急性黄胆型肝炎和慢性病毒性肝炎比较理想的药物,且毒性低,不良反应少。由于其药理活性较多,副作用和细胞毒性相对较低,近年来国内外对齐墩果酸的提取、含量测定和药理活性等方面做了大量的研究工作。部分研究小组也对其衍生物的抗肿瘤和抗艾滋病活性进行了研究,但对其衍生物的抗菌活性研究较少。
为了更加深入的研究齐墩果酸及其衍生物的生物活性与结构的关系,本文以具有多种生物活性的天然化合物齐墩果酸为先导化合物,以有机化学理论和药物合成原理为指导,以有机合成技术为手段,结合生物活性测试,对其结构进行了修饰和改造,并开发了乙醇酸、丁二酸酐和丁二醇等连接片段,并进行了抑菌活性测试,以期得到高效低毒的齐墩果酸衍生物。
本论文的研究主要分为三部分：
第一部分：对齐墩果酸的药理作用进行了阐述,介绍了齐墩果酸的研究进展、临床应用及发展前景。
第二部分：齐墩果酸衍生物的合成与表征及连接片段的使用。通过探索合成、分离和纯化的条件,设计并合成了35种齐墩果酸衍生物。采用IR、1HNMR等技术对所合成的化合物进行了结构表征,其中有32种化合物未见文献报道。
第三部分：对先导化合物齐墩果酸和所合成的衍生物进行了抑菌活性测试。
Oleanolic acid is an oleanane-type compound of pentacyclic triterpenoids, and it is the main functional components of various natural products. Oleanolic acid distributes in nature widely, such as swertia mileenis, oldenlandia diffusa, fruit of glossy privet and other plants, with free form existence or with sugar to combine into the glucoside exist. It shows a variety of biological activities such as anti-inflammatory, antitumor, hypoglycemic, anti-high blood cholesterol, and many other kinds of pharmacological effects. Oleanolic acid is a perfect drug to treat acute icterohepatitis and chronic viral hepatitis, and it is in the nature of low toxicity and fewer side effects. Due to its superior pharmacological activities, fewer side effects and lower toxicity, a lot of research work about the extraction, content determination and pharmacological activity of oleanolic acid has been done at home and abroad in recent years. Some of the research teams have studied the derivatives of oieanolic acid on anti-tumor and anti-AIDS activity, but researches on antibacterial activity are very little.
In order to study the structure activity relationship of oleanolic acid and its derivatives in depth, this dissertation use oleanolic acid as a lead compound and combine the achievements of biological activity test to modified its structure based on the theories of organic chemistry and pharmaceutical synthesis and the methods of organic synthesis technology. Some derivatives of oleanolic acid were synthesized, and their antibacterial activities were tested in order to obtain high efficiency and low toxicity derivatives of oleanolic acid.
Three parts are included in this dissertation.
The first part described the pharmacological effects of oleanolic acid and introduced the progress, clinical application and development prospects of oleanolic acid.
The second part synthesized and characterized the derivatives of oleanolic acid. By exploring the synthesis, separation and purification conditions,35 kinds of oleanolic acid derivatives were designed and synthesized.32 kinds of the compounds have not been reported. All the structures were characterized by the methods of IR and 1HNMR.
The third part tested the antibacterial activity of the oleanolic acid and its derivatives.
为了更加深入的研究齐墩果酸及其衍生物的生物活性与结构的关系,本文以具有多种生物活性的天然化合物齐墩果酸为先导化合物,以有机化学理论和药物合成原理为指导,以有机合成技术为手段,结合生物活性测试,对其结构进行了修饰和改造,并开发了乙醇酸、丁二酸酐和丁二醇等连接片段,并进行了抑菌活性测试,以期得到高效低毒的齐墩果酸衍生物。
本论文的研究主要分为三部分：
第一部分：对齐墩果酸的药理作用进行了阐述,介绍了齐墩果酸的研究进展、临床应用及发展前景。
第二部分：齐墩果酸衍生物的合成与表征及连接片段的使用。通过探索合成、分离和纯化的条件,设计并合成了35种齐墩果酸衍生物。采用IR、1HNMR等技术对所合成的化合物进行了结构表征,其中有32种化合物未见文献报道。
第三部分：对先导化合物齐墩果酸和所合成的衍生物进行了抑菌活性测试。
Oleanolic acid is an oleanane-type compound of pentacyclic triterpenoids, and it is the main functional components of various natural products. Oleanolic acid distributes in nature widely, such as swertia mileenis, oldenlandia diffusa, fruit of glossy privet and other plants, with free form existence or with sugar to combine into the glucoside exist. It shows a variety of biological activities such as anti-inflammatory, antitumor, hypoglycemic, anti-high blood cholesterol, and many other kinds of pharmacological effects. Oleanolic acid is a perfect drug to treat acute icterohepatitis and chronic viral hepatitis, and it is in the nature of low toxicity and fewer side effects. Due to its superior pharmacological activities, fewer side effects and lower toxicity, a lot of research work about the extraction, content determination and pharmacological activity of oleanolic acid has been done at home and abroad in recent years. Some of the research teams have studied the derivatives of oieanolic acid on anti-tumor and anti-AIDS activity, but researches on antibacterial activity are very little.
