NMR在中药质量控制及在药物立体结构研究中的应用
|
摘要
核磁共振技术已成为结构分析表征、动态过程追踪、生物代谢组学分析等方面不可或缺的重要工具,广泛应用于药物研发的各个层面。本论文主要对NMR技术在中药质量控制及在药物立体结构研究中的应用进行了探索性的研究。研究内容主要包括：通过1H NMR指纹图谱-模式识别方法建立升麻药材的质量评价和控制体系；利用动态NMR方法对抗高血压药物群多普利和抗癌药物卡培他滨在溶液中的构象行为进行研究。
第一部分,本文应用1H NMR指纹图谱-模式识别方法对升麻药材的品种和品质进行鉴别研究。升麻是我国传统中药之一,也是一种典型的多基源药材,仅被《中国药典》所收载的品种就有3种,而根据药典方法并不能实现对不同品种升麻的鉴别。本研究共收集了38个升麻Cimicifuga foetida(西升麻)样本、15个大三叶升麻C. heracleifolia(关升麻)样本和15个兴安升麻C. dahurica(北升麻)样本,经简单预处理后得到其甲醇提取物,再经NMR测试获得其1HNMR图谱。对提取方法和测试过程的重现性及精密度进行了考察,并对其进行了初步的谱峰归属,由此建立了升麻的1H NMR指纹图谱。在此基础上,以1H NMR为识别变量,运用主成分分析(PCA)、判别偏最小二乘(DPLS)及人工神经网络(ANN)等多种数据分析方法建立了不同品种升麻的识别模型。研究结果表明,关升麻和北升麻之间具有很高的相似性,二者与西升麻之间则存在较为显著的差异。PCA得分和载荷分析则表明三萜皂苷类化合物是引起这一区分的主要化学成分,此类化合物在西升麻中的含量较高,而关升麻和北升麻中糖类化合物的含量较高。采用DPLS方法建立了西升麻与关升麻和北升麻之间的分类识别模型；采用偶合的ANN-DPLS方法,建立了关升麻和北升麻之间的分类识别模型。两个模型均具有良好的分离度和稳定性,预测准确率达200%,能够实现不同种样本之间的快速、准确分类。对西升麻样本的PCA分析表明,舟曲县和宕昌县所产的西升麻中三萜皂苷类物质的含量相对较高且质量较为稳定,可以作为三萜皂苷提取物制剂的原料药材主产区。
第二部分则应用动态NMR方法对两种化学合成药物在溶液中的构象行为进行研究。药物分子的空间构象决定了它与受体结合的特异性、选择性和生物活性,其在溶液中的构象尤为重要。本研究采用2D和2D NMR技术结合量了化学中分子动力学(MD)模拟和密度泛函理论(DFT)的方法,对群多普利和卡培他滨的立体结构进行了研究。对群多普利的研究表明,因酰胺键的受阻旋转,该药物分子在不同溶液中均存在顺式和反式两种构象,且顺式构象为其优势构象；溶剂化效应的影响导致DMSO溶液中两种构象的能量差远小于在CDCl3溶液中的能量差,由动态NMR实验结果可以计算出酰胺键旋转的活化自由能为16.2kcal/mol。卡培他滨的研究结果表明,其分子结构中存在两个C-N键,即氨基甲酸酯C-N键以及连接吠喃环和嘧啶环的C-N键,前者因本身所具有的半双键性质而旋转受阻,后者则受空间位阻的作用而旋转受阻,导致卡培他滨在CDCl3溶液中存在4个构象异构体。通过动态NMR实验发现其中3个异构体相互转换所需的能垒极低,需在极低的测试温度下方可观测得到,而在265K时仅显示者的平均构象；另外1个异构体则因酰胺键上NH质子的迁移而形成了分子内氢键。本研究还应用密度泛函理论(DFT)方法对上述两个药物分子进行了最低能量结构的优化计算,进一步验证了NMR实验结论。
综上所述,本研究首次以升麻中的三萜皂苷类化合物为研究对象,建立了升麻药材的1H NMR指纹图谱,并以此为基础建立了完整全面的升麻质量评价和控制体系。研究结果表明,1H NMR指纹图谱-化学模式识别方法是一种简便易行且准确可靠的检测手段,非常适合于升麻药材的品种鉴别和化学分类研究,不仅能够更为全面地反映药材的内在品质,而且为升麻资源的合理开发和有效利用提供了必要的依据。同时,本研究首次发现群多普利和卡培他滨在溶液中存在多种构象异构体,并通过NMR实验和量子化学计算阐明了其立体结构。不仅从分子结构水平上对其构象行为做出了合理的解释,也为进一步研究药物的药效性能以及药物分子与靶酶分子的作用方式奠定了基础。
Nuclear magnetic resonance (NMR) technique has become an indispensable tool for structure characterization, dynamic process tracking and metabonomics analysis, widely used in drug development at all levels. This work studies the application of NMR in Chinese medicine quality control and drug stereostructure study. Studies include the establishment of quality evaluation and control system of Cimicifuga by1H NMR fingerprint combined with pattern recognition (PR) method, and the investigation of conformational behavior of antihypertensive agent trandolapril and anti-cancer drug capecitabine in solution by using dynamic NMR experiment.
It is well known, at least eight species of Cimicifuga are distributed in China, and most are used in traditional Chinese medicine. Three species, C. foetida, C. heracleifolia and C. dahurica, all known by the same common Chinese name "shengma" and have been record in Chinese Pharmacopoeia. However, according to the pharmacopoeia method can not achieve the authentification of Cimicifuga species. In order to identify their species and quality, the metabolomic analysis of the three Cimicifuga species was performed using1H NMR spectroscopy and PR techniques in the first part.
Dried plant material of38C. foetida,15C. heracleifolia and15C. dahurica were extracted by methanol to give extracts, which were detected by1H NMR spectroscopy. The reproducibility and precision of the all samples and the testing process were investigated, and the main peaks were assigned, thereby establishing the1H NMR fingerprint of Cimicifuga. The analysis using principal component analysis (PCA) and discriminant partial least square (DPLS) of the1H NMR spectra showed a clear discrimination between C. foetida and the other two species. The major metabolites responsible for the discrimination were triterpenoid saponins and saccharides. A coupled artificial neural network (ANN) and DPLS model was applied to the classification of C. heracleifolia and C. dahurica.
In the second part, the conformational behaviors of two synthetic drugs in solution were investigated by dynamic NMR technique. To the best of our knowledge, the structure and conformational behavior of drug molecule is essential in obtaining information about the active site of the enzyme. In this study, the stereostructure of capecitabine and trandolapril were investigated by NMR spectroscopy combined with quantum chemical calculations. Trandopril was studied by NMR in various solvents and at various temperatures. The results showed that the two conformers interchange via rotation about the amide bond, and the cis conformation was the preferred conformation. The free energy of activation for the rotation about the amide bond was16.2kcal/mol. Quantum chemical calculations for trandolapril and capecitabine have been performed, and the results verified the NMR experiment conclusion.
In addition, two concurrent exchanges arising due to the restricted rotation around the carbamate C-N bond and alkyl C-N bond were investigated in capecitabine. A total of four low energy conformers were evaluated in the molecule, two were coexisted with a ratio of1:0.7in CDCl3solution at265K. Dynamic NMR experiment indicate that the major conformer is actually a mixture of three conformers with an extremely low barrier for them to interconvert, and the minor conformer form intramolecular hydrogen bond because of the NH proton migration.
This work established the quality evaluation and control system of Cimicifuga by1H NMR fingerprint combined with pattern recognition (PR) method for the first time. It provided an important method for authenticating C. foetida and distinguishing it from other species of Cimicifuga. This should facilitate the continued development of high-quality, unadulterated C. foetida products. Furthermore, we also found the presence of a variety conformers in solution of capecitabine and trandolapril, and then elucidated its stereostructure by NMR spectroscopy and quantum chemistry calculation for the first time. These results are not only a reasonable explanation of their conformational behavior from the level of molecular structure, also laid the foundation for further study about the drug efficacy and the mode of action of the drug molecule with the target enzyme molecule.
第一部分,本文应用1H NMR指纹图谱-模式识别方法对升麻药材的品种和品质进行鉴别研究。升麻是我国传统中药之一,也是一种典型的多基源药材,仅被《中国药典》所收载的品种就有3种,而根据药典方法并不能实现对不同品种升麻的鉴别。本研究共收集了38个升麻Cimicifuga foetida(西升麻)样本、15个大三叶升麻C. heracleifolia(关升麻)样本和15个兴安升麻C. dahurica(北升麻)样本,经简单预处理后得到其甲醇提取物,再经NMR测试获得其1HNMR图谱。对提取方法和测试过程的重现性及精密度进行了考察,并对其进行了初步的谱峰归属,由此建立了升麻的1H NMR指纹图谱。在此基础上,以1H NMR为识别变量,运用主成分分析(PCA)、判别偏最小二乘(DPLS)及人工神经网络(ANN)等多种数据分析方法建立了不同品种升麻的识别模型。研究结果表明,关升麻和北升麻之间具有很高的相似性,二者与西升麻之间则存在较为显著的差异。PCA得分和载荷分析则表明三萜皂苷类化合物是引起这一区分的主要化学成分,此类化合物在西升麻中的含量较高,而关升麻和北升麻中糖类化合物的含量较高。采用DPLS方法建立了西升麻与关升麻和北升麻之间的分类识别模型；采用偶合的ANN-DPLS方法,建立了关升麻和北升麻之间的分类识别模型。两个模型均具有良好的分离度和稳定性,预测准确率达200%,能够实现不同种样本之间的快速、准确分类。对西升麻样本的PCA分析表明,舟曲县和宕昌县所产的西升麻中三萜皂苷类物质的含量相对较高且质量较为稳定,可以作为三萜皂苷提取物制剂的原料药材主产区。
第二部分则应用动态NMR方法对两种化学合成药物在溶液中的构象行为进行研究。药物分子的空间构象决定了它与受体结合的特异性、选择性和生物活性,其在溶液中的构象尤为重要。本研究采用2D和2D NMR技术结合量了化学中分子动力学(MD)模拟和密度泛函理论(DFT)的方法,对群多普利和卡培他滨的立体结构进行了研究。对群多普利的研究表明,因酰胺键的受阻旋转,该药物分子在不同溶液中均存在顺式和反式两种构象,且顺式构象为其优势构象；溶剂化效应的影响导致DMSO溶液中两种构象的能量差远小于在CDCl3溶液中的能量差,由动态NMR实验结果可以计算出酰胺键旋转的活化自由能为16.2kcal/mol。卡培他滨的研究结果表明,其分子结构中存在两个C-N键,即氨基甲酸酯C-N键以及连接吠喃环和嘧啶环的C-N键,前者因本身所具有的半双键性质而旋转受阻,后者则受空间位阻的作用而旋转受阻,导致卡培他滨在CDCl3溶液中存在4个构象异构体。通过动态NMR实验发现其中3个异构体相互转换所需的能垒极低,需在极低的测试温度下方可观测得到,而在265K时仅显示者的平均构象；另外1个异构体则因酰胺键上NH质子的迁移而形成了分子内氢键。本研究还应用密度泛函理论(DFT)方法对上述两个药物分子进行了最低能量结构的优化计算,进一步验证了NMR实验结论。
综上所述,本研究首次以升麻中的三萜皂苷类化合物为研究对象,建立了升麻药材的1H NMR指纹图谱,并以此为基础建立了完整全面的升麻质量评价和控制体系。研究结果表明,1H NMR指纹图谱-化学模式识别方法是一种简便易行且准确可靠的检测手段,非常适合于升麻药材的品种鉴别和化学分类研究,不仅能够更为全面地反映药材的内在品质,而且为升麻资源的合理开发和有效利用提供了必要的依据。同时,本研究首次发现群多普利和卡培他滨在溶液中存在多种构象异构体,并通过NMR实验和量子化学计算阐明了其立体结构。不仅从分子结构水平上对其构象行为做出了合理的解释,也为进一步研究药物的药效性能以及药物分子与靶酶分子的作用方式奠定了基础。
Nuclear magnetic resonance (NMR) technique has become an indispensable tool for structure characterization, dynamic process tracking and metabonomics analysis, widely used in drug development at all levels. This work studies the application of NMR in Chinese medicine quality control and drug stereostructure study. Studies include the establishment of quality evaluation and control system of Cimicifuga by1H NMR fingerprint combined with pattern recognition (PR) method, and the investigation of conformational behavior of antihypertensive agent trandolapril and anti-cancer drug capecitabine in solution by using dynamic NMR experiment.
