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新疆特色药材贝母属化学成分比较研究及其质量评价
艾则孜·莫合买提
学位类型博士
导师阿吉艾克拜尔·艾萨
2017-06-03
学位授予单位中国科学院大学
学位授予地点北京
学位专业有机化学
关键词贝母 质量评价 含量测定 异甾体类的生物碱 化学成分
摘要

摘要 贝母是百合科(Liliaceae)贝母属(Fritillaria)植物的干燥鳞茎,收载于《中国药典》(2015年版)第一部,具有清热润肺、化痰止咳、散结消痈之功效。全世界贝母属植物约有130种。主要分布在北半球的欧洲、亚洲及北美洲的温带,国内主产于四川、新疆、甘肃、安徽、湖北、浙江北部等省亦有。新疆作为我国贝母药材的主要产区。新疆贝母属植物已发表并命名的16种和21变种。伊犁贝母(F. pallidiflora)、新疆贝母(F. walujewii)、托里贝母(F. tortifolia)、裕民贝母(F. yuminensis)和砂贝母(F. karelinii )等为新疆地区分布广泛的5个特有品种。伊贝母是新疆产贝母的商品总称,为新疆贝母或伊犁贝母植物的地下干燥鳞茎。据《哈萨克斯坦植物志》记载:中亚地区分布于中亚丝绸之路一带的贝母属植物有14种。市场上贝母类药材种类繁多,外观形态相似,鉴别难度较大。由于贝母具有很高的开发价值,价格较高,市场上经常出现贝母混售或以其人工栽培充当野生贝母出售的现象,致使贝母的质量控制难度加大。为有效监管贝母质量,保证临床疗效,本文开展了不同技术对新疆贝母属植物化学成分分析及质量评价研究,其结果如下:1. 采用显微、薄层色谱、近红外光谱法,热重/差示扫描量热分析方法(TGA/DSC)等方法对不同产地贝母进行比较研究。观察到:1) 利用显微鉴别法进行鉴别,在显微镜下难以见到贝母的显微特征,所有品种主要是均呈现淀粉粒等显微特征。2)利用薄层色谱法(TLC)将各贝母药材溶液点样于同一个薄层板上,经展开,检视所得的色谱图对比,进行了定性鉴别。3)采用热重-微商热重(TG-DTG)和差示扫描量热法(DSC)对不同产地的贝母药材进行热分析研究,气氛为N2的条件下,固定反应的升温速率和温度范围,所有样品的热重(TG)和微商热重(DTG)曲线都有各自的谱图特征,其DSC曲线的峰形、峰位置和峰值也有特征,利用药材热分析图谱的差异,可以快速鉴别了不同产地的贝母药材。4)采用聚类分析、二阶倒数加矢量归一化的组合等方法结合OPUS 5.0软件,分析贝母样品的近红外光谱特征,建立可以方便地进行产地识别和药材质量检查的识别方法。2.对不同产地贝母属药材的化学成分进行了研究。1)建立超高效液相色谱-四极杆飞行时间质谱(UPLC-QTof-MS)法分析贝母的化学成分,利用UPLC-QTof-MS法从野生贝母和人工栽培贝母中分别检测到89个和83个特征峰,通过对照品比对和文献参考,推断了其中40余个生物碱类成分,且野生贝母和人工栽培贝母化学成分含量有一定差异。应用聚类分析法,可以大致将野生贝母和人工栽培贝母分开。该研究比较全面地阐明了贝母的化学组成,为此药材的质量控制和物质基础研究奠定了基础;同时测定贝母中西贝母碱苷、西贝母碱、贝母辛、伊贝母碱苷A,并比较不同来源的贝母中4种生物碱成分的含量差异。所建立的方法经方法学验证 该方法可用于贝母药材的质量控制。2)建立了一种同时测定贝母药材中尿苷、胸苷、腺苷3种核苷类化合物的含量的RP-HPLC法。经方法学验证 该方法准确可靠,并测定了新疆23批贝母药材3种化学成分的含量。3) 使用电感耦合等离子体质谱(ICP-MS)仪,建立以Sc、Ge、Bi为内标,测定贝母中Li、B、Na等21种金属元素的方法。完成了23批贝母药材中微量元素的ICP-MS进行测定,可为贝母属药材中金属元素的检测与控制提供方法参考。4)建立同时测定新疆产贝母中17种氨基酸含量的方法。采用阳离子交换色谱柱分离17种氨基酸,柱后衍生阳离子交换色谱法测定药材中17种氨基酸的含量。精密度、重复性、稳定性试验的RSD<2.0%;检测限除胱氨酸外(0.08 nmol/mL)其余氨基酸均为0.16 nmol/mL;加样回收率为98.5%~99.5%。5.HPLC-ELSD法同时测定21批贝母药材中西贝母碱苷、伊贝碱苷A、西贝母碱3种生物碱类成分的含量。在30 min内,贝母药材中的3种成分可实现完全分离。适用于贝母中活性生物碱成分含量的初步测定。 3. 基于UPLC-QTof-MS法开展了地产及部分进口贝母中化学成分比较研究。为了充分的研究新疆产贝母化学成分,本文采用基于超高效液相色谱-四极杆飞行时间质谱法分析新疆贝母属化学成分。利用UPLC-QTof-MS技术对样品进行分析,得到地产贝母和部分进口贝母的正基峰离子色谱图。测得各色谱峰的准分子离子峰的精确分子质量,应用 MassLynx 质谱分析软件计算可能的分子式,鉴定了成分。本次研究,对更好地评价贝母属药材具有重要的参考价值。为后续中亚丝绸之路这一带地区的贝母药材的开发奠定基础。

其他摘要

AbstractFritillaria is a plant of the dry bulb which is a genus of Liliaceae Fritillaria, it's contained in the the first part of Chinese Pharmacopoeia (2015 Edition), with the effect of clearing heat and moistening lung, eliminating phlegm and relieving cough, heat lungs, phlegm and cough, and eliminating carbuncle. There are about 130 species of Fritillaria in the world. Mainly distributed in the northern hemisphere of Europe, Asia and the temperate regions of North america, Domestic producted in Sichuan, Gansu, Xinjiang, Anhui, Hubei and other provinces in northern Zhejiang. Xinjiang is the main producing area of Fritillaria in China. There are 16 species and 21 varieties of the genus Fritillaria in Xinjiang. F. pallidiflora, F. walujewii, F. tortifolia, F. yuminensisand F. kareliniiwere special knids of plant in Xinjiang.A Among them, Fritillaria pallidiflora Schrek is the