几种中药材的化学成分及其定性定量检测方法研究
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摘要
本论文由四部分组成。第一部分报道了藏药佛手参的化学成分研究，建立了该药材活性成分的高效液相含量测定方法，进行了高效液相指纹图谱的探索，并采用液质联用技术鉴定了药材提取物的主要色谱峰；第二部分报道了中药丹参及其复方制剂的特征图谱研究；第三部分探讨了中药两面针生物碱的电喷雾质谱裂解规律，并采用液质联用技术分离鉴定了该药材提取物中的多种生物碱。第四部分为综述，概述了液质联用在药物代谢研究中的运用。
第一部分包括第一、第二和第三章。第一章针对佛手参(Gymnadenia conopsea)块茎的甲醇提取物，采用大孔吸附树脂和反相硅胶柱层析等各种分离方法，首次从佛手参中分离纯化出4个琥珀酸葡萄糖苷类化合物，通过波谱分析将它们的结构分别鉴定为dactylorhin B(1)、loroglossin(2)、dactylorhin A(3)和militarine(4)。第二章采用高效液相色谱法对西藏、四川、河北、青海和尼泊尔等不同地区产的十个佛手参样品进行腺嘌呤核苷和对羟基苯甲醇的定量分析，结果表明这2个成份的共同出现可视为鉴定佛手参药材的成分特征，但也注意到产地不同这2个特征成分的含量也有所不同。第三章采用标准中药指纹图谱相似度计算软件，以不同产地的10个佛手参样品HPLC图谱的平均值为相似性评价对照模板，对它们进行了相似度评价。此外，经液质联用分析指认了7个共有峰，其结构分别为腺嘌呤核苷(1)、对羟基苯甲醇(2)、对羟基苯甲醛(3)、dactylorhin B(4)、loroglossin(5)、dactylorhin A(6)和militarine(7)。
第二部分包括第四、第五、第六和第七章。第四章运用电喷雾质谱检测了对照药材和五个不同产地的丹参药材中脂溶性和水溶性成分，系统地探讨了多种成分的电喷雾质谱规律，并以对照药材为标准建立了特征指纹图谱。五个产地的药材通过与对照药材相对比，采用聚类分析的方法，得到了定性的鉴别与判断。此外，采用液质联用技术对丹参药材提取液中的化学成份进行分析，推测了九个特征峰，并对六样品的液相色谱图进行了聚类分析。第五章探讨了三七皂苷的电喷雾质谱电离和裂解规律，并采用电喷雾质谱法对三七标准药材以及血通片中的皂苷成分进行了分析。第六章运用电喷雾质谱研究复方丹参片提取液的特征图谱，并和单味药材丹参和三七的特征图谱进行了对比研究，并运用HPLC-ESI MS~n分析鉴定了复方丹参片提取液中的化学成分，推测出12个色谱峰所对应化学成份的结构。第七章总结了电喷雾质谱和液质联用技术在分析丹参药材、三七药材及复方丹参制剂中的运用应用情况以及其优势和局限性。
第三部分(第八章)研究了两面针生物碱中二氢白屈菜红碱(1)、二氢两面针碱(2)、8-酮基二氢白屈菜红碱(3)、8-丙酮基二氢两面针碱(4)、两面针碱(5)、和1，3-二(8-二氢两面针碱)丙酮(6)等六个苯并菲啶型生物碱的电喷雾质谱裂解规律，其中二氢两面针碱和二氢白屈菜红碱，8-丙酮基二氢两面针碱和8-酮基二氢白屈菜红碱是两对二个甲氧基分别在C-9和C-10，C-10和C-11的同分异构体。实验结果表明，在相同的碰撞能下，这类位置异构体的ESI-MS~2质谱二级碎片离子的相对丰度存在很大差异，这可以用于区分该类同分异构体。受此提示，我们采用液-质联用成功地对两面针总生物碱提取物中的这些同分异构体加于区分，并通过与对照品的保留时间、紫外吸收光谱及质谱图对照，共鉴定出11个主要色谱峰。
第四部分(第九章)是针对液质联用技术在药物代谢中的运用进行了综述。
This dissertation consisted of four sections. The first two sections elaborated the phytochemical investigation of the rhizomes Gymnadenia conopsea R. Br., method development for rapid identifying and qutifying the chemical condtituent of this tibetant medicine, and the chemical fingerprint analysis of rhizomes of G. conopsea, Salviae miltiorrhiza and P. notoginseng. The third section studied the fragmentation mechanism of six alkaloids from Zanthoxylum nitidium and method development for rapid identifying varieties of alkaloids from the extract of this herbal medicine. The fourth section reviewed HPLC-MS method in drug metabolism studies.