In order to study the structure activity relationship of oleanolic acid and its derivatives in depth, this dissertation use oleanolic acid as a lead compound and combine the achievements of biological activity test to modified its structure based on the theories of organic chemistry and pharmaceutical synthesis and the methods of organic synthesis technology. Some derivatives of oleanolic acid were synthesized, and their antibacterial activities were tested in order to obtain high efficiency and low toxicity derivatives of oleanolic acid.
Three parts are included in this dissertation.
The first part described the pharmacological effects of oleanolic acid and introduced the progress, clinical application and development prospects of oleanolic acid.
The second part synthesized and characterized the derivatives of oleanolic acid. By exploring the synthesis, separation and purification conditions,35 kinds of oleanolic acid derivatives were designed and synthesized.32 kinds of the compounds have not been reported. All the structures were characterized by the methods of IR and 1HNMR.
The third part tested the antibacterial activity of the oleanolic acid and its derivatives.
引文
[1]Sander C C, Sander W E. β-lactam resistance in Gram-negative bacteria:Global trends and clinical impact.Clin infect Dis,1992,15(6):824-839.
[2]Jacoby C A, Archer G L. New mechanisms of bacterial resistance to antimicrobial agents. Med,1991,324(9):601-612.
[3]Jones R N, Pfaloller M A. Bacterial resistance:A worldwide problem. Diagn Microbiol Infect Dis,1998,31(2):379-388.
[4]Mederios A A. Evolution and dissemination of β-lactamases accelerated by Generations of β-lactam antibiotics. Clin Infect Dis,1997,24(suppl 1): s19-s45.
[5]Kumarasamy K K, Toleman M A, Walsh T R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK:a molecular, biological, and epidemiological study. Lancet Infect Dis,2010,10(9):597-602.
[6]何浙生.“超级细菌”的过去、现在和未来.国际流行病学传染病学杂志,2010,37(5)：289-290.
[7]Yong D, Toleman M A, Giske C G, et al. Characterization of a new metallo-beta-lactamase gene, bal(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Anti-microb Agents Chemother,2009,53(12):5046-5054.
[8]Queenan A M, Bush K. Carbapenemases:the versatile beta-lactamases. Clin Microbiol Rev,2007,20(3):440-458.
[9]方峰.超级细菌——离中国大陆还有多远.中国循证儿科杂志,2010,5(5)：321-322.
[10]Muir A, Weinbren M J. New Delhi metallo-beta-lactamase:a cautionary tale. J Hosp Infect,2010,75:239-240.
[11]杨瑞馥.携带新德里金属-β-内酰胺酶耐药基因的“超级细菌”可怕吗.中华预防医学杂志,2010,44(10)：874-875.
[12]石心红,郭江宁,翟静华.HPLC法测定女贞子中齐墩果酸、熊果酸的含量.海峡药学,2005,17(4)：41-43.
[13]Maryadele J.0'Neil. The merck index 13th edition. Merck and Co., Inc.2001, 6897.
[14]田丽婷,马龙,堵年生.齐墩果酸的药理作用研究概况.中国中药杂志2002,27(12)：884-886.
[15]Liu J. Pharmacology of Oleanolic Acid and Ursolic Acid. J Ethnopharmacol.1995, 49(2):57-68.
[16]Li Y, Matsuda H, Yoshikawa M, et al. Effects of oleanolic acid glycosides on gastrointestinal transit and ileus in mice. Bioorg Med Chem.1999,7: 1201-1205.
[17]李杰,许良中,朱伟萍等.熊果酸与齐墩果酸体外抗jurkat淋巴瘤细胞的研究.中国癌症杂志,1999,9(5-6)：395-397.
[18]黄敏珊,黄炜,吴其年等.齐墩果酸诱导人乳腺癌细胞凋亡及与细胞内Ca2+水平关系的研究.中国现代医学杂志,2004,14：58-63.
[19]Ovesna Z, Kozics K, Slamenova D. Protective effects of ursolic acid and oleanolic acid in leukemic cells. Mutation Res,2006,600(1-2):131-137.
[20]张东方,黄济群,黄炜等.齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究.肿瘤防治研究,2003,30(3)：180-183.
[21]Marquina S, Maldonado N, Garduno-Ramirez M L. Bioactive oleanolic acid saponins and other constituents from the roots of Viguiera decurrens. Phytochemistry, 2001,56:93-97.
[22]Yoshikawa M, Matsuda H. Antidiabetogenic activity of oleanolic acid glycosides from medicinal foodstuffs. Biofactors,2000,13(1-4):231-237.
[23]殷峻,陈名道,胡仁明等,小檗碱、齐墩果酸和大蒜新素对糖代作用的体外研究.北京中医药大学学报,2003,26(2)：36-38.
[24]王兵,将朝晖.齐墩果酸的研究.中国药学杂志,1992,27(7)：393-397.
[25]Jeong H G. Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury. Toxicology Letters,1999,105(3):215-222.