It is well known, at least eight species of Cimicifuga are distributed in China, and most are used in traditional Chinese medicine. Three species, C. foetida, C. heracleifolia and C. dahurica, all known by the same common Chinese name "shengma" and have been record in Chinese Pharmacopoeia. However, according to the pharmacopoeia method can not achieve the authentification of Cimicifuga species. In order to identify their species and quality, the metabolomic analysis of the three Cimicifuga species was performed using1H NMR spectroscopy and PR techniques in the first part.
Dried plant material of38C. foetida,15C. heracleifolia and15C. dahurica were extracted by methanol to give extracts, which were detected by1H NMR spectroscopy. The reproducibility and precision of the all samples and the testing process were investigated, and the main peaks were assigned, thereby establishing the1H NMR fingerprint of Cimicifuga. The analysis using principal component analysis (PCA) and discriminant partial least square (DPLS) of the1H NMR spectra showed a clear discrimination between C. foetida and the other two species. The major metabolites responsible for the discrimination were triterpenoid saponins and saccharides. A coupled artificial neural network (ANN) and DPLS model was applied to the classification of C. heracleifolia and C. dahurica.
In the second part, the conformational behaviors of two synthetic drugs in solution were investigated by dynamic NMR technique. To the best of our knowledge, the structure and conformational behavior of drug molecule is essential in obtaining information about the active site of the enzyme. In this study, the stereostructure of capecitabine and trandolapril were investigated by NMR spectroscopy combined with quantum chemical calculations. Trandopril was studied by NMR in various solvents and at various temperatures. The results showed that the two conformers interchange via rotation about the amide bond, and the cis conformation was the preferred conformation. The free energy of activation for the rotation about the amide bond was16.2kcal/mol. Quantum chemical calculations for trandolapril and capecitabine have been performed, and the results verified the NMR experiment conclusion.
In addition, two concurrent exchanges arising due to the restricted rotation around the carbamate C-N bond and alkyl C-N bond were investigated in capecitabine. A total of four low energy conformers were evaluated in the molecule, two were coexisted with a ratio of1:0.7in CDCl3solution at265K. Dynamic NMR experiment indicate that the major conformer is actually a mixture of three conformers with an extremely low barrier for them to interconvert, and the minor conformer form intramolecular hydrogen bond because of the NH proton migration.
This work established the quality evaluation and control system of Cimicifuga by1H NMR fingerprint combined with pattern recognition (PR) method for the first time. It provided an important method for authenticating C. foetida and distinguishing it from other species of Cimicifuga. This should facilitate the continued development of high-quality, unadulterated C. foetida products. Furthermore, we also found the presence of a variety conformers in solution of capecitabine and trandolapril, and then elucidated its stereostructure by NMR spectroscopy and quantum chemistry calculation for the first time. These results are not only a reasonable explanation of their conformational behavior from the level of molecular structure, also laid the foundation for further study about the drug efficacy and the mode of action of the drug molecule with the target enzyme molecule.
引文
[1]林玉萍,邱明华,李忠荣.升麻属植物的化学成分与生物活性研究.天然产物研究与开发,2002,14(6)：58-68
[2]鞠建华,杨峻山.升麻族植物三萜皂甙的研究进展.中国中药杂志,1999,24(9)：517
[3]但春.丁香和升麻的化学成分研究.[博士学位论文].成都：中国科学院研究生院,2006年
[4]Takemoto T, Kusano G. Studies on the Constituents of Cimicifuga spp. Ⅱ. Constituents of Cimicifuga acerina (2). Structure of Cimigenol. Yakugaku Zasshi,1967,87 (12):1569
[5]Sakurai N, Inoue T, Nagai M. Studies on the Chinese Crude Drug "Shoma." Ⅱ. Triterpenes of Cimicifuga dahurica Maxim. Yakugaku Zasshi,1972,92 (6):724
[6]Kusano G, Takemoto T. Studies on the Constituents of Cimicifuga spp. Ⅸ. Structures of Cimigol. Yakugaku Zasshi,1975,90(10):1133
[7]Kusano G, Hojo S, Kondo Y, Takemoto T. Studies on the Constituents of Cimicifuga spp. Ⅷ. Structure of cimicifugoside. Chem. Pharm. Bull.,1977,25 (12):3182
[8]Sakurai N, Koeda M, Inoue T, el al. Studies on the Chinese Crude Drug "Shoma." Ⅷ. Two New Triterpenol Bisdesmosides,3-Arabinosyl-24-O-acetylshengmanol 15-Glucoside and 3-Xylosyl-24-O-acetylshengmanol 15-Glucoside, from Cimicifuga dahurica. Chem. Pharm. Bull.,1994,42(1):48
[9]Takemoto T, Kusano G, Kawahara M. Studies on the Constituents of Cimicifuga spp. Ⅵ. Structures of 25-O-Acetylcimigenoside and 25-O-Methylcimigenoside. Yakugaku Zasshi, 1970,90(1):64
[10]李从军,陈迪华,肖培根.中药升麻的化学成分.药学学报,1993,28(10)：777
[11]Kusano G, Idoji M, Sogoh Y, et al. Studies on the Constituents of Cimicifuga Species. ⅪⅤ. A New Xyloside from the Aerial Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull., 1994,42(5):1106
[12]Sakurai N, Kimura O, Inoue T, et al. Studies on the Chinese Crude Drug "Shoma." Ⅴ. Structure of 24-O-Acetylhydroshengmanol Xyloside and 22-Hydroxycimigenol Xyloside. Chem. Pharm. Bull.,1981,29 (4):955
[13]Kusano A, Shibano M, Kitagawa S, et al. Studies on the Constituents of Cimicifuga Species. ⅩⅤ. Two New Diglycosides from the Aerial Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1994,42 (9):1940
[14]Sakurai N, Inoue T, Nagai M. Studies on the Chinese Crude Drug "Shoma." Ⅳ. Structure of Acetyl Shengmanol Xyloside, a Probable Precursor of Some Known Cimicifuga Glycosides. Chew. Pharm. Bull.,1979,25 (1):158
[15]Li J X, Kadota S, Hattori M, et al. Constituents of Cimicifugae Rhizoma.Ⅰ. Isolation and Characterization of Ten New Cycloartenol Triterpenes from Cimicifuga heracleifolia Komarov. Chem. Pharm. Bull.,1993,41 (5):832
[16]李从军.中药升麻的化学成分及其化学分类意义.[博士学位论文].北京：中国协和医科大学,1994年
[17]Kadota S, Li JX, Tanaka K, et al. Constituents of Cimicifugae Rhizoma. Ⅱ. Isolation and Structureo of New Cycloartenol Triterpenoids and Related Compounds from Cimicifuga foetida L. Tetrahedron,1995,51 (4):1143
[18]Koeda M, Aoki Y, Sakurai N, et al. Studies on the Chinese Crude Drug "Shoma." Ⅸ. Three Novel Cyclolanstanol Xylosides, Cimicifugosides H-1, H-2 and H-5, from Cimicifugae Rhizoma. Chem. Pharm. Bull.,1995,43 (5):771
[19]Bedir E, Khan I A. Cimiracemoside A:A New Cyclolanostanol Xyloside from the Rhizome of Cimicifuga racemosa. Chem. Pharm. Bull.,2000,48 (3):425
[20]Kusano A, Shibano M, Kusano G. Studies on the Constituents of Cimicifuga Species.ⅩⅦ. Four New Glycosides from the Aerial Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1995,43(7):1167
[21]Koeda M, Aoki Y, Sakurai N, et al. Three Novel Cyclolanostanol Xylosides from Cimicifugae Rhizoma. Chem. Pharm. Bull.,1994,42 (10):2205
[22]Sakurai N, Koeda M, Aoki Y, el al. Studies on the Chinese Crude Drug "Shoma." Ⅹ. Three New Trinor-9,19-cyclolanstanol Xylosides, Cimicifugosides H-3, H-4 and H-6, from Cimicifugae Rhizoma and Transformation of Cimicifugosides H-1 into Cimicifugosides H-2, H-3 and H-4. Chem. Pharm. Bull.,1995,43 (9):1475
[23]Kusano A, Shibano M, Taukamoto D, et al. Studies on the Constituents of Cimicifuga Species. ⅩⅩⅧ. Four New Cycloart-7-enol Glycosides from the Underground Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,2001,49 (4):437
[24]Zhang QW, Ye WC, Hsiao WWL, et al. Cycloartane Glycosides from Cimicifuga dahurica. Chem. Pharm. Bull.,2001,49 (11):1468
[25]Watanabe K, Mimaki Y, Sakagami H, et al. Cycloartane Glycosides from the Rhizomes of Cimicifuga racemosa and Their Cytotoxic Activities. Chem. Pharm. Bull.,2002,50(1):121
[26]Kusano A, Shibano M, Kusano G, et al. Studies on the Constituents of Cimicifuga Species. XIX. Eight New Glycosides from Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1996,44 (11):2078