The first section consisted of chapters 1, 2 and 3. Chapter 1 elaborated the phytochemical investigation of G conopsea. Four succinate derivative esters were isolated from the methanol extract of the rhizomes of G. conopsea through repeated column chromatography on normal and reversed phase silica gel, their structures were determined by ESI-MS, 1D and 2D NMR evidence. They were firstly discovered from this species. In chapter 2, a high-performance liquid chromatography-diode array detection (HPLC-DAD) method has been firstly developed for quantitation of two characteristic constituents, adenosine and 4-hydroxybenzyl alcohol, from the extract of rhizomes of G conopsea. All 10 samples of G. conopsea contained different amount of adenosine and 4-hydroxybenzyl alcohol. Adenosine and the 4-hydroxybenzyl alcohol can be applied in identification and quality control for the roots of G. conopsea. In chapter 3, a high-performance liquid chromatography-diode array detection-tandem mass spectrometry (HPLC-DAD-MS~n) method has been firstly developed for chemical fingerprint analysis of rhizomes of G. conopsea and rapid identification of major compounds in the fingerprints. Comparing the UV and MS spectra with those of authentic compounds, seven main peaks in the fingerprints were identified as adenosine, 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde, dactylorhin B, loroglossin, dactylorhin A and militarine. The Computer Aided Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (CASES) was employed to evaluate the similarities of 10 samples of the rhizomes of G. conopsea collected from Sichuan, Qinghai and Hebei provinces and Tibet autonomous region of China, and Nepal. These samples from different sources had similar chemical fingerprints to each other.
The second section consisted of chapters 4, 5, 6 and 7. In chapter 4, both the characteristic spectra of liposoluble tanshinones and aqueous-soluble salvianolic acids were established by the electrospray ionization mass spectrometry (ESI-MS) technique and the differences between standard and crude rhizomes of S. miltiorrhiza from 5 sources were analyzed. The law of electrospray ion trap mass (ESI-ITMS) of typical tanshinones and salvianolic acids is studied.
The analysis of the chemical constituent of rhizomes of S. miltiorrhiza by liquid chromatography coupled with mass spectrum (LC/MS) technique was established, and the distances among standard herb and crude herb from 5 sources were calculated by clustering analysis. According the DAD spectra and MS~2 data, 9 tanshinones could be speculated. In chapter 5, the character spectra of total saponins in P. notoginseng extracts were established by ESI ITMS and selective ion monitoring (SIM) technology. The law of notoginsenosides by ESI-MS~2 was studied. In chapter 6, the characteristic spectra of Compound Danshen Tablet established and compared by ESI-MS and HPLC/DAD/MS, 6 known tanshinones and 3 saponins were speculated. In chapter 7, the advantage and disadvantage of the strategy, using the ESI-ITMS and LC/MS techniques for study of characteristic spetra of danshen and Compound Danshen Tablet, were summerized.
The third section (chapter 8) studied the fragmentation mechanism of six alkaloids, dihydronitidine, dihydrochelerythrine, 8-acetonyl dihydronitidine, 8-acetonyldrochelerythrine, nitidine and l,3-bis(8-dihydronitidinyl)-acetone, by ESI-MS~n. Tandem mass spectrometry experiments indicated that different substitution sites of the methoxyl groups at C-9 and C-10 or at C-10 and C-11 determined the different abundances of the MS~2 fragmentation ions using the same collision energy. According to the different abundances of MS~2 product ions, positional isomeric benzo[c] phenanthridine alkaloids can be differentiated. Moreover, ten constituents in the crude alkaloids extract from the roots of Z. nitidium were rapidly identified by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS~n), through comparing the retention times and ESI-MS~n spectra with the authentic standards.
