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题名	LC-MS研究一枝蒿药材及制剂的化学成分和一枝蒿酮酸的代谢产物
作者	顾冬雨
学位类别	博士
答辩日期	2012-05-26
授予单位	中国科学院研究生院
授予地点	北京
导师	阿吉艾克拜尔.艾萨
关键词	HPLC/QTOF-MS/MS 新疆一枝蒿 复方一枝蒿颗粒 维吾尔药 一枝蒿酮酸 代谢
学位专业	有机化学
中文摘要	本论文采用液质联用技术（LC-MS）对维吾尔医常用药材--一枝蒿的抗病毒活性部位、复方一枝蒿颗粒、野生人工栽培的药材，活性化合物一枝蒿酮酸的代谢进行了研究。 1、一枝蒿有效部位的化学成分鉴定 本论文对维吾尔医常用药材新疆一枝蒿有效部位化学成分进行了研究，采用HPLC/QTOF-MS/MS对其中的常量成分和微量成分进行了鉴定，共鉴定了91个化合物，包括：14个绿原酸、9个黄酮苷元、55个黄酮-O-苷、4个黄酮-C-苷、3个倍半萜和6个一枝蒿酮酸的类似物。并总结了苯氧基色原酮和一枝蒿酮酸的裂解规律。所鉴定的化合物中，大部分为首次从新疆一枝蒿中发现，其中，5个化合物为潜在的新化合物。本研究为阐明新疆一枝蒿的化学成分组成提供了一定的科学依据。 2、复方一枝蒿颗粒化学成分分析 复方一枝蒿颗粒对治疗感冒具有很好的疗效，但它的物质基础目前还没有进行广泛系统的研究。本论文建立了一种LC-QTOF-MS/MS快速分析复方一枝蒿颗粒中化学成分的方法，并最终鉴定了复方一枝蒿颗粒中的66个化合物，类型包括氨基酸、有机酸、生物碱、黄酮、倍半萜以及蔗糖、表告伊春、鸟苷等。该方法解决了中药复方体系分离分析问题，完整系统地体现中药复方中多类别成分的复杂性，为复方一枝蒿颗粒的物质基础研究提供了科学依据。 3、野生和人工栽培新疆一枝蒿化学成分的比较研究 为了研究野生和人工栽培新疆一枝蒿化学成分的差别，我们采用LC-MS对野生和人工栽培新疆一枝蒿95%乙醇提取物的主要成分进行了分析。本研究发现，野生和人工栽培一枝蒿中的大部分化合物种类相同，主要成分为黄酮和酮酸类，但含量有所差别。野生新疆一枝蒿中的黄酮类成分和一枝蒿酮酸类似物的含量要高于人工栽培新疆一枝蒿。标志性化合物一枝蒿酮酸含量在野生一枝蒿中略高。野生和人工栽培品种的主要区别化合物是酮酸氢化羟基化衍生物，该化合物在野生中含量很高，仅次于一枝蒿酮酸，而在人工栽培中几乎检测不到。除此之外，木犀草素和木犀草素-7-O-葡萄糖苷以及酮酸氢化物在野生品种中也较高。该研究比较了野生和人工栽培一枝蒿的不同，还进一步鉴定了产生差别的成分，为野生和人工栽培一枝蒿的利用提供了基础。 4、一枝蒿酮酸的代谢研究 已有研究表明，一枝蒿酮酸及其衍生物具有较好的抗流感病毒活性，研究其代谢产物，对发现真正的活性成分以及能为结构改造、给药途径、剂型研究等提供重要依据。本研究采用体外和体内代谢方法对一枝蒿酮酸的代谢进行了研究。体外代谢研究中，采用肝细胞代谢，经HPLC-MS检测，发现了1个一枝蒿酮酸的Ⅱ相代谢产物-一枝蒿酮酸葡萄糖醛酸结合产物；体内研究采用SD大鼠灌胃，HPLC-MS检测尿样，结果显示有四个一枝蒿酮酸的代谢产物，包括2个Ⅰ相代谢产物-酮酸氧化产物、酮酸氢化产物，2个Ⅱ相代谢产物-酮酸葡萄糖醛酸结合产物、氢化酮酸葡萄糖醛酸结合产物。同时，还对酮酸的代谢速率进行了研究，发现酮酸在体外和体内代谢都比较缓慢。研究表明，体外代谢实验和体内代谢实验有一定的一致性，结合体内体外代谢结果，可以推断酮酸可能在Ⅰ相酶的作用下先发生氧化还原的反应，然后再在Ⅱ相酶的作用下和葡萄糖醛酸结合，生成极性大的代谢产物，排出体外。 关键词：HPLC/QTOF-MS/MS，新疆一枝蒿，复方一枝蒿颗粒，维吾尔药，一枝蒿酮酸，代谢
英文摘要	In this paper, LC-MS was used to investigate the chemical compositions of the active extract of Artemisia rupestris L. and its product Yizhihao granule (YG), also the comparison of wild Artemisia rupestris L. and cultivated Artemisia rupestris L.. Besides, the metabolism of rupestonic acid which was the active compound in Artemisia rupestris L. was studied by LC-MS. 1. Characterization and identification of chemical compositions in the extract of Artemisia rupestris L. by HPLC/QTOF-MS/MS In the present study, HPLC/QTOF-MS/MS was used to analyze components of the extract from Artemisia rupestris L. which showed an antivirus activity. A total of 91 compounds were identified or tentatively characterized,including 14 chlorogenic acids, 9 free flavonoid aglycones,55 flavonoid O-glycosides, 4 flavonoid C-glycosides, 3 sesquiterpenoids and 6 unknown sesquiterpenoid derivatives. Most of them were found from Artemisia rupestris L. for the first time. Among them, seven unique 2-phenoxychromones were detected in the extract, and their fragmentation rules were summarized. Also the possible fragmentation pathway rules of rupestonic acid were proposed, and two novel rupestonic acid glycosides were characterized. 