[26]Chen Y J, Liu J, Yang X L, et al. Oleanolic acid nanosuspensions:preparation, in-vitro characterization and enhancedhepatoprotective effect. J Pharm Pharmacol,2005,57(2):259-264.
[27]Kim K A, Lee J S, Park H J, et al. Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sci,2004, 74(22):2769-2779.
[28]Kashiwada Y; Wang H K. Anti-AIDS agents.30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids. J Nat Prod,1998,61 (9): 1090-1095.
[29]Ma C M, Nakamura N, Hattori M, et al. Inhibitory effects on HIV-1 protease of constituents from the wood of xanthoceras sorbifolia. J Nat Prod,2000,63(2): 238-242.
[30]王立新,韩广轩,刘文庸等.齐墩果酸的化学及药理研究.药学实践杂志,2001,19(2)：104-107.
[31]宁兰.中药中齐墩果酸的提取工艺研究进展.内蒙古中医药,2000,(19)：109-110.
[32]王锐.碱溶盐析法从女贞子中提取齐墩果酸.企业导报,2010,6：295-296.
[33]唐春红,项昭保,石铁松等.木瓜中齐墩果酸的提取工艺研究.食品工业科技,2000,21(4)：10-12.
[34]刘汉兰,唐静,王志芳等.木瓜皮中齐墩果酸的提取及含量测定.食品科学,2005,26(9)：365-367.
[35]曹艳丽,张秋香.薄层扫描法测定女贞子中齐墩果酸的含量.陕西中医,2002,23(8)：745-746.
[36]闫花丽,赵陆华,朱丹妮等.衍生化气相色谱法测定夏枯苹齐墩果酸和熊果酸的含量.中国中药杂志,1999,24(12)：744-745.
[37]刘垣升,周静.气相色谱法测定女贞子中齐墩果酸和熊果酸的含量.中国新药与临床杂志,2003,22(10)：596-598.
[38]黄秋妹,李宗.HPLC法测定山楂中熊果酸和齐墩果酸的含量.海峡药学,2007,19(3)：43-45.
[39]曹艳萍,薛成虎,杨秀利.红枣中齐墩果酸提取工艺的研究.食品科技,2007,28(10)：165-167.
[40]石敏娟,刘耀明,朱卫丰.苦丁荼中的熊果酸和齐墩果酸的含量测定.中医药学报,2007,35(2)：45-46.
[41]Liu HX, Shi YH, Wang DX, et al. MECC determination of oleanolic acid and ursolic acid isomers in Ligustrum lucidum Ait.Journal of Pharmaceutical and Biomedical Analysis,2003,32(3),479-485.
[42]张东方,黄济群,黄炜等.齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究.肿瘤防治研究,2003,30(3)：180-183.
[43]Huang D, Ding Y, Li Y, etal.Anti-tumor activity of a 3-oxo derivative of oleanolic acid. Cancer Letters,2006,233(2):289-296.
[44]Li J, Guo W J, Yang Q Y. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J Gastroenterol,2002,8(3):493-495.
[45]黄炜,黄济群,张东方等.五环三萜类化合物抗人肺癌细胞侵袭和诱导细胞凋亡的研究.中国肺癌杂志,2003,6(4)：254-257.
[46]Resende F A. Claudete Aparecida Mattos de Andrade Bareala, Marcia Cristina da Silva Faria, et al. Antimutagenicity of ursolic acid and oleanolic acid against doxorubicin-induced clastogenesis in Balb/c mice. Life Sciences,2006,79 (13): 1268-1273.
[47]Ovesna Z, Vachalkova A, Horvathova K, et al. Pentacyclic triterpenoic acids: new chemo-protective compounds. Minireview Neoplasma,2004,51(5):327-333.
[48]冀春萱,纪红,韩德伍等.齐墩果酸对急性实验性肝损伤的防治作用.山西医药杂志,1980,9(6)：5-7.
[49]孟艳秋,赵临襄,于趱等.五环三萜类化合物的构效关系.中国新药杂志,2004,13(12)：1098-1102.
[50]韩德伟.齐墩果酸防治实验性肝硬变发生的研究.中医杂志,1981,22(3)：217.
[51]Honjo I, Suou T, Hirayama C.Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol,1988,61: 149-165.
[52]宫新江,丁虹,邱银生等.OA抗环磷酰胺所致大鼠肝细胞损伤作用.医药导报,2006,25(11)：1114-1116.
[53]田丽婷,堵年生,马龙.齐墩果酸的药理作用研究概况.中国中药杂志,2002,27(12)：884-886.
[54]殷峻,陈名道,胡仁明等.小檗碱、齐墩果酸和大蒜新素对糖代谢作用的体外研究.北京中医药大学学报,2003,26(2)：36-38.
[55]Yoshikawa M, Matsuda H. Antidiabetogenic activity of oleanolic acid glycosides from medicinal foodstuffs. Biofactor,2000,13(1-4):231-237.
[56]Ortiz-Andrade R R, Garcia-jimenez S, Castillo-Espana P, et al. a -Glucosidase inhibitory activity of the methanolic extract from Tournefortia hartwegiana: An anti-hyperglycemic agent. Journal of Ethnopharacology,2007,109(1): 48-53.