[27]Kusano A, Takahira M, Shibano M, et al. Studies on the Constituents of Cimicifuga Species. XXI. Two New Cyclolanostanol Xylosides, Bugbanosides A and B from Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1998,46 (6):1001
[28]Kusano A, Takahira M, Shibano M, et al. Studies on the Constituents of Cimicifuga Species. ⅩⅩⅥ. Twelve New Cyclolanostanol Glycosides from the Underground Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1999,47 (4):511
[29]Akihisa T, Hideshima R, Koike K, et al. Cycloarta-16,24-dien-3β-ol:Revised Structure of Cimicifugenol, a Cycloartane Triterpenoid. Chem. Pharm. Bull.,1999,47 (8):1157
[30]Kusano A, Shibano M, Kusano G. Studies on the Constituents of Cimicifuga Species.ⅩⅩⅦ. Malonyl Cyclolanostanol Glycosides from the Underground Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1999,47 (8):1175
[31]刘勇,陈迪华,斯建勇,等.兴安升麻地上部分化学成分的研究.药学学报,2003,38(10)：763
[32]Shao Y, Harris A, Wang MF, et al. Triterpene Glycosides from Cimicifuga racemosa. J. Nat. Prod.,2000,63:905
[33]Sun LR, Yan J, Nian Y, et al. New Triterpene Diglycosides from the Rhizome of Cimicifuga foetida. Molecules,2008,13:1712
[34]Chen SN, Li WK, Fabricant DS, et al. Isolation, Structure Elucidation, and Absolute Configuration of 26-Deoxyactein from Cimicifuga racemosa and Clarification of Nomenclature Associated with 27-Deoxyactein. J. Nat. Prod.,2002,65:601
[35]Nishida M, Yoshimitsu H, Nohara T. Three Cycloartane Glycosides from Cimicifuga Rhizome and Their Immunosuppressive Activities in Mouse Allogeneic Mixed Lymphocyte Reaction. Chem. Pharm. Bull.,2003,51 (3):354
[36]Nishida M, Yoshimitsu H, Nohara T. Two New Tetranor-Cycloartane Glycosides from Cimicifuga Rhizome. Chem. Pharm. Bull.,2003,51 (9):1117
[37]Nishida M, Yoshimitsu H, Okawa M, et al. Two New 15,16-Seco-cycloartane Glycosides from Cimicifuga Rhizome. Chem. Pharm. Bull.,2003,51 (10):1215
[38]Dan C, Wang R, Peng SL, et al. Two New Acetyl Cimicifugosides from the Rhizomes of Cimicifuga Racemosa. Chinese Chemical Letters,2006,17 (3):347
[39]Yoshimitsu H, Nishida M, Sakaguchi M, et al. Two New 15-Deoxycimigenol-Type and Three New 24-epi-Cimigenol-Type Glycosides from Cimicifugae Rhizoma. Chem. Pharm. Bull., 2006,54(9):1322
[40]Yoshimitsu H, Nishida M, Nohara T. Three New 15,16-Seco-cycloartane Glycosides from Cimicifuga Rhizome. Chem. Pharm. Bull.,2007,55 (5):789
[41]刘勇.兴安升麻地上部分化学成分研究及抗骨质疏松活性筛选.[博士学位论文].北京：中国协和医科大学,2003年,
[42]张庆文,叶文才,车镇涛,等.小升麻中的环菠萝蜜烷型三萜及其糖苷成分.药学学报,2001,36(4)：287
[43]潘瑞乐,陈迪华,斯建勇,等.升麻地上部分皂苷类成分研究.药学学报,2002,37(2)：11 7
[44]赵晓宏,陈迪华,斯建勇,等.中药升麻酚酸类化学成分研究.药学学报,2002,37(7)：535-538
[45]Takahira M, Kusano A, Shibano M, et al. Piscidic Acid and Fukiic Acid Esters from Cimicifuga simplex. Phytochemistry,1998,49 (7):2115
[46]Iwanaga A, Kusano G, Warashina T, et al. Phenolic Constituents of the Aerial Parts of Cimicifuga simplex and Cimicifuga japonica. J. Nat. Prod.,2010,65:601
[47]Ito M, Kondo Y, Takemot T. Spasmolytic Substances from Cimicifuga dahurica MAXIM. Chem. Pharm. Bull.,1976,24 (4):580
[48]李从军,陈迪华,肖培根,等.中药升麻的化学成分V.中草药,1995,26(6)：288
[49]Kusano G., Hojo S, Kondo Y, Takemoto T. Studies on the Constituents of Cimicifuga spp. Ⅷ. Structure of cimicifugoside. Chem. Pharm. Bull.,1977,25 (12):3182
[50]H Hemmi, F Kitame, N Ishida, G Kusano, Y Kondo, S Nozoe. Inhibition of thymidine transport into phytohemagglutinin-stimulated lymphocytes by triterpenoids fro Cimicifuga species. J. Pharm. Dyn.1979,2:339
[5]]林新,蔡有余,肖培根.兴安升麻皂甙体外SIV抑制作用及其机制.华西药学杂志,1994, 9 (4):221-224
[52]F Borrelli, A A Izzo, E Ernst. Pharmacological effects of Cimicifuga racemosa. Life Sciences, 2003,73(10):1215-1229
[53]Gabor Vermes, Ferenc Banhidy, NandorAcs. The Effects of Remifemin on Subjective Symptoms of Menopause. Advance in Therapy,2005,22 (2):148
[54]自文佩,王淑玉,刘建立,耿力,胡丽娜,张忠兰,陈淑玲,郑淑蓉.莉芙敏片与替勃龙改善围绝经期症状的效果和安全性比较.中华妇产科杂志,2009,44(8)：597-600
[55]李建新,门田重利.升麻三萜类化合物的抗骨质疏松活性.《药用植物研究与中药现代化——第四届全国药用植物学与植物药学术研讨会论文集》2004年,197-199
[56]D. Seidlova-Wuttke, H. Jarry, T. Becker, V. Christoffel, W. Wuttke. Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats:bone, fat and uterus. Maturitas,2003,44(S1): S39-S50,
[57]Thomas Niblein, Johannes Freudenstein. Effects of an isopropanolic extract of Cimicifuga racemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J. Bone Miner. Metab.2003,21:370-376
[58]刘培淑,李霞,刘媛,毛洪鸾,孙玉兰.希明婷片治疗女性围绝经期综合征的临床研究.山东大学学报(医学版),2008,46(8)：791-794
[59]张丹,徐克惠,段秀蓉.希明婷片治疗妇女围绝经期综合征的临床观察.现代妇产科进展,2006,15(12)：934-936
[60]张春燕,杨钟莉.希明婷片对卵巢功能低下所致骨质疏松症的疗效观察.中国医师进修杂志,2011,34(21)：4-6
[61]薛赛琴,姜坤,张琼.希明婷片治疗女性更年期综合征364例.中国中西医结合杂志,2006,62(10)：891
[62]潘瑞乐,陈迪华,斯建勇,赵晓宏,朱古军.反相高效液像色谱法测定不同品种升麻中27-脱氧升麻亭的含量.中南药学,2007,5(3)：206-20
[63]姚梅芬,王岳峰,李展,潘瑞乐,赵晓宏,斯建勇.反相高效液相色谱法测定升麻药材中升麻苷H-1的含量.天然产物研究与开发,2011,23：696-699
[64]中华人民共和国生部药典委员会.中国药典(一部)1963年版.北京,人民卫生出版社,1963年,54-55
[65]中华人民共和国卫生部药典委员会.中国药典(一部)1977年版.北京,人民卫生出版 社,1978年,110
[66]中华人民共和国卫生部药典委员会.中国药典(一部)1985年版.北京,人民卫生出版社,1985年,56
[67]国家药典委员会.中国药典(一部)2000年版.北京,化学工业出版社,2000年,55
[68]国家药典委员会.中国药典(一部)2005年版.北京,化学工业出版社,2005年,50
[69]潘瑞乐,陈迪华,沈连刚,斯建勇.高效液相色谱法测定中药升麻中阿魏酸和异阿魏酸的含量.药物分析杂志,2000,20(6)：396-399
[70]司丹丹,李清,陈晓辉,康莉,冯毅,毕开顺.RP-HPLC法同时测定升麻中3种有机酸的含量.沈阳药科大学学报,2007,24(12)：727-731
[71]梁逸曾,俞汝勤编著.化学计量学.北京：高等教育出版社,2003
[72]梁逸曾,吴海龙,俞汝勤.化学计量学.现代科学仪器,1998,5：3-6
[73]Eriksson L, Hermens J L M. Chemometrics in Environmental Chemistry-Applications, Vol.2, Part H. Springer-Verlag, Berlin, Heidelberg,1995,135-169
[74]王惠文,吴载斌,孟洁.偏最小二乘回归的线性与非线性方法.北京：国防工业出版社,2006
[75]White H. Artificial neural networks:approximation and learning theory. Blackwell Publishers. USA,1992
[76]鞠建华,刘东,杨峻山.天然环菠萝蜜烷型三萜皂苷类化合物的波谱学规律的探讨.波谱学杂志,2001,18(1)：79-90
[77]The United States Pharmacopeial Convention Inc. The United States Pharmacopoeia.29th 1997:56
[1]Gund P. Three-dimensional pharmacophoric pattern searching. Prog Mol Subcell Biol.1977, 5:117
[2]Langer T, Wolber G, Pharmacophore definition and 3D searches. Drug Discovery Today: Technologies.2004,1(3):203
[3]Copeland R A. Conformational adaptation in drug-target interactions and residence time. Future Med. Chem.2011,3(12):1491
[4]Attia M I, Giiclii D, Hertlein B, et al. Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a]diindole analogues as melatonin receptor ligands. Org. Biomol. Chem.,2007,5:2129
[5]Lucyk S, Taha H, Yamamoto H, et al. NMR conformational analysis of proadrenomedullin N-terminal 20 peptide, a proangiogenic factor involved in tumor growth. Biopolymers,2006, 81 (4):295
[6]Biftu T, Gambel N F, Doebber T, el al. Conformation and activity of tetrahydrofuran lignans and analogues as specific platelet activating factor antagonists. J. Med. Chem.1986,29 (10): 1917
[7]Perez-Hernandez N, Morales-Rios, Cerda-Garcia-Rojas C M, et al. Conformational evaluation and detailed 1H and 13C NMR assignments of flavoxate, a urinary tract antispasmodic agent. JPBA.2006,41:603
[8]Amodeo P, Naider F, Picone D, et al. Conformational sampling of bioactive conformers:a low-temperature NMR study of 15N-leu-enkephalin. J. Peptide Sci.1998,4:253
[9]Smith A B, LaMarche M J, Falcone-Hindley M. Solution Structure of (+)-discodermolide. Org. Lett.2001,3 (5):695
[10]Gaggelli E, Marchettini N, Valensin G.1H and 13C NMR conformational analysis in solution of isoproterenol a pure β-agonist drug. Magn. Reson. Chem.1987,25 (11):970
[11]Li F, Wang L, Xiao N, et al. Dominant conformation of valsartan in sodium dodecyl sulfate micelle environment. J. Phys. Chem.2010,114:2719
[12]Li F, Zhang H, Jiang L, et al. Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compouns. Magn. Reson. Chem.2007,45: 929
[13]Potamitis C, Zervou M, Katsiaras V, et al. Antihypertensive drug valsartan in solution and at the AT1 receptor:conformational analysis, dynamic NMR spectroscopy, in silico docking, and molecular dynamics simulations. J. Chem. Inf. Model.2009,49:726
[14]Saran A, Srivastava S, Coutinho E. Conformation and macromolecular interaction of ACE inhibitors enalapril and lisinopril by NMR. Eur. J. Pharm. Sci.1994,1:181