The fourth section (chapter 9) is a review on HPLC-MS method development in drug metabolism studies.
第一部分包括第一、第二和第三章。第一章针对佛手参(Gymnadenia conopsea)块茎的甲醇提取物，采用大孔吸附树脂和反相硅胶柱层析等各种分离方法，首次从佛手参中分离纯化出4个琥珀酸葡萄糖苷类化合物，通过波谱分析将它们的结构分别鉴定为dactylorhin B(1)、loroglossin(2)、dactylorhin A(3)和militarine(4)。第二章采用高效液相色谱法对西藏、四川、河北、青海和尼泊尔等不同地区产的十个佛手参样品进行腺嘌呤核苷和对羟基苯甲醇的定量分析，结果表明这2个成份的共同出现可视为鉴定佛手参药材的成分特征，但也注意到产地不同这2个特征成分的含量也有所不同。第三章采用标准中药指纹图谱相似度计算软件，以不同产地的10个佛手参样品HPLC图谱的平均值为相似性评价对照模板，对它们进行了相似度评价。此外，经液质联用分析指认了7个共有峰，其结构分别为腺嘌呤核苷(1)、对羟基苯甲醇(2)、对羟基苯甲醛(3)、dactylorhin B(4)、loroglossin(5)、dactylorhin A(6)和militarine(7)。
第二部分包括第四、第五、第六和第七章。第四章运用电喷雾质谱检测了对照药材和五个不同产地的丹参药材中脂溶性和水溶性成分，系统地探讨了多种成分的电喷雾质谱规律，并以对照药材为标准建立了特征指纹图谱。五个产地的药材通过与对照药材相对比，采用聚类分析的方法，得到了定性的鉴别与判断。此外，采用液质联用技术对丹参药材提取液中的化学成份进行分析，推测了九个特征峰，并对六样品的液相色谱图进行了聚类分析。第五章探讨了三七皂苷的电喷雾质谱电离和裂解规律，并采用电喷雾质谱法对三七标准药材以及血通片中的皂苷成分进行了分析。第六章运用电喷雾质谱研究复方丹参片提取液的特征图谱，并和单味药材丹参和三七的特征图谱进行了对比研究，并运用HPLC-ESI MS~n分析鉴定了复方丹参片提取液中的化学成分，推测出12个色谱峰所对应化学成份的结构。第七章总结了电喷雾质谱和液质联用技术在分析丹参药材、三七药材及复方丹参制剂中的运用应用情况以及其优势和局限性。
第三部分(第八章)研究了两面针生物碱中二氢白屈菜红碱(1)、二氢两面针碱(2)、8-酮基二氢白屈菜红碱(3)、8-丙酮基二氢两面针碱(4)、两面针碱(5)、和1，3-二(8-二氢两面针碱)丙酮(6)等六个苯并菲啶型生物碱的电喷雾质谱裂解规律，其中二氢两面针碱和二氢白屈菜红碱，8-丙酮基二氢两面针碱和8-酮基二氢白屈菜红碱是两对二个甲氧基分别在C-9和C-10，C-10和C-11的同分异构体。实验结果表明，在相同的碰撞能下，这类位置异构体的ESI-MS~2质谱二级碎片离子的相对丰度存在很大差异，这可以用于区分该类同分异构体。受此提示，我们采用液-质联用成功地对两面针总生物碱提取物中的这些同分异构体加于区分，并通过与对照品的保留时间、紫外吸收光谱及质谱图对照，共鉴定出11个主要色谱峰。
第四部分(第九章)是针对液质联用技术在药物代谢中的运用进行了综述。
This dissertation consisted of four sections. The first two sections elaborated the phytochemical investigation of the rhizomes Gymnadenia conopsea R. Br., method development for rapid identifying and qutifying the chemical condtituent of this tibetant medicine, and the chemical fingerprint analysis of rhizomes of G. conopsea, Salviae miltiorrhiza and P. notoginseng. The third section studied the fragmentation mechanism of six alkaloids from Zanthoxylum nitidium and method development for rapid identifying varieties of alkaloids from the extract of this herbal medicine. The fourth section reviewed HPLC-MS method in drug metabolism studies.