[57]黄婉,杨耀芳.女贞子及其有效成分的药理及临床研究进展.现代中西医结合杂志,2003,12(7)：772-774.
[58]Cai L, Wu C D. Compounds from Syzygira Aromaticum Possessing Growth Inhibitory Activity Against Oral Pathogens. Jnat Prod,1996,59(10):987-990.
[59]Steele J C, Warhurst D C, Kirby G C, et al. In Vitro and in Vivo Evaluation of Betulinic Acid as An Antimalarial. Phytother Res,1999,13(2):115-119.
[60]Kozai K, Suzuki J, Okada M, et al. Effect of Oleanolic Acid-cyclodextrin Inclusion Compounds on Dental Caries by in Vitro Experiment and rat-caries Model. Microbios,1999,97(388):179-188.
[61]吴虹,魏伟,吴成义.木瓜化学成分及药理活性的研究.安徽中医学院学报,2004, 23(2)：62-64.
[62]Zheng C J, Sohn M J, Kim K Y, et al. Olean-27-carboxylic acid-type triterpenes with Potent antibacterial activity from aceriphyllum rossii. Agric Food Chem, 2008,56(24):11752-11756.
[63]田奇伟,唐绍海,郭成立等.木瓜的抗菌作用.微生物学通报,1982,(16)：271-272.
[64]郭成立,田昌本,唐绍海等.木瓜治疗急性细菌性痢疾107例临床观察.中华医学杂志,1984,64(11)：689-690.
[65]赵驻,蓝茹.从齐墩果酸结构分析抗肝细胞损伤的作用机制.中草药,1998,29(12)：844-844.
[66]Kashiwad Y, Wang H K, Nagao T. et al.Anti-AIDS agents 30. Anti-HIV activity of oleanolic acid, pomolic aci.1 and structrurally related triterpenoides. J Nat Prod,1998,61 (9):1090-1095.
[67]Ma C, Nakamura N, Miyashiro H, et al. Inhibitory effects of constituents from cynomorium songarium and related triterpene derivatives on HIV-I protease. Chem Pharm Bull (Tokyo),1999,47(2):141-145.
[68]孙燕,袁瑞荣,吴西居等.齐墩果酸的促免疫作用.中国临床病理学杂志,1988,4(1)：26-31.
[69]王德仁.齐墩果酸研究新进展.天津药学,2003,15(3)：56-58.
[70]任骏.齐墩果酸对前列腺素及环核苷酸的影响.中国药理学通报,1991,7(3)：179-181.
[71]丁安伟,盂丽.女贞子多糖的免疫调节作用研究.中药药理与临床,2001,17(2)：11-12.
[72]Somova L I, Shode F 0, Ramnanan P, et al. Cardiotonic and anti-dysrhythrnic effects of oleanolic and ursolic acids, methylmaslinate and uvaol. Phytomedicine,2004,11(2-3):121-129.
[73]Astudillo L, Rodriguez J A, Schmeda-Hirschmann G. Gastroprotective activity of oleanolic acid derivatives on experimentally induced gastric lesions in rats and mice. J Pharm Pharmacol,2002,54(4):583-588.
[74]薄显辉,杨景仁,刘君富等.薄层扫描法测定祛风止痛片中齐墩果酸含量.哈尔滨医科大学学报,1998.32(6)：462-462.
[75]中国药典2005年版[S].2005.
[76]江苏新医学院.中药大辞典[M].上册.上海：上海人民出版社,1977：189.
[77]田原,李晓,刘艳玲等.RP-HPLC法测定肝喜乐胶囊中齐墩果酸的含量.辽宁中医杂志,2007,34(3)：345-345.
[78]王强,王跃飞,潘桂湘等.RP-HPLC法测定舒肝保健茶中齐墩果酸的含量.广东药学院学报,2007,23(5)：516-517.
[79]廖利江,曾英彤,梁海勇.RP-HPLC法测定滋阴舒肝颗粒中齐墩果酸的含量.中国药房,2008,19(24)：1896-1897.
[80]国家药典委员会编.中华人民共和国药典(一部)[S].2005年版.北京：化学工业出版社,2005：附录ⅥB.
[81]赵陆华,丁黎,陈玉荚等.克疣淋溶液中四种酸性成分的气相色谱测定法.中国药科大学学报,1998,29(6)：453-455.
[82]Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol,1995, 49(2):57-68.
[83]Jeong H J, Chai H B, Park S Y, et al. Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Bioorg Med Chem Lett,1999, 9(8):1201-1204.
[84]齐藤节生.具有烷基侧链的甘草次酸甙元的合成与抗HIV活性.国外医学中医中药分册,1995,(4)：40-40.
[85]Shim S B, Kim D H. Beta-glucuronidase inhibitory activity and hepatoprotective effect of glycyrrhiza uralensis. Planta Medica:Natural Products and Medicinal Plant Research,2000,66(1):40-43.
[86]Cinatl J, Morgenstem B, Bauer G, et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. The Lancet, 2003,361(9374):2045-2046.