[15]Hannongbua S, Prasithichokekul S, Pungpo P. Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations. J Comput Aid Mol Des.2001,15:997-1004
[16]Branca M, Alezra V, Kouklovsky C, et al. Accurate conformation analysis in solution:NMR and DFT/PCM study of the S-3-(1-naphthoyl)-4-isopropyl-2,2-dimethyloxazolidin-5-one in CDCl3. Tetrahedron.2008,50:1-10
[17]Fragaki G, Stefanaki I, Dais P, et al. Conformational properties of the macrocyclic trichothecene mycotoxin verrucarin A in solution. Magn Reson Chem.2008,46:1102-1111
[18]Tousek J, Malinakova K, Dostal J. et al. Theoretical and experimental NMR study of protopine hydrochloride isomers. Magn Reson Chem.2005,43:578-581
[19]Dutrey-Dupagne C, Girard A, Ulmann A, et al. Effects of the converting enzyme inhibitor trandolapril on short-term variability of blood pressure in essential hypertension. Clin. Auton. Res.1991,1(4):303
[20]Diaz A, Ducharme A. Update on the use of trandolapril in the management of cardiovascular disorders Vase. Health Risk Manag.2008,4 (6):1147
[21]上雯估,刘皋林.群多普利在心血.管疾病中的应用.2000,27(1)：24
[22]Venturini M. Rational development of capecitabine. Eur. J. Cancer.2002,38:S3-S9
[23]Dooley M, Goa K L. Capecitabine. Drugs.1999,58 (1):69-76
[24]Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (Capecitabine, UFT, S-1):a review. Oncologist,2002,7:288
[25]Koukourakis G V, Kouloulias V, Koukourakis M J, el al. Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment:a review. Molecules.2008,13:1897-1922
[26]Stewart W E, Siddall T H. Nuclear magnetic resonance studies of amides. Chem. Rev.1970, 70(5):517
[27]Insight Ⅱ 2000, San Diego:MSI Biosym.,2000
[28]Frisch M J, Trucks G W, Schlegel H B, et. al. Gaussian 03 Revision E.01, Gaussian Inc., Pittsburgh, PA,2003
[29]Frisch M J, Trucks G W, Schlegel H B, et al. Gaussian 09, Revision C.01, Gaussian, Inc., Wallingford CT,2010
[30]Kemnitz C R, Loewen M J. "Amide resonance" correlates with a breadth of C-N rotation barriers. J. Am. Chem. Soc.2007,129:2521
[31]Venturini M. Rational development of capecitabine. Eur. J. Cancer.2002,38:S3
[32]Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1):a review. Oncologist,2002,7:288
[33]Costanzo F D, Sdrobolini A, Gasperoni S. Capecitabine, a new oral fluoropyrimidine for the treatment of coloectal cancer. Crit. Rev. Oncol. Hemat.2000,35:101-108
[34]Shimma N, Okabe H, Ishitsuka H. Discovery of capecitabine, a rationally designed and tumor-activated oral prodrug of 5-FU, and beyond. CH/MIA,2008,62:928
[35]Modarresi-Alamo A R, Najafi P, Rostamizadeh M, et al. Dynamic 1H NMR study of the barrier to rotation about the C-N bond in primary carbamates and its solvent dependence. J. Org. Chem.,2007,72:2208
[36]Deetz M J, Forbes C C, Jonas M, et al. Unusually low barrier to carbamate C-N rotation. J. Org. Chem.2002,67:3949
[37]Rohlicek J, Husak M, Gavenda A, et al. Capecitabine from X-ray powder synchrotron data Acta Cryst.2009, E65:1325
[38]Moraczewski A L, Banaszynski L A, From A M, et al. Using hydrogen bonding to control carbamate C-N rotamer equilibria. J. Org. Chem. 1998,63:7258
[39]Fliszar S, Cardinal G, Beraldin M T. Charge Distributions and Chemical Effects.30. Relationships between Nuclear Magnetic Resonance Shifts and Atomic Charges. J. Am. Chem. Soc.1982,104:5287
[1]Bloch F, Hansen W W, Pachard M. Nuclear induction. Phys. Rev.1946,69:127
[2]Purcell E M, Torrey H C, Pound R V. Resonance absorption by nuclear magnetic moments in a solid. Phys. Rev.1946,69:37
[3]Claridge T D W. High-resolution NMR techniques in organic chemistry (2nd Ed). Elsevier, UK,2009
[4]Dingley A J. Pascal S M. Biomolecular NMR spectroscopy. IOS Press, Netherlands,2011
[5]Lees M. Food Authenticity and Traceability. Woodhead Publishing Ltd, UK,2003
[6]Barbotin J N, Portais J C. NMR in microbiology:theory and application. Horizon Scientific Press, UK,2000
[7]Holzgrabe U. Wawer I. Diehl B. NMR spectroscopy in pharmaceutical analysis. Elsevier, UK, 2008
[8]Holzgrabe U. Wawer I. Diehl B. NMR spectroscopy in drug development and analysis. Wiley Press. Germany,1999
[9]Lian L Y. Roberts G. Protein NMR Spectroscopy:Practical Techniques and Applications. Wiley Press. UK.2011
[10]Keun H C. Metabonomic modeling of drug toxicity. Pharmacology & Therapeutics,2006, 109:92-106
[11]Kubeczka K. H, Formacek V. Essential oils:analysis by capillary gas chromatography and carbon 13-NMR spectroscopy. London:John Wiley & Sons Ltd.; 1980
[12]梁逸曾,俞汝勤编著.《化学计量学》北京：高度教育出版社,2003
[13]秦海林,尚玉俊,赵伟,等.核磁共振氢谱法鉴别黄连的研究.中草药,2000,31(1)：48
[14]聂映,姚卫峰,沈文斌.厚朴的1H-NMR指纹图谱研究.2008,40(11)：91
[15]时新刚,李淑娥,孙庆雷,等.北沙参的1H-NMR指纹纹图谱研究.山东科学,2009,22(3)：24
(16]于思宏,金香淑,姚艳红,等.野生和栽培高山红景天的核磁共振指纹图谱的研究,延边大学学报,2001,27(4)：274
[17]秦海林,赵天增,袁卫梅,等.虎杖、何首乌和掌叶大黄、唐古特大黄的1H NMR指纹 图解析.药学学报,1999,34(11)：828
[18]祝贺,袁延强,孙庆雷,等.丹参的13C-NMR旨纹图谱研究.亚太传统医药,2008,4(10)：21
[19]孙庆雷,林云良,祝贺,等.黄芩的13C-NMR指纹图潜研究.波谱学杂志,2008,25(4)：486
[20]孙庆雷,林云良,王晓,等.金银花的13C-NMR指纹图谱研究.波谱学杂志,2006,23(2)：181
[21]Nicholson J K, Lindon J C, Holmes E. "Metabonomics":understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica,1999,29 (11):1181
[22]Lindon J C, Holmes E, Nicholson J K. Pattern recognition methods and applications in biomedical magnetic resonance. Prog. Nucl. Mag. Res. Sp.2001,39:1-40
[23]Nicholson J K, Wilson I D. Understanding "Golbal" systems biology:metabonomics and the continuum of metabolism. Nature, Drug Discovery.2003,2 (8):668
[24]Theodoridis S, Koutroumbas K. Pattern Recognition. Academic Press. USA,2008
[25]Eriksson L, Hermens J L M. Chemometrics in Environmental Chemistry-Applications, Vol.2, Part H. Springer-Verlag, Berlin, Heidelberg,1995
[26]Trygg J, Holmes E, Lundstedt T. Chemometrics in metabonomics. J Proteome Res.2007,6: 469
[27]Griffin J L. Metabonomics:NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterization of xenobiotic toxicity and disease diagnosis. Curr. Opin. Chem. Biol.2003,7 (5):648-654
[28]Lindon J C, Holmes E, Nicholson J K. Toxicological applications of magnetic resonance. Prog. Nucl. Mag. Res. Sp.2004,45:109-143
[29]Dumas M, Maibaum E C, Teague C, et al. Assessment of analytical reproducibility of 1H NMR spectroscopy based metabonomics for large-scale epidemiological research:the INTERMAP study. Anal. Chem.2006,78:2199
[30]Robosky L C, Robertson D G, Baker J D, et al. In vivo toxicity screening programs using metabonomics. Comb Chem High T Scr.2002,5:651
[31]Verpoorte R, Choi Y H, Kim H K. NMR-based metabolomics at work in phytochemistry. Phytochem. Rev.2007,6:3
[32]Kooy F V D, Maltese F, Choi Y H, et al. Quality control of herbal material and phytopharmaceuticals with MS and NMR based metabolic fingerprinting. Planta Med.2009, 75:763-775
[33]Ward J L, Baker J M, Beale M H. Recent applications of NMR spectroscopy in plant metabolomics. FEBS Journal,2007,274:1126-1131
[34]Chan K. Generating finger printing from analytical techniques alone is not enough in assurance for quality, efficacy and safety of Chinese medicinal herbs and herbal products. Analytical Sciences,2001,17S:409-412
[35]Skin Y S, Bang K H, In D S, et al. Finerprinting analysis of fresh ginseng roots of different ages using 1H-NMR spectroscopy and principal component analysis. Arch. Pharm. Res.2007, 30(12):1625-1628
[36]Yang S O, Shin Y S, Hyum S H, et al. NMR-based metabolic profiling and differentiation of ginseng roots according to cultivation ages. J Pharm. Bio. Anal.2012,58:19-26
[37]Whang W K, Lee M W, Choi H K. Metabolic discrimination of safflower petals of various origins using 1H NMR spectroscopy and multivariate statistical analysis. Bull. Korean Chem. Soc.2007,28 (4):557-560
[38]Bailey N J C, Sampson J, Hylands P J, et al. Multi-component metabolic classification of commercial feverfew preparations via high-field'H-NMR spectroscopy and chemometrics. Plant a Med.2002,68:734-738
[39]Rasmussen B, Cloarec O, Tang H, et al. Multivariate analysis of integrated and full-resolution 1H-NMR spectral data from complex pharmaceutical preparations:St. John's Wort. Planta Med.2006,72:556-563