The first section consisted of chapters 1, 2 and 3. Chapter 1 elaborated the phytochemical investigation of G conopsea. Four succinate derivative esters were isolated from the methanol extract of the rhizomes of G. conopsea through repeated column chromatography on normal and reversed phase silica gel, their structures were determined by ESI-MS, 1D and 2D NMR evidence. They were firstly discovered from this species. In chapter 2, a high-performance liquid chromatography-diode array detection (HPLC-DAD) method has been firstly developed for quantitation of two characteristic constituents, adenosine and 4-hydroxybenzyl alcohol, from the extract of rhizomes of G conopsea. All 10 samples of G. conopsea contained different amount of adenosine and 4-hydroxybenzyl alcohol. Adenosine and the 4-hydroxybenzyl alcohol can be applied in identification and quality control for the roots of G. conopsea. In chapter 3, a high-performance liquid chromatography-diode array detection-tandem mass spectrometry (HPLC-DAD-MS~n) method has been firstly developed for chemical fingerprint analysis of rhizomes of G. conopsea and rapid identification of major compounds in the fingerprints. Comparing the UV and MS spectra with those of authentic compounds, seven main peaks in the fingerprints were identified as adenosine, 4-hydroxybenzyl alcohol, 4-hydroxybenzyl aldehyde, dactylorhin B, loroglossin, dactylorhin A and militarine. The Computer Aided Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine (CASES) was employed to evaluate the similarities of 10 samples of the rhizomes of G. conopsea collected from Sichuan, Qinghai and Hebei provinces and Tibet autonomous region of China, and Nepal. These samples from different sources had similar chemical fingerprints to each other.
The second section consisted of chapters 4, 5, 6 and 7. In chapter 4, both the characteristic spectra of liposoluble tanshinones and aqueous-soluble salvianolic acids were established by the electrospray ionization mass spectrometry (ESI-MS) technique and the differences between standard and crude rhizomes of S. miltiorrhiza from 5 sources were analyzed. The law of electrospray ion trap mass (ESI-ITMS) of typical tanshinones and salvianolic acids is studied.
The analysis of the chemical constituent of rhizomes of S. miltiorrhiza by liquid chromatography coupled with mass spectrum (LC/MS) technique was established, and the distances among standard herb and crude herb from 5 sources were calculated by clustering analysis. According the DAD spectra and MS~2 data, 9 tanshinones could be speculated. In chapter 5, the character spectra of total saponins in P. notoginseng extracts were established by ESI ITMS and selective ion monitoring (SIM) technology. The law of notoginsenosides by ESI-MS~2 was studied. In chapter 6, the characteristic spectra of Compound Danshen Tablet established and compared by ESI-MS and HPLC/DAD/MS, 6 known tanshinones and 3 saponins were speculated. In chapter 7, the advantage and disadvantage of the strategy, using the ESI-ITMS and LC/MS techniques for study of characteristic spetra of danshen and Compound Danshen Tablet, were summerized.
The third section (chapter 8) studied the fragmentation mechanism of six alkaloids, dihydronitidine, dihydrochelerythrine, 8-acetonyl dihydronitidine, 8-acetonyldrochelerythrine, nitidine and l,3-bis(8-dihydronitidinyl)-acetone, by ESI-MS~n. Tandem mass spectrometry experiments indicated that different substitution sites of the methoxyl groups at C-9 and C-10 or at C-10 and C-11 determined the different abundances of the MS~2 fragmentation ions using the same collision energy. According to the different abundances of MS~2 product ions, positional isomeric benzo[c] phenanthridine alkaloids can be differentiated. Moreover, ten constituents in the crude alkaloids extract from the roots of Z. nitidium were rapidly identified by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS~n), through comparing the retention times and ESI-MS~n spectra with the authentic standards.
The fourth section (chapter 9) is a review on HPLC-MS method development in drug metabolism studies.
引文
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