[87]包金凤.甘草次酸药理作用研究进展.兰州医学院学报,1994,20(1)：50-52.
[88]张宝恒.甘草药理作用研究的进展.药学学报,1963,10(11)：688-700.
[89]Honda T, Rounds B V, Gribble G W, et al. Design and synthesis of 2-eyano-3, 12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett,1998,8(19): 2711-2714.
[90]Snh N, Wang Y, Honda T, et al. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolcana-1,9-dien-28-oic acid, with potent differentiating, anti-proliferative, and anti-inflammatory activity. Cancer Pea,1999,59(2): 336-341.
[91]Haregewei A, Alison N, Larry W, el al. Synthesis and evaluation of potential complement inhibitory semisynthetic analogs of oleanolic acid. Bioorganic & Medicinal Chemistry Letters,1999,9:1889-1894.
[92]Zhu Y M, Shen J K, Wang H K, el al. Synthesis and anti-HIV activity of oleanolic acid derivatives.Bioorganic & Medicinal Chemistry Letters,2001,11: 3115-3118.
[93]Ma C M, Nakamura N, Miyashiro H, et al. Inhibitory effect of constituents from cynomorium songaricum and related triterpene derivatives on HIV-1 protease. Chem Pharm Bull,1999,47(2):141-145.
[94]Ma C M, Nakamura N, Hattor M. Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization. Chem Pharm Bull,2000,48(1):1681-1688.
[95]Evers M, Poujade C, Soler F, et al.Betunilic acid derivatives:a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. J Med Chem,1996,39(5):1056-1068.
[96]Takiura K, Honda S, Yamamoto M, et al. Studies of oligosaccharides. XII. Hydrophilization of glycyrrhetinic acid by coupling to gentio oligosaccharides. Chemical and Pharmaceutical Bulletin,1974,22(7): 1618-1623.
[97]孙华,胡春,方唯硕.3-氧代齐墩果酸氨基酸偶联物的合成、水溶性的测定及抗肿瘤活性研究.中国药物化学杂志,2008,18(1)：11-15.
[98]赵德千.齐墩果酸和甘草次酸衍生物的合成与表征及其抗菌和抗癌活性的研究：(硕士学位论文).大连：辽宁师范大学,2010.
[99]李建新,李俊峰.齐墩果酸衍生物及其制备方法和应用.中国专利,CN 101298466A.2008.
[100]李建新.齐墩果酸及其衍生物、制备及用途.中国专利,CN 1724556A.2006.
[101]张奕华,陈莉,田季德等.齐墩果酸偶联衍生物及其药物用途.中国专利.CN1594354A.2005.
[102]Zhao L X, Moon Y S, Basnet A, et al. Design, synthesis and anticonvulsive activities of potential prodrugs linked by two-carbon chan. Arch Pharm Res, 2003,26(10):785-795.
[2]Jacoby C A, Archer G L. New mechanisms of bacterial resistance to antimicrobial agents. Med,1991,324(9):601-612.
[3]Jones R N, Pfaloller M A. Bacterial resistance:A worldwide problem. Diagn Microbiol Infect Dis,1998,31(2):379-388.
[4]Mederios A A. Evolution and dissemination of β-lactamases accelerated by Generations of β-lactam antibiotics. Clin Infect Dis,1997,24(suppl 1): s19-s45.
[5]Kumarasamy K K, Toleman M A, Walsh T R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK:a molecular, biological, and epidemiological study. Lancet Infect Dis,2010,10(9):597-602.
[6]何浙生.“超级细菌”的过去、现在和未来.国际流行病学传染病学杂志,2010,37(5)：289-290.
[7]Yong D, Toleman M A, Giske C G, et al. Characterization of a new metallo-beta-lactamase gene, bal(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Anti-microb Agents Chemother,2009,53(12):5046-5054.
[8]Queenan A M, Bush K. Carbapenemases:the versatile beta-lactamases. Clin Microbiol Rev,2007,20(3):440-458.
[9]方峰.超级细菌——离中国大陆还有多远.中国循证儿科杂志,2010,5(5)：321-322.
[10]Muir A, Weinbren M J. New Delhi metallo-beta-lactamase:a cautionary tale. J Hosp Infect,2010,75:239-240.
[11]杨瑞馥.携带新德里金属-β-内酰胺酶耐药基因的“超级细菌”可怕吗.中华预防医学杂志,2010,44(10)：874-875.
[12]石心红,郭江宁,翟静华.HPLC法测定女贞子中齐墩果酸、熊果酸的含量.海峡药学,2005,17(4)：41-43.
[13]Maryadele J.0'Neil. The merck index 13th edition. Merck and Co., Inc.2001, 6897.
[14]田丽婷,马龙,堵年生.齐墩果酸的药理作用研究概况.中国中药杂志2002,27(12)：884-886.
[15]Liu J. Pharmacology of Oleanolic Acid and Ursolic Acid. J Ethnopharmacol.1995, 49(2):57-68.
[16]Li Y, Matsuda H, Yoshikawa M, et al. Effects of oleanolic acid glycosides on gastrointestinal transit and ileus in mice. Bioorg Med Chem.1999,7: 1201-1205.