underground dry bulb of Fritillaria pallidiflora Schrenk or Fritillaria walujewii Regel. Fritillaria pallidiflora Schrek is the commodity name of Fritillaria in Xinjiang. In outside Xinjiang, it is distributed along the Silk Road in Central Asia. According to the records of, there are 14 species of Fritillaria in Central Asia.There are many kinds of Fritillaria in the market, they have same appearance, and it is difficult to identify. Because of the high development value of Fritillaria, the price is high, the Fritillaria is often sealed by mixed all kinds or scaled the artificial cultivation as the wild Fritillaria on the market. Mixed with the sale of Fritillaria or artificial cultivation as a phenomenon of the sale of wild Fritillaria, resulting in the difficulty of quality control. In order to effectively control the quality of Fritillaria and to ensure the clinical curative effect, In this paper, the chemical constituents and quality evaluation of Fritillaria in Xinjiang. The results are as follows: 1. Study on the Difference of Fritillaria with Different Varieties. The differences of Fritillaria were studied by microscopic, thin layer chromatography, near infrared spectroscopy, thermogravimetric/differential scanning calorimetry (TGA/DSC). Observed:1)the microscopic identification method was used to identify, and after the experiment was carried out, it was difficult to see some microscopic features under the microscope,Mainly starch and other microscopic features. 2)Thin layer chromatography (TLC) was used to identify the samples of each Fritillaria on the same thin layer plate. The chromatograms were compared and identified qualitatively. 3)The thermogravimetry (TG-DTG) and differential scanning calorimetry (DSC) thermal analysis study of Fritillaria from different habitats, the atmosphere is N2, the heating rate and the temperature range of the fixed reaction, all samples of thermogravimetry (TG) and differential thermogravimetry (DTG) the curves have spectra of their respective characteristics, the DSC curve shape, peak position and peak value have the characteristics, using the medicinal thermal analysis pattern of difference, Fritillaria can quickly identify the different habitats. 4) Cluster analysis, two order reciprocal and vector normalization combination were used to combine OPUS5 software,The near infrared spectra of Fritillaria samples were analyzed,The identification method of origin identification and quality inspection of medicinal materials can be easily established. 2. Study on Chemical Constituents of Fritillaria in Different Producing Areas. 