[401 Lin W N, Lu H Y, Lee M S, et al. Evaluation of the cultivation age of dried ginseng radix and its commercial products by using 1H-NMR fingerprint analysis. Am. J. Chin. Med.2010,38 (1):205-218
[41]Wang Y, Tang H, Nicholson J K, et al. Metabolomis strategy for the classification and quality control of phytomedicine:a case study of chamomile flower (Matricaria recutita L.). Planta Med.2004,70:250-255
[42]Xiao C, Dai H, Liu H, et al. Revealing the Metabonomic Variation of Rosemary Extracts Using 1H NMR Spectroscopy and Multivariate Data Analysis. J. Agric. Food Chem.2008,56 (21):10142-10153
[43]Watson D G, Peyfoon E, Zheng L, et al. Application of principal components analysis to 1H-NMR data obtained from propolis samples of different geographical origin. Phytochem Anal.2006,17:323
[44]谭小燕,罗乔奇,马郑红,等.不同产地麦冬1H-NMR模式识别研究.中草药,2009,40(5)：792-797
[45]王丽.沙棘的氧核磁共振图谱-多元统计分析研究.[硕士学位论文].成都：四川大学,2007
[46]朱芸.(1)辛苓颗粒氢核磁共振-模式识别研究；(2)九管血地下部分化学成分的研究.[颁士学位论文].成都：四川大学,2007
[47]Frederich M, Jansen C, Tullio P, et al. Metabolomic analysis of Echinacea spp. by 1H nuclear magnetic resonance spectrometry and multivariate data analysis technique. Phytochem. Anal. 2010,21:61-65
[48]Frederich M, Choi Y H, Angenot L, et al. Metabolomic analysis of Strychnos mux-vomica, Strychnos icaja and Strychnos ignatii extracts by 1H nuclear magnetic resonance spectrometry and multivariate data analysis techniques. Phytochemistry,2004,65:1993-2001
[49]Choi Y H, Sertic S, Kim H Y, et al. Classification of IIex species based on metabolomic fingerprinting using nuclear magnetic resonance and multivariate data analysis. J. Agric. Food Chem.2005,53:1237-1245
[50]Kim H K, Choi Y H, Erkelens C, et al. Metabolic fingerprinting of Ephedra species using 1H-NMR spectroscopy and principal component analysis. Chem. Pharm. Bull.2005,53 (1): 105-109
[51]Ward J L, Harris C, Lewis J, et al. Assessment of 1H NMR spectroscopy and multivariate analysis as a technique fro metabolite fingerprinting of Arabidopsis thaliana. Phytochemistry. 2003,62:949-957
[52]Nord L I, Kenne L, Jacobsson S P. Multivariate analysis of 1H-NMR spectra for saponins from Quillaja saponaria Molina. Analytica Chimica Acta.2001,446:199-209
[53]Alcantara G B, Honda N K, Ferreira M M C, et al. Chemometric analysis applied in 1H HR-MAS NMR and FT-IR data for chemotaxonornic distinction of intact lichen samples. Analytica Chimica Acta.2007,595:3-8
[54]Choi H, Choi Y H, Verberne M, et al. Metabolic fingerprinting of wild type and transgenic tobacco plants by 1H NMR and multivariate analysis technique. Phytochemistry.2004,65 (7): 857-864
[55]Choi Y H, Kim H K, Hazekamp A, et al. Metabolomic differentiation of Cannabis sativa cultivars using 1H NMR spectroscopy and principal component analysis. J. Nat. Prod.2004, 67:953-957
[56]Choi Y H, Tapias E C, Kim H K, et al. Metabolic discrimination of Catharanthus roseus eaves infected by phytoplasma using 1H-NMR spectroscopy and multivariate data analysis. American Society of Plant Biologists.2004,135 (4):2398-2410
[57]Cevallos-Cevallos J M, Reyes-De-Corcuera J I, Danyluk M D, et al. Metabolomic analysis in food science:a review. Trends Food Sci Tech.2009,20:557
[58]Arvanitoyannis I S, Vaitsi O B. A Review on Tomato Authenticity:Quality Control Methods in Conjunction with Multivariate Analysis (Chemometrics) Crit Rev Food Sci.2007,47:675
[59]Choi H K, Choi Y H, Verberne M, et al. Metabolic fingerprinting of wild type transgenic tobacco plants by'H NMR and multivariate analysis technique. Phytochemistry.2004,65: 857-864
[60]Alonso-Salces R M, Heberger K, Holland M V, et al. Multivariate analysis of NMR fingerprint of the unsaponifiable fraction of virgin olive oils for authentication purposes. Food Chemistry.2010,118:956-965
[61]Spraul M, Schutz B, Humpfer E, et al. Mixture analysis by NMR as applied to fruit juice quality control. Magn. Reson. Chem.2009,47:S130-S137
[62]Duarte I F, Barros A, Almeida C, et al. Multivariate analysis of NMR and FTIR data as a potential tool for the quality control of beer. J. Agric. Food Chem.2004,52:1031-1038
[63]Son H, Hwang G, Kim K M, et al. Metabolomic studies on geographical grapes and their wines using 1H-NMR analysis coupled with multivariate statistics. J. Agric. Food Chem. 2009,57:1481-1490
[64]Charlton A J, Farrington W H H, Brereton P. Application of'H NMR and multivariate statistics for screening complex mixtures:quality control and authenticity of instant coffee.J. Agric. Food Chem.2002,50:3098-3103
[65]Tarachiwin L, Masako O, Fukusaki E. Quality evaluation and prediction of Cirullus lanatus by 1H NMR-based metabolomics and multivariate analysis. J. Agric. Food Chem.2008,56: 5827-5835
[66]Fujiwara M, Ando I, Arifuku K. Multivariate analysis for'H-NMR spectra of two hundred kinds of tea in the world. Anal. Sci.2006,22 (10):1307-1314
[67]Rezzi S, Giani I, Heberger K, et al. Classification of Gilthead Sea Bream (Sparus aurata) from 1H NMR lipid profiling combined with principal component and linear discriminant analysis. J. Agric. Food Chem.,2007,55 (24):9963-9968
[68]Sacco D, Brescia M A, Buccolieri A, et al. Geographical origin and breed discrimination of Apulian lamb meat samples by means of analytical and spectroscopic determinations. Meat Science.2005,71:542-548
[69]Shintu L, Caldarelli S. High-resolution MAS NMR and chemometrics:characterization of the ripening of Parmigiano Reggiano cheese. J. Agr. Food Chem.2005,53 (10):4026-4031
[70]Shintu L, Caldarelli S, Franke B M. Pre-selection of potential molecular markers for the geographic origin of dried beef by HR-MAS NMR spectroscopy. Meat Science.2007,76 (4): 700-707
[71]Nicholson J K. Metabonomics:a generic platform for the investigation of drug toxicity, altered gene function and disease processes. Drug Discover World Summer.2004,23-28
[2]鞠建华,杨峻山.升麻族植物三萜皂甙的研究进展.中国中药杂志,1999,24(9)：517
[3]但春.丁香和升麻的化学成分研究.[博士学位论文].成都：中国科学院研究生院,2006年
[4]Takemoto T, Kusano G. Studies on the Constituents of Cimicifuga spp. Ⅱ. Constituents of Cimicifuga acerina (2). Structure of Cimigenol. Yakugaku Zasshi,1967,87 (12):1569
[5]Sakurai N, Inoue T, Nagai M. Studies on the Chinese Crude Drug "Shoma." Ⅱ. Triterpenes of Cimicifuga dahurica Maxim. Yakugaku Zasshi,1972,92 (6):724
[6]Kusano G, Takemoto T. Studies on the Constituents of Cimicifuga spp. Ⅸ. Structures of Cimigol. Yakugaku Zasshi,1975,90(10):1133
[7]Kusano G, Hojo S, Kondo Y, Takemoto T. Studies on the Constituents of Cimicifuga spp. Ⅷ. Structure of cimicifugoside. Chem. Pharm. Bull.,1977,25 (12):3182
[8]Sakurai N, Koeda M, Inoue T, el al. Studies on the Chinese Crude Drug "Shoma." Ⅷ. Two New Triterpenol Bisdesmosides,3-Arabinosyl-24-O-acetylshengmanol 15-Glucoside and 3-Xylosyl-24-O-acetylshengmanol 15-Glucoside, from Cimicifuga dahurica. Chem. Pharm. Bull.,1994,42(1):48
[9]Takemoto T, Kusano G, Kawahara M. Studies on the Constituents of Cimicifuga spp. Ⅵ. Structures of 25-O-Acetylcimigenoside and 25-O-Methylcimigenoside. Yakugaku Zasshi, 1970,90(1):64
[10]李从军,陈迪华,肖培根.中药升麻的化学成分.药学学报,1993,28(10)：777
[11]Kusano G, Idoji M, Sogoh Y, et al. Studies on the Constituents of Cimicifuga Species. ⅪⅤ. A New Xyloside from the Aerial Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull., 1994,42(5):1106
[12]Sakurai N, Kimura O, Inoue T, et al. Studies on the Chinese Crude Drug "Shoma." Ⅴ. Structure of 24-O-Acetylhydroshengmanol Xyloside and 22-Hydroxycimigenol Xyloside. Chem. Pharm. Bull.,1981,29 (4):955
[13]Kusano A, Shibano M, Kitagawa S, et al. Studies on the Constituents of Cimicifuga Species. ⅩⅤ. Two New Diglycosides from the Aerial Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1994,42 (9):1940
[14]Sakurai N, Inoue T, Nagai M. Studies on the Chinese Crude Drug "Shoma." Ⅳ. Structure of Acetyl Shengmanol Xyloside, a Probable Precursor of Some Known Cimicifuga Glycosides. Chew. Pharm. Bull.,1979,25 (1):158
[15]Li J X, Kadota S, Hattori M, et al. Constituents of Cimicifugae Rhizoma.Ⅰ. Isolation and Characterization of Ten New Cycloartenol Triterpenes from Cimicifuga heracleifolia Komarov. Chem. Pharm. Bull.,1993,41 (5):832