[17]李杰,许良中,朱伟萍等.熊果酸与齐墩果酸体外抗jurkat淋巴瘤细胞的研究.中国癌症杂志,1999,9(5-6)：395-397.
[18]黄敏珊,黄炜,吴其年等.齐墩果酸诱导人乳腺癌细胞凋亡及与细胞内Ca2+水平关系的研究.中国现代医学杂志,2004,14：58-63.
[19]Ovesna Z, Kozics K, Slamenova D. Protective effects of ursolic acid and oleanolic acid in leukemic cells. Mutation Res,2006,600(1-2):131-137.
[20]张东方,黄济群,黄炜等.齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究.肿瘤防治研究,2003,30(3)：180-183.
[21]Marquina S, Maldonado N, Garduno-Ramirez M L. Bioactive oleanolic acid saponins and other constituents from the roots of Viguiera decurrens. Phytochemistry, 2001,56:93-97.
[22]Yoshikawa M, Matsuda H. Antidiabetogenic activity of oleanolic acid glycosides from medicinal foodstuffs. Biofactors,2000,13(1-4):231-237.
[23]殷峻,陈名道,胡仁明等,小檗碱、齐墩果酸和大蒜新素对糖代作用的体外研究.北京中医药大学学报,2003,26(2)：36-38.
[24]王兵,将朝晖.齐墩果酸的研究.中国药学杂志,1992,27(7)：393-397.
[25]Jeong H G. Inhibition of cytochrome P450 2E1 expression by oleanolic acid: hepatoprotective effects against carbon tetrachloride-induced hepatic injury. Toxicology Letters,1999,105(3):215-222.
[26]Chen Y J, Liu J, Yang X L, et al. Oleanolic acid nanosuspensions:preparation, in-vitro characterization and enhancedhepatoprotective effect. J Pharm Pharmacol,2005,57(2):259-264.
[27]Kim K A, Lee J S, Park H J, et al. Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomes. Life Sci,2004, 74(22):2769-2779.
[28]Kashiwada Y; Wang H K. Anti-AIDS agents.30. Anti-HIV activity of oleanolic acid, pomolic acid, and structurally related triterpenoids. J Nat Prod,1998,61 (9): 1090-1095.
[29]Ma C M, Nakamura N, Hattori M, et al. Inhibitory effects on HIV-1 protease of constituents from the wood of xanthoceras sorbifolia. J Nat Prod,2000,63(2): 238-242.
[30]王立新,韩广轩,刘文庸等.齐墩果酸的化学及药理研究.药学实践杂志,2001,19(2)：104-107.
[31]宁兰.中药中齐墩果酸的提取工艺研究进展.内蒙古中医药,2000,(19)：109-110.
[32]王锐.碱溶盐析法从女贞子中提取齐墩果酸.企业导报,2010,6：295-296.
[33]唐春红,项昭保,石铁松等.木瓜中齐墩果酸的提取工艺研究.食品工业科技,2000,21(4)：10-12.
[34]刘汉兰,唐静,王志芳等.木瓜皮中齐墩果酸的提取及含量测定.食品科学,2005,26(9)：365-367.
[35]曹艳丽,张秋香.薄层扫描法测定女贞子中齐墩果酸的含量.陕西中医,2002,23(8)：745-746.
[36]闫花丽,赵陆华,朱丹妮等.衍生化气相色谱法测定夏枯苹齐墩果酸和熊果酸的含量.中国中药杂志,1999,24(12)：744-745.
[37]刘垣升,周静.气相色谱法测定女贞子中齐墩果酸和熊果酸的含量.中国新药与临床杂志,2003,22(10)：596-598.
[38]黄秋妹,李宗.HPLC法测定山楂中熊果酸和齐墩果酸的含量.海峡药学,2007,19(3)：43-45.
[39]曹艳萍,薛成虎,杨秀利.红枣中齐墩果酸提取工艺的研究.食品科技,2007,28(10)：165-167.
[40]石敏娟,刘耀明,朱卫丰.苦丁荼中的熊果酸和齐墩果酸的含量测定.中医药学报,2007,35(2)：45-46.
[41]Liu HX, Shi YH, Wang DX, et al. MECC determination of oleanolic acid and ursolic acid isomers in Ligustrum lucidum Ait.Journal of Pharmaceutical and Biomedical Analysis,2003,32(3),479-485.
[42]张东方,黄济群,黄炜等.齐墩果酸抗人肺癌细胞增殖、侵袭和诱导细胞凋亡的研究.肿瘤防治研究,2003,30(3)：180-183.
[43]Huang D, Ding Y, Li Y, etal.Anti-tumor activity of a 3-oxo derivative of oleanolic acid. Cancer Letters,2006,233(2):289-296.
[44]Li J, Guo W J, Yang Q Y. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J Gastroenterol,2002,8(3):493-495.
[45]黄炜,黄济群,张东方等.五环三萜类化合物抗人肺癌细胞侵袭和诱导细胞凋亡的研究.中国肺癌杂志,2003,6(4)：254-257.