1)The establishment of ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTof-MS) method to analyze the chemical constituents of Fritillaria. simultaneous determination of Sipeimine-3β-D-glucoside, sipeimine, peimisine,YibeinosideA contents of 4 alkaloids in Fritillaria and comparison of different sources of difference. UPLC-QTof-MS method was used to detect 89 and 83 peaks from wild and cultivated Fritillaria, through the standard comparison and reference, from which more than 40 alkaloids, there are some differences between the wild and cultivated Fritillaria ussuriensis and the content of chemical components. Using the method of cluster analysis, we can divide the wild Fritillaria and the cultivated Fritillaria. The chemical composition of Fritillaria was comprehensively elucidated in this study, which laid the foundation for the quality control and material basis study of Fritillaria. Methods the contents of the method validation of the established for the simultaneous determination of 4 alkaloids in Fritillaria, can be used for the quality control of Fritillaria. 2) A RP-HPLC method for the simultaneous determination of uridine glycosides, thymidine and adenosine nucleoside compounds in Fritillaria was established. The method was proved to be accurate and reliable, and the contents of three chemical constituents were determined. 3) The method of determination of 21 kinds of metal elements such as Li, B and Na in Fritillaria by using Sc, Ge and Bi as internal standard was established by inductively coupled plasma mass spectrometry (ICP-MS). Completed the determination of trace elements in 23 batches of Fritillaria, and can provide reference for the detection and control of metal elements in Fritillaria. 4)To establish a method of contents determination of 17 amino acids in Fritillaria in Xinjiang. Cation-exchange column was used to separate 17 kinds of amino acids,post-column derivatiza-tion liquid chromatography was used to determine the contents of amino acids.stability and reproducibility tests were lower than 2.0%, limits of detection were 0.16 nmol/mL except for cystine (0.08 nmol/mL), recovery was 98.5%-99.5%. 5)A HPLC-ELSD method was used to determine the contents of three alkaloid components of Sipeimine-3β-D-glucoside, YibeinosideA, sipeimine in 21 batches of Fritillaria. In 30 min, the three components of Fritillaria can be completely separated, a preliminary determination of the content of active alkaloids in Fritillaria. which can be used for simultaneous determination of three compounds in Fritillaria. 3. Based on the UPLC-QTof-MS method, the study on the chemical composition of real estate and some imported Fritillaria. The samples were analyzed by UPLC-QTof-MS technique to obtain the positive peak ion chromatogram of Fritillaria and some imported Fritillaria. The precise molecular mass of the excimer ion peak of each chromatographic peak was measured. The molecular formula was calculated by MassLynx mass spectrometry software. This study has an important reference value for better evaluation of Fritillaria. For the follow-up to the Silk Road in Central Asia area of the development of Fritillaria lay the foundation.

文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4974
专题资源化学研究室
作者单位中国科学院新疆理化技术研究所
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艾则孜·莫合买提. 新疆特色药材贝母属化学成分比较研究及其质量评价[D]. 北京. 中国科学院大学,2017.
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