[16]李从军.中药升麻的化学成分及其化学分类意义.[博士学位论文].北京：中国协和医科大学,1994年
[17]Kadota S, Li JX, Tanaka K, et al. Constituents of Cimicifugae Rhizoma. Ⅱ. Isolation and Structureo of New Cycloartenol Triterpenoids and Related Compounds from Cimicifuga foetida L. Tetrahedron,1995,51 (4):1143
[18]Koeda M, Aoki Y, Sakurai N, et al. Studies on the Chinese Crude Drug "Shoma." Ⅸ. Three Novel Cyclolanstanol Xylosides, Cimicifugosides H-1, H-2 and H-5, from Cimicifugae Rhizoma. Chem. Pharm. Bull.,1995,43 (5):771
[19]Bedir E, Khan I A. Cimiracemoside A:A New Cyclolanostanol Xyloside from the Rhizome of Cimicifuga racemosa. Chem. Pharm. Bull.,2000,48 (3):425
[20]Kusano A, Shibano M, Kusano G. Studies on the Constituents of Cimicifuga Species.ⅩⅦ. Four New Glycosides from the Aerial Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1995,43(7):1167
[21]Koeda M, Aoki Y, Sakurai N, et al. Three Novel Cyclolanostanol Xylosides from Cimicifugae Rhizoma. Chem. Pharm. Bull.,1994,42 (10):2205
[22]Sakurai N, Koeda M, Aoki Y, el al. Studies on the Chinese Crude Drug "Shoma." Ⅹ. Three New Trinor-9,19-cyclolanstanol Xylosides, Cimicifugosides H-3, H-4 and H-6, from Cimicifugae Rhizoma and Transformation of Cimicifugosides H-1 into Cimicifugosides H-2, H-3 and H-4. Chem. Pharm. Bull.,1995,43 (9):1475
[23]Kusano A, Shibano M, Taukamoto D, et al. Studies on the Constituents of Cimicifuga Species. ⅩⅩⅧ. Four New Cycloart-7-enol Glycosides from the Underground Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,2001,49 (4):437
[24]Zhang QW, Ye WC, Hsiao WWL, et al. Cycloartane Glycosides from Cimicifuga dahurica. Chem. Pharm. Bull.,2001,49 (11):1468
[25]Watanabe K, Mimaki Y, Sakagami H, et al. Cycloartane Glycosides from the Rhizomes of Cimicifuga racemosa and Their Cytotoxic Activities. Chem. Pharm. Bull.,2002,50(1):121
[26]Kusano A, Shibano M, Kusano G, et al. Studies on the Constituents of Cimicifuga Species. XIX. Eight New Glycosides from Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1996,44 (11):2078
[27]Kusano A, Takahira M, Shibano M, et al. Studies on the Constituents of Cimicifuga Species. XXI. Two New Cyclolanostanol Xylosides, Bugbanosides A and B from Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1998,46 (6):1001
[28]Kusano A, Takahira M, Shibano M, et al. Studies on the Constituents of Cimicifuga Species. ⅩⅩⅥ. Twelve New Cyclolanostanol Glycosides from the Underground Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1999,47 (4):511
[29]Akihisa T, Hideshima R, Koike K, et al. Cycloarta-16,24-dien-3β-ol:Revised Structure of Cimicifugenol, a Cycloartane Triterpenoid. Chem. Pharm. Bull.,1999,47 (8):1157
[30]Kusano A, Shibano M, Kusano G. Studies on the Constituents of Cimicifuga Species.ⅩⅩⅦ. Malonyl Cyclolanostanol Glycosides from the Underground Parts of Cimicifuga simplex Wormsk. Chem. Pharm. Bull.,1999,47 (8):1175
[31]刘勇,陈迪华,斯建勇,等.兴安升麻地上部分化学成分的研究.药学学报,2003,38(10)：763
[32]Shao Y, Harris A, Wang MF, et al. Triterpene Glycosides from Cimicifuga racemosa. J. Nat. Prod.,2000,63:905
[33]Sun LR, Yan J, Nian Y, et al. New Triterpene Diglycosides from the Rhizome of Cimicifuga foetida. Molecules,2008,13:1712
[34]Chen SN, Li WK, Fabricant DS, et al. Isolation, Structure Elucidation, and Absolute Configuration of 26-Deoxyactein from Cimicifuga racemosa and Clarification of Nomenclature Associated with 27-Deoxyactein. J. Nat. Prod.,2002,65:601
[35]Nishida M, Yoshimitsu H, Nohara T. Three Cycloartane Glycosides from Cimicifuga Rhizome and Their Immunosuppressive Activities in Mouse Allogeneic Mixed Lymphocyte Reaction. Chem. Pharm. Bull.,2003,51 (3):354
[36]Nishida M, Yoshimitsu H, Nohara T. Two New Tetranor-Cycloartane Glycosides from Cimicifuga Rhizome. Chem. Pharm. Bull.,2003,51 (9):1117
[37]Nishida M, Yoshimitsu H, Okawa M, et al. Two New 15,16-Seco-cycloartane Glycosides from Cimicifuga Rhizome. Chem. Pharm. Bull.,2003,51 (10):1215
[38]Dan C, Wang R, Peng SL, et al. Two New Acetyl Cimicifugosides from the Rhizomes of Cimicifuga Racemosa. Chinese Chemical Letters,2006,17 (3):347
[39]Yoshimitsu H, Nishida M, Sakaguchi M, et al. Two New 15-Deoxycimigenol-Type and Three New 24-epi-Cimigenol-Type Glycosides from Cimicifugae Rhizoma. Chem. Pharm. Bull., 2006,54(9):1322
[40]Yoshimitsu H, Nishida M, Nohara T. Three New 15,16-Seco-cycloartane Glycosides from Cimicifuga Rhizome. Chem. Pharm. Bull.,2007,55 (5):789
[41]刘勇.兴安升麻地上部分化学成分研究及抗骨质疏松活性筛选.[博士学位论文].北京：中国协和医科大学,2003年,
[42]张庆文,叶文才,车镇涛,等.小升麻中的环菠萝蜜烷型三萜及其糖苷成分.药学学报,2001,36(4)：287
[43]潘瑞乐,陈迪华,斯建勇,等.升麻地上部分皂苷类成分研究.药学学报,2002,37(2)：11 7
[44]赵晓宏,陈迪华,斯建勇,等.中药升麻酚酸类化学成分研究.药学学报,2002,37(7)：535-538
[45]Takahira M, Kusano A, Shibano M, et al. Piscidic Acid and Fukiic Acid Esters from Cimicifuga simplex. Phytochemistry,1998,49 (7):2115
[46]Iwanaga A, Kusano G, Warashina T, et al. Phenolic Constituents of the Aerial Parts of Cimicifuga simplex and Cimicifuga japonica. J. Nat. Prod.,2010,65:601
[47]Ito M, Kondo Y, Takemot T. Spasmolytic Substances from Cimicifuga dahurica MAXIM. Chem. Pharm. Bull.,1976,24 (4):580
[48]李从军,陈迪华,肖培根,等.中药升麻的化学成分V.中草药,1995,26(6)：288
[49]Kusano G., Hojo S, Kondo Y, Takemoto T. Studies on the Constituents of Cimicifuga spp. Ⅷ. Structure of cimicifugoside. Chem. Pharm. Bull.,1977,25 (12):3182
[50]H Hemmi, F Kitame, N Ishida, G Kusano, Y Kondo, S Nozoe. Inhibition of thymidine transport into phytohemagglutinin-stimulated lymphocytes by triterpenoids fro Cimicifuga species. J. Pharm. Dyn.1979,2:339
[5]]林新,蔡有余,肖培根.兴安升麻皂甙体外SIV抑制作用及其机制.华西药学杂志,1994, 9 (4):221-224
[52]F Borrelli, A A Izzo, E Ernst. Pharmacological effects of Cimicifuga racemosa. Life Sciences, 2003,73(10):1215-1229
[53]Gabor Vermes, Ferenc Banhidy, NandorAcs. The Effects of Remifemin on Subjective Symptoms of Menopause. Advance in Therapy,2005,22 (2):148
[54]自文佩,王淑玉,刘建立,耿力,胡丽娜,张忠兰,陈淑玲,郑淑蓉.莉芙敏片与替勃龙改善围绝经期症状的效果和安全性比较.中华妇产科杂志,2009,44(8)：597-600
[55]李建新,门田重利.升麻三萜类化合物的抗骨质疏松活性.《药用植物研究与中药现代化——第四届全国药用植物学与植物药学术研讨会论文集》2004年,197-199
[56]D. Seidlova-Wuttke, H. Jarry, T. Becker, V. Christoffel, W. Wuttke. Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats:bone, fat and uterus. Maturitas,2003,44(S1): S39-S50,
[57]Thomas Niblein, Johannes Freudenstein. Effects of an isopropanolic extract of Cimicifuga racemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J. Bone Miner. Metab.2003,21:370-376
[58]刘培淑,李霞,刘媛,毛洪鸾,孙玉兰.希明婷片治疗女性围绝经期综合征的临床研究.山东大学学报(医学版),2008,46(8)：791-794
[59]张丹,徐克惠,段秀蓉.希明婷片治疗妇女围绝经期综合征的临床观察.现代妇产科进展,2006,15(12)：934-936
[60]张春燕,杨钟莉.希明婷片对卵巢功能低下所致骨质疏松症的疗效观察.中国医师进修杂志,2011,34(21)：4-6
[61]薛赛琴,姜坤,张琼.希明婷片治疗女性更年期综合征364例.中国中西医结合杂志,2006,62(10)：891
[62]潘瑞乐,陈迪华,斯建勇,赵晓宏,朱古军.反相高效液像色谱法测定不同品种升麻中27-脱氧升麻亭的含量.中南药学,2007,5(3)：206-20
[63]姚梅芬,王岳峰,李展,潘瑞乐,赵晓宏,斯建勇.反相高效液相色谱法测定升麻药材中升麻苷H-1的含量.天然产物研究与开发,2011,23：696-699
[64]中华人民共和国生部药典委员会.中国药典(一部)1963年版.北京,人民卫生出版社,1963年,54-55
[65]中华人民共和国卫生部药典委员会.中国药典(一部)1977年版.北京,人民卫生出版 社,1978年,110
[66]中华人民共和国卫生部药典委员会.中国药典(一部)1985年版.北京,人民卫生出版社,1985年,56
[67]国家药典委员会.中国药典(一部)2000年版.北京,化学工业出版社,2000年,55
[68]国家药典委员会.中国药典(一部)2005年版.北京,化学工业出版社,2005年,50
[69]潘瑞乐,陈迪华,沈连刚,斯建勇.高效液相色谱法测定中药升麻中阿魏酸和异阿魏酸的含量.药物分析杂志,2000,20(6)：396-399
[70]司丹丹,李清,陈晓辉,康莉,冯毅,毕开顺.RP-HPLC法同时测定升麻中3种有机酸的含量.沈阳药科大学学报,2007,24(12)：727-731
[71]梁逸曾,俞汝勤编著.化学计量学.北京：高等教育出版社,2003
[72]梁逸曾,吴海龙,俞汝勤.化学计量学.现代科学仪器,1998,5：3-6
[73]Eriksson L, Hermens J L M. Chemometrics in Environmental Chemistry-Applications, Vol.2, Part H. Springer-Verlag, Berlin, Heidelberg,1995,135-169
[74]王惠文,吴载斌,孟洁.偏最小二乘回归的线性与非线性方法.北京：国防工业出版社,2006
[75]White H. Artificial neural networks:approximation and learning theory. Blackwell Publishers. USA,1992
[76]鞠建华,刘东,杨峻山.天然环菠萝蜜烷型三萜皂苷类化合物的波谱学规律的探讨.波谱学杂志,2001,18(1)：79-90
[77]The United States Pharmacopeial Convention Inc. The United States Pharmacopoeia.29th 1997:56
[1]Gund P. Three-dimensional pharmacophoric pattern searching. Prog Mol Subcell Biol.1977, 5:117
[2]Langer T, Wolber G, Pharmacophore definition and 3D searches. Drug Discovery Today: Technologies.2004,1(3):203