[46]Resende F A. Claudete Aparecida Mattos de Andrade Bareala, Marcia Cristina da Silva Faria, et al. Antimutagenicity of ursolic acid and oleanolic acid against doxorubicin-induced clastogenesis in Balb/c mice. Life Sciences,2006,79 (13): 1268-1273.
[47]Ovesna Z, Vachalkova A, Horvathova K, et al. Pentacyclic triterpenoic acids: new chemo-protective compounds. Minireview Neoplasma,2004,51(5):327-333.
[48]冀春萱,纪红,韩德伍等.齐墩果酸对急性实验性肝损伤的防治作用.山西医药杂志,1980,9(6)：5-7.
[49]孟艳秋,赵临襄,于趱等.五环三萜类化合物的构效关系.中国新药杂志,2004,13(12)：1098-1102.
[50]韩德伟.齐墩果酸防治实验性肝硬变发生的研究.中医杂志,1981,22(3)：217.
[51]Honjo I, Suou T, Hirayama C.Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol,1988,61: 149-165.
[52]宫新江,丁虹,邱银生等.OA抗环磷酰胺所致大鼠肝细胞损伤作用.医药导报,2006,25(11)：1114-1116.
[53]田丽婷,堵年生,马龙.齐墩果酸的药理作用研究概况.中国中药杂志,2002,27(12)：884-886.
[54]殷峻,陈名道,胡仁明等.小檗碱、齐墩果酸和大蒜新素对糖代谢作用的体外研究.北京中医药大学学报,2003,26(2)：36-38.
[55]Yoshikawa M, Matsuda H. Antidiabetogenic activity of oleanolic acid glycosides from medicinal foodstuffs. Biofactor,2000,13(1-4):231-237.
[56]Ortiz-Andrade R R, Garcia-jimenez S, Castillo-Espana P, et al. a -Glucosidase inhibitory activity of the methanolic extract from Tournefortia hartwegiana: An anti-hyperglycemic agent. Journal of Ethnopharacology,2007,109(1): 48-53.
[57]黄婉,杨耀芳.女贞子及其有效成分的药理及临床研究进展.现代中西医结合杂志,2003,12(7)：772-774.
[58]Cai L, Wu C D. Compounds from Syzygira Aromaticum Possessing Growth Inhibitory Activity Against Oral Pathogens. Jnat Prod,1996,59(10):987-990.
[59]Steele J C, Warhurst D C, Kirby G C, et al. In Vitro and in Vivo Evaluation of Betulinic Acid as An Antimalarial. Phytother Res,1999,13(2):115-119.
[60]Kozai K, Suzuki J, Okada M, et al. Effect of Oleanolic Acid-cyclodextrin Inclusion Compounds on Dental Caries by in Vitro Experiment and rat-caries Model. Microbios,1999,97(388):179-188.
[61]吴虹,魏伟,吴成义.木瓜化学成分及药理活性的研究.安徽中医学院学报,2004, 23(2)：62-64.
[62]Zheng C J, Sohn M J, Kim K Y, et al. Olean-27-carboxylic acid-type triterpenes with Potent antibacterial activity from aceriphyllum rossii. Agric Food Chem, 2008,56(24):11752-11756.
[63]田奇伟,唐绍海,郭成立等.木瓜的抗菌作用.微生物学通报,1982,(16)：271-272.
[64]郭成立,田昌本,唐绍海等.木瓜治疗急性细菌性痢疾107例临床观察.中华医学杂志,1984,64(11)：689-690.
[65]赵驻,蓝茹.从齐墩果酸结构分析抗肝细胞损伤的作用机制.中草药,1998,29(12)：844-844.
[66]Kashiwad Y, Wang H K, Nagao T. et al.Anti-AIDS agents 30. Anti-HIV activity of oleanolic acid, pomolic aci.1 and structrurally related triterpenoides. J Nat Prod,1998,61 (9):1090-1095.
[67]Ma C, Nakamura N, Miyashiro H, et al. Inhibitory effects of constituents from cynomorium songarium and related triterpene derivatives on HIV-I protease. Chem Pharm Bull (Tokyo),1999,47(2):141-145.
[68]孙燕,袁瑞荣,吴西居等.齐墩果酸的促免疫作用.中国临床病理学杂志,1988,4(1)：26-31.
[69]王德仁.齐墩果酸研究新进展.天津药学,2003,15(3)：56-58.
[70]任骏.齐墩果酸对前列腺素及环核苷酸的影响.中国药理学通报,1991,7(3)：179-181.
[71]丁安伟,盂丽.女贞子多糖的免疫调节作用研究.中药药理与临床,2001,17(2)：11-12.
[72]Somova L I, Shode F 0, Ramnanan P, et al. Cardiotonic and anti-dysrhythrnic effects of oleanolic and ursolic acids, methylmaslinate and uvaol. Phytomedicine,2004,11(2-3):121-129.
[73]Astudillo L, Rodriguez J A, Schmeda-Hirschmann G. Gastroprotective activity of oleanolic acid derivatives on experimentally induced gastric lesions in rats and mice. J Pharm Pharmacol,2002,54(4):583-588.
[74]薄显辉,杨景仁,刘君富等.薄层扫描法测定祛风止痛片中齐墩果酸含量.哈尔滨医科大学学报,1998.32(6)：462-462.
[75]中国药典2005年版[S].2005.
[76]江苏新医学院.中药大辞典[M].上册.上海：上海人民出版社,1977：189.
[77]田原,李晓,刘艳玲等.RP-HPLC法测定肝喜乐胶囊中齐墩果酸的含量.辽宁中医杂志,2007,34(3)：345-345.
[78]王强,王跃飞,潘桂湘等.RP-HPLC法测定舒肝保健茶中齐墩果酸的含量.广东药学院学报,2007,23(5)：516-517.
[79]廖利江,曾英彤,梁海勇.RP-HPLC法测定滋阴舒肝颗粒中齐墩果酸的含量.中国药房,2008,19(24)：1896-1897.
[80]国家药典委员会编.中华人民共和国药典(一部)[S].2005年版.北京：化学工业出版社,2005：附录ⅥB.
[81]赵陆华,丁黎,陈玉荚等.克疣淋溶液中四种酸性成分的气相色谱测定法.中国药科大学学报,1998,29(6)：453-455.
[82]Liu J. Pharmacology of oleanolic acid and ursolic acid. J Ethnopharmacol,1995, 49(2):57-68.
[83]Jeong H J, Chai H B, Park S Y, et al. Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Bioorg Med Chem Lett,1999, 9(8):1201-1204.
[84]齐藤节生.具有烷基侧链的甘草次酸甙元的合成与抗HIV活性.国外医学中医中药分册,1995,(4)：40-40.
[85]Shim S B, Kim D H. Beta-glucuronidase inhibitory activity and hepatoprotective effect of glycyrrhiza uralensis. Planta Medica:Natural Products and Medicinal Plant Research,2000,66(1):40-43.
[86]Cinatl J, Morgenstem B, Bauer G, et al. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. The Lancet, 2003,361(9374):2045-2046.
[87]包金凤.甘草次酸药理作用研究进展.兰州医学院学报,1994,20(1)：50-52.
[88]张宝恒.甘草药理作用研究的进展.药学学报,1963,10(11)：688-700.
[89]Honda T, Rounds B V, Gribble G W, et al. Design and synthesis of 2-eyano-3, 12-dioxoolean-1,9-dien-28-oic acid, a novel and highly active inhibitor of nitric oxide production in mouse macrophages. Bioorg Med Chem Lett,1998,8(19): 2711-2714.
[90]Snh N, Wang Y, Honda T, et al. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolcana-1,9-dien-28-oic acid, with potent differentiating, anti-proliferative, and anti-inflammatory activity. Cancer Pea,1999,59(2): 336-341.
[91]Haregewei A, Alison N, Larry W, el al. Synthesis and evaluation of potential complement inhibitory semisynthetic analogs of oleanolic acid. Bioorganic & Medicinal Chemistry Letters,1999,9:1889-1894.
[92]Zhu Y M, Shen J K, Wang H K, el al. Synthesis and anti-HIV activity of oleanolic acid derivatives.Bioorganic & Medicinal Chemistry Letters,2001,11: 3115-3118.
[93]Ma C M, Nakamura N, Miyashiro H, et al. Inhibitory effect of constituents from cynomorium songaricum and related triterpene derivatives on HIV-1 protease. Chem Pharm Bull,1999,47(2):141-145.
[94]Ma C M, Nakamura N, Hattor M. Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization. Chem Pharm Bull,2000,48(1):1681-1688.
[95]Evers M, Poujade C, Soler F, et al.Betunilic acid derivatives:a new class of human immunodeficiency virus type 1 specific inhibitors with a new mode of action. J Med Chem,1996,39(5):1056-1068.
[96]Takiura K, Honda S, Yamamoto M, et al. Studies of oligosaccharides. XII. Hydrophilization of glycyrrhetinic acid by coupling to gentio oligosaccharides. Chemical and Pharmaceutical Bulletin,1974,22(7): 1618-1623.
[97]孙华,胡春,方唯硕.3-氧代齐墩果酸氨基酸偶联物的合成、水溶性的测定及抗肿瘤活性研究.中国药物化学杂志,2008,18(1)：11-15.
[98]赵德千.齐墩果酸和甘草次酸衍生物的合成与表征及其抗菌和抗癌活性的研究：(硕士学位论文).大连：辽宁师范大学,2010.
[99]李建新,李俊峰.齐墩果酸衍生物及其制备方法和应用.中国专利,CN 101298466A.2008.
[100]李建新.齐墩果酸及其衍生物、制备及用途.中国专利,CN 1724556A.2006.
[101]张奕华,陈莉,田季德等.齐墩果酸偶联衍生物及其药物用途.中国专利.CN1594354A.2005.
[102]Zhao L X, Moon Y S, Basnet A, et al. Design, synthesis and anticonvulsive activities of potential prodrugs linked by two-carbon chan. Arch Pharm Res, 2003,26(10):785-795.