[3]Copeland R A. Conformational adaptation in drug-target interactions and residence time. Future Med. Chem.2011,3(12):1491
[4]Attia M I, Giiclii D, Hertlein B, et al. Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a]diindole analogues as melatonin receptor ligands. Org. Biomol. Chem.,2007,5:2129
[5]Lucyk S, Taha H, Yamamoto H, et al. NMR conformational analysis of proadrenomedullin N-terminal 20 peptide, a proangiogenic factor involved in tumor growth. Biopolymers,2006, 81 (4):295
[6]Biftu T, Gambel N F, Doebber T, el al. Conformation and activity of tetrahydrofuran lignans and analogues as specific platelet activating factor antagonists. J. Med. Chem.1986,29 (10): 1917
[7]Perez-Hernandez N, Morales-Rios, Cerda-Garcia-Rojas C M, et al. Conformational evaluation and detailed 1H and 13C NMR assignments of flavoxate, a urinary tract antispasmodic agent. JPBA.2006,41:603
[8]Amodeo P, Naider F, Picone D, et al. Conformational sampling of bioactive conformers:a low-temperature NMR study of 15N-leu-enkephalin. J. Peptide Sci.1998,4:253
[9]Smith A B, LaMarche M J, Falcone-Hindley M. Solution Structure of (+)-discodermolide. Org. Lett.2001,3 (5):695
[10]Gaggelli E, Marchettini N, Valensin G.1H and 13C NMR conformational analysis in solution of isoproterenol a pure β-agonist drug. Magn. Reson. Chem.1987,25 (11):970
[11]Li F, Wang L, Xiao N, et al. Dominant conformation of valsartan in sodium dodecyl sulfate micelle environment. J. Phys. Chem.2010,114:2719
[12]Li F, Zhang H, Jiang L, et al. Dynamic NMR study and theoretical calculations on the conformational exchange of valsartan and related compouns. Magn. Reson. Chem.2007,45: 929
[13]Potamitis C, Zervou M, Katsiaras V, et al. Antihypertensive drug valsartan in solution and at the AT1 receptor:conformational analysis, dynamic NMR spectroscopy, in silico docking, and molecular dynamics simulations. J. Chem. Inf. Model.2009,49:726
[14]Saran A, Srivastava S, Coutinho E. Conformation and macromolecular interaction of ACE inhibitors enalapril and lisinopril by NMR. Eur. J. Pharm. Sci.1994,1:181
[15]Hannongbua S, Prasithichokekul S, Pungpo P. Conformational analysis of nevirapine, a non-nucleoside HIV-1 reverse transcriptase inhibitor, based on quantum mechanical calculations. J Comput Aid Mol Des.2001,15:997-1004
[16]Branca M, Alezra V, Kouklovsky C, et al. Accurate conformation analysis in solution:NMR and DFT/PCM study of the S-3-(1-naphthoyl)-4-isopropyl-2,2-dimethyloxazolidin-5-one in CDCl3. Tetrahedron.2008,50:1-10
[17]Fragaki G, Stefanaki I, Dais P, et al. Conformational properties of the macrocyclic trichothecene mycotoxin verrucarin A in solution. Magn Reson Chem.2008,46:1102-1111
[18]Tousek J, Malinakova K, Dostal J. et al. Theoretical and experimental NMR study of protopine hydrochloride isomers. Magn Reson Chem.2005,43:578-581
[19]Dutrey-Dupagne C, Girard A, Ulmann A, et al. Effects of the converting enzyme inhibitor trandolapril on short-term variability of blood pressure in essential hypertension. Clin. Auton. Res.1991,1(4):303
[20]Diaz A, Ducharme A. Update on the use of trandolapril in the management of cardiovascular disorders Vase. Health Risk Manag.2008,4 (6):1147
[21]上雯估,刘皋林.群多普利在心血.管疾病中的应用.2000,27(1)：24
[22]Venturini M. Rational development of capecitabine. Eur. J. Cancer.2002,38:S3-S9
[23]Dooley M, Goa K L. Capecitabine. Drugs.1999,58 (1):69-76
[24]Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (Capecitabine, UFT, S-1):a review. Oncologist,2002,7:288
[25]Koukourakis G V, Kouloulias V, Koukourakis M J, el al. Efficacy of the oral fluorouracil pro-drug capecitabine in cancer treatment:a review. Molecules.2008,13:1897-1922
[26]Stewart W E, Siddall T H. Nuclear magnetic resonance studies of amides. Chem. Rev.1970, 70(5):517
[27]Insight Ⅱ 2000, San Diego:MSI Biosym.,2000
[28]Frisch M J, Trucks G W, Schlegel H B, et. al. Gaussian 03 Revision E.01, Gaussian Inc., Pittsburgh, PA,2003
[29]Frisch M J, Trucks G W, Schlegel H B, et al. Gaussian 09, Revision C.01, Gaussian, Inc., Wallingford CT,2010
[30]Kemnitz C R, Loewen M J. "Amide resonance" correlates with a breadth of C-N rotation barriers. J. Am. Chem. Soc.2007,129:2521
[31]Venturini M. Rational development of capecitabine. Eur. J. Cancer.2002,38:S3
[32]Malet-Martino M, Martino R. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1):a review. Oncologist,2002,7:288
[33]Costanzo F D, Sdrobolini A, Gasperoni S. Capecitabine, a new oral fluoropyrimidine for the treatment of coloectal cancer. Crit. Rev. Oncol. Hemat.2000,35:101-108
[34]Shimma N, Okabe H, Ishitsuka H. Discovery of capecitabine, a rationally designed and tumor-activated oral prodrug of 5-FU, and beyond. CH/MIA,2008,62:928
[35]Modarresi-Alamo A R, Najafi P, Rostamizadeh M, et al. Dynamic 1H NMR study of the barrier to rotation about the C-N bond in primary carbamates and its solvent dependence. J. Org. Chem.,2007,72:2208
[36]Deetz M J, Forbes C C, Jonas M, et al. Unusually low barrier to carbamate C-N rotation. J. Org. Chem.2002,67:3949
[37]Rohlicek J, Husak M, Gavenda A, et al. Capecitabine from X-ray powder synchrotron data Acta Cryst.2009, E65:1325
[38]Moraczewski A L, Banaszynski L A, From A M, et al. Using hydrogen bonding to control carbamate C-N rotamer equilibria. J. Org. Chem. 1998,63:7258
[39]Fliszar S, Cardinal G, Beraldin M T. Charge Distributions and Chemical Effects.30. Relationships between Nuclear Magnetic Resonance Shifts and Atomic Charges. J. Am. Chem. Soc.1982,104:5287
[1]Bloch F, Hansen W W, Pachard M. Nuclear induction. Phys. Rev.1946,69:127
[2]Purcell E M, Torrey H C, Pound R V. Resonance absorption by nuclear magnetic moments in a solid. Phys. Rev.1946,69:37
[3]Claridge T D W. High-resolution NMR techniques in organic chemistry (2nd Ed). Elsevier, UK,2009
[4]Dingley A J. Pascal S M. Biomolecular NMR spectroscopy. IOS Press, Netherlands,2011
[5]Lees M. Food Authenticity and Traceability. Woodhead Publishing Ltd, UK,2003
[6]Barbotin J N, Portais J C. NMR in microbiology:theory and application. Horizon Scientific Press, UK,2000
[7]Holzgrabe U. Wawer I. Diehl B. NMR spectroscopy in pharmaceutical analysis. Elsevier, UK, 2008
[8]Holzgrabe U. Wawer I. Diehl B. NMR spectroscopy in drug development and analysis. Wiley Press. Germany,1999
[9]Lian L Y. Roberts G. Protein NMR Spectroscopy:Practical Techniques and Applications. Wiley Press. UK.2011
[10]Keun H C. Metabonomic modeling of drug toxicity. Pharmacology & Therapeutics,2006, 109:92-106
[11]Kubeczka K. H, Formacek V. Essential oils:analysis by capillary gas chromatography and carbon 13-NMR spectroscopy. London:John Wiley & Sons Ltd.; 1980
[12]梁逸曾,俞汝勤编著.《化学计量学》北京：高度教育出版社,2003
[13]秦海林,尚玉俊,赵伟,等.核磁共振氢谱法鉴别黄连的研究.中草药,2000,31(1)：48
[14]聂映,姚卫峰,沈文斌.厚朴的1H-NMR指纹图谱研究.2008,40(11)：91
[15]时新刚,李淑娥,孙庆雷,等.北沙参的1H-NMR指纹纹图谱研究.山东科学,2009,22(3)：24
(16]于思宏,金香淑,姚艳红,等.野生和栽培高山红景天的核磁共振指纹图谱的研究,延边大学学报,2001,27(4)：274
[17]秦海林,赵天增,袁卫梅,等.虎杖、何首乌和掌叶大黄、唐古特大黄的1H NMR指纹 图解析.药学学报,1999,34(11)：828
[18]祝贺,袁延强,孙庆雷,等.丹参的13C-NMR旨纹图谱研究.亚太传统医药,2008,4(10)：21
[19]孙庆雷,林云良,祝贺,等.黄芩的13C-NMR指纹图潜研究.波谱学杂志,2008,25(4)：486
[20]孙庆雷,林云良,王晓,等.金银花的13C-NMR指纹图谱研究.波谱学杂志,2006,23(2)：181
[21]Nicholson J K, Lindon J C, Holmes E. "Metabonomics":understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica,1999,29 (11):1181
[22]Lindon J C, Holmes E, Nicholson J K. Pattern recognition methods and applications in biomedical magnetic resonance. Prog. Nucl. Mag. Res. Sp.2001,39:1-40
[23]Nicholson J K, Wilson I D. Understanding "Golbal" systems biology:metabonomics and the continuum of metabolism. Nature, Drug Discovery.2003,2 (8):668
[24]Theodoridis S, Koutroumbas K. Pattern Recognition. Academic Press. USA,2008
[25]Eriksson L, Hermens J L M. Chemometrics in Environmental Chemistry-Applications, Vol.2, Part H. Springer-Verlag, Berlin, Heidelberg,1995
[26]Trygg J, Holmes E, Lundstedt T. Chemometrics in metabonomics. J Proteome Res.2007,6: 469
[27]Griffin J L. Metabonomics:NMR spectroscopy and pattern recognition analysis of body fluids and tissues for characterization of xenobiotic toxicity and disease diagnosis. Curr. Opin. Chem. Biol.2003,7 (5):648-654
[28]Lindon J C, Holmes E, Nicholson J K. Toxicological applications of magnetic resonance. Prog. Nucl. Mag. Res. Sp.2004,45:109-143
[29]Dumas M, Maibaum E C, Teague C, et al. Assessment of analytical reproducibility of 1H NMR spectroscopy based metabonomics for large-scale epidemiological research:the INTERMAP study. Anal. Chem.2006,78:2199
[30]Robosky L C, Robertson D G, Baker J D, et al. In vivo toxicity screening programs using metabonomics. Comb Chem High T Scr.2002,5:651
[31]Verpoorte R, Choi Y H, Kim H K. NMR-based metabolomics at work in phytochemistry. Phytochem. Rev.2007,6:3
[32]Kooy F V D, Maltese F, Choi Y H, et al. Quality control of herbal material and phytopharmaceuticals with MS and NMR based metabolic fingerprinting. Planta Med.2009, 75:763-775
[33]Ward J L, Baker J M, Beale M H. Recent applications of NMR spectroscopy in plant metabolomics. FEBS Journal,2007,274:1126-1131
[34]Chan K. Generating finger printing from analytical techniques alone is not enough in assurance for quality, efficacy and safety of Chinese medicinal herbs and herbal products. Analytical Sciences,2001,17S:409-412
[35]Skin Y S, Bang K H, In D S, et al. Finerprinting analysis of fresh ginseng roots of different ages using 1H-NMR spectroscopy and principal component analysis. Arch. Pharm. Res.2007, 30(12):1625-1628
[36]Yang S O, Shin Y S, Hyum S H, et al. NMR-based metabolic profiling and differentiation of ginseng roots according to cultivation ages. J Pharm. Bio. Anal.2012,58:19-26
[37]Whang W K, Lee M W, Choi H K. Metabolic discrimination of safflower petals of various origins using 1H NMR spectroscopy and multivariate statistical analysis. Bull. Korean Chem. Soc.2007,28 (4):557-560
[38]Bailey N J C, Sampson J, Hylands P J, et al. Multi-component metabolic classification of commercial feverfew preparations via high-field'H-NMR spectroscopy and chemometrics. Plant a Med.2002,68:734-738
[39]Rasmussen B, Cloarec O, Tang H, et al. Multivariate analysis of integrated and full-resolution 1H-NMR spectral data from complex pharmaceutical preparations:St. John's Wort. Planta Med.2006,72:556-563
[401 Lin W N, Lu H Y, Lee M S, et al. Evaluation of the cultivation age of dried ginseng radix and its commercial products by using 1H-NMR fingerprint analysis. Am. J. Chin. Med.2010,38 (1):205-218
[41]Wang Y, Tang H, Nicholson J K, et al. Metabolomis strategy for the classification and quality control of phytomedicine:a case study of chamomile flower (Matricaria recutita L.). Planta Med.2004,70:250-255
[42]Xiao C, Dai H, Liu H, et al. Revealing the Metabonomic Variation of Rosemary Extracts Using 1H NMR Spectroscopy and Multivariate Data Analysis. J. Agric. Food Chem.2008,56 (21):10142-10153
[43]Watson D G, Peyfoon E, Zheng L, et al. Application of principal components analysis to 1H-NMR data obtained from propolis samples of different geographical origin. Phytochem Anal.2006,17:323
[44]谭小燕,罗乔奇,马郑红,等.不同产地麦冬1H-NMR模式识别研究.中草药,2009,40(5)：792-797
[45]王丽.沙棘的氧核磁共振图谱-多元统计分析研究.[硕士学位论文].成都：四川大学,2007
[46]朱芸.(1)辛苓颗粒氢核磁共振-模式识别研究；(2)九管血地下部分化学成分的研究.[颁士学位论文].成都：四川大学,2007
[47]Frederich M, Jansen C, Tullio P, et al. Metabolomic analysis of Echinacea spp. by 1H nuclear magnetic resonance spectrometry and multivariate data analysis technique. Phytochem. Anal. 2010,21:61-65
[48]Frederich M, Choi Y H, Angenot L, et al. Metabolomic analysis of Strychnos mux-vomica, Strychnos icaja and Strychnos ignatii extracts by 1H nuclear magnetic resonance spectrometry and multivariate data analysis techniques. Phytochemistry,2004,65:1993-2001
[49]Choi Y H, Sertic S, Kim H Y, et al. Classification of IIex species based on metabolomic fingerprinting using nuclear magnetic resonance and multivariate data analysis. J. Agric. Food Chem.2005,53:1237-1245
[50]Kim H K, Choi Y H, Erkelens C, et al. Metabolic fingerprinting of Ephedra species using 1H-NMR spectroscopy and principal component analysis. Chem. Pharm. Bull.2005,53 (1): 105-109
[51]Ward J L, Harris C, Lewis J, et al. Assessment of 1H NMR spectroscopy and multivariate analysis as a technique fro metabolite fingerprinting of Arabidopsis thaliana. Phytochemistry. 2003,62:949-957
[52]Nord L I, Kenne L, Jacobsson S P. Multivariate analysis of 1H-NMR spectra for saponins from Quillaja saponaria Molina. Analytica Chimica Acta.2001,446:199-209
[53]Alcantara G B, Honda N K, Ferreira M M C, et al. Chemometric analysis applied in 1H HR-MAS NMR and FT-IR data for chemotaxonornic distinction of intact lichen samples. Analytica Chimica Acta.2007,595:3-8
[54]Choi H, Choi Y H, Verberne M, et al. Metabolic fingerprinting of wild type and transgenic tobacco plants by 1H NMR and multivariate analysis technique. Phytochemistry.2004,65 (7): 857-864
[55]Choi Y H, Kim H K, Hazekamp A, et al. Metabolomic differentiation of Cannabis sativa cultivars using 1H NMR spectroscopy and principal component analysis. J. Nat. Prod.2004, 67:953-957
[56]Choi Y H, Tapias E C, Kim H K, et al. Metabolic discrimination of Catharanthus roseus eaves infected by phytoplasma using 1H-NMR spectroscopy and multivariate data analysis. American Society of Plant Biologists.2004,135 (4):2398-2410
[57]Cevallos-Cevallos J M, Reyes-De-Corcuera J I, Danyluk M D, et al. Metabolomic analysis in food science:a review. Trends Food Sci Tech.2009,20:557
[58]Arvanitoyannis I S, Vaitsi O B. A Review on Tomato Authenticity:Quality Control Methods in Conjunction with Multivariate Analysis (Chemometrics) Crit Rev Food Sci.2007,47:675
[59]Choi H K, Choi Y H, Verberne M, et al. Metabolic fingerprinting of wild type transgenic tobacco plants by'H NMR and multivariate analysis technique. Phytochemistry.2004,65: 857-864
[60]Alonso-Salces R M, Heberger K, Holland M V, et al. Multivariate analysis of NMR fingerprint of the unsaponifiable fraction of virgin olive oils for authentication purposes. Food Chemistry.2010,118:956-965
[61]Spraul M, Schutz B, Humpfer E, et al. Mixture analysis by NMR as applied to fruit juice quality control. Magn. Reson. Chem.2009,47:S130-S137
[62]Duarte I F, Barros A, Almeida C, et al. Multivariate analysis of NMR and FTIR data as a potential tool for the quality control of beer. J. Agric. Food Chem.2004,52:1031-1038
[63]Son H, Hwang G, Kim K M, et al. Metabolomic studies on geographical grapes and their wines using 1H-NMR analysis coupled with multivariate statistics. J. Agric. Food Chem. 2009,57:1481-1490
[64]Charlton A J, Farrington W H H, Brereton P. Application of'H NMR and multivariate statistics for screening complex mixtures:quality control and authenticity of instant coffee.J. Agric. Food Chem.2002,50:3098-3103
[65]Tarachiwin L, Masako O, Fukusaki E. Quality evaluation and prediction of Cirullus lanatus by 1H NMR-based metabolomics and multivariate analysis. J. Agric. Food Chem.2008,56: 5827-5835
[66]Fujiwara M, Ando I, Arifuku K. Multivariate analysis for'H-NMR spectra of two hundred kinds of tea in the world. Anal. Sci.2006,22 (10):1307-1314
[67]Rezzi S, Giani I, Heberger K, et al. Classification of Gilthead Sea Bream (Sparus aurata) from 1H NMR lipid profiling combined with principal component and linear discriminant analysis. J. Agric. Food Chem.,2007,55 (24):9963-9968
[68]Sacco D, Brescia M A, Buccolieri A, et al. Geographical origin and breed discrimination of Apulian lamb meat samples by means of analytical and spectroscopic determinations. Meat Science.2005,71:542-548
[69]Shintu L, Caldarelli S. High-resolution MAS NMR and chemometrics:characterization of the ripening of Parmigiano Reggiano cheese. J. Agr. Food Chem.2005,53 (10):4026-4031
[70]Shintu L, Caldarelli S, Franke B M. Pre-selection of potential molecular markers for the geographic origin of dried beef by HR-MAS NMR spectroscopy. Meat Science.2007,76 (4): 700-707
[71]Nicholson J K. Metabonomics:a generic platform for the investigation of drug toxicity, altered gene function and disease processes. Drug Discover World Summer.2004,23-28