2. An efficient LC-QTOF-MS/MS method for analysis of Yizhihao granule The famous traditional Uighur medicine, Yizhihao granule (YG) was clinically used to treat colds in China with a higher market share. However, few attempts have been made to develop a method for the comprehensive analysis of its chemical compositions. Thus, an efficient LC-QTOF-MS/MS method for rapid analysis of YG was presented in this paper. In the present study, a total of 69 compounds including amino acids, organic acids, alkaloids, flavonoids, sesquiterpenoids and other compounds (sucrose, epigoitrin and guanosine) were identified or tentatively identified. This method studied the prescription comprehensively without separation, and showed better understanding of the pharmacological basis. 3. Comparison of wild Artemisia rupestris L. and cultivated Artemisia rupestris L.. To study the difference between wild Artemisia rupestris L. and cultivated Artemisia rupestris L., LC-MS was used to analyze the 95% ethanol extracts of the herbal. It showed that the kinds of compounds in wild and cultivated Artemisia rupestris L. were almost the same, chiefly flavonoids and rupestonic acid derivatives, but differed in the content. The content of flavonoids and rupestonic acid derivatives in wild Artemisia rupestris L. were higher than that in cultivated Artemisia rupestris L.. The marker compound was Dihydro-hydroxyl-rupestonic acid, the content of this compound was high in wild Artemisia rupestris L., however, it was almost undetectable in cultivated Artemisia rupestris L.. Besides, the content of luteolin, luteolin-7-O-β-D-glucoside and Dihydro-rupestonic acid in wild Artemisia rupestris L. were higher than that in cultivated Artemisia rupestris L.. This study can be used reference in exploration of wild Artemisia rupestris L. and cultivated Artemisia rupestris L.. 4. LC-MS evaluation of metabolism of rupestonic acid It is reported that rupestonic acid poss good antivirus activities, the studies of its metabolism could discover the real active compounds, and provide the basis for structure modification, administration and formulation study. In the present study, rupestonic acid was metabolism in vitro and in vivo. The in vitro metabolites of rupestonic acid in rat liver hepatocytes were studied by HPLC-MS, and a Phase Ⅱ metabolites rupestonic acid-glucuronic acid was detected. The in vivo metabolites of rupestonic acid in rat urine were also studied, 4 metabolites were detected, including 2 Phase Ⅰmetabolites, oxidation- rupestonic acid and dihyro- rupestonic acid, 2 Phase Ⅱ metabolites, rupestonic acid-glucuronic acid and dihyro-rupestonic acid-glucuronic acid. The in vitro and in vivo metabolite rates of rupestonic acid are all slow in our study. Our results showed good correlation between in vitro and in vivo, and rupestonic acid was proposed to proceed oxidation and reduction reaction by Phase Ⅰenzymes first and than glucuronidation reaction under Phase Ⅱ enzymes, and excreted from the body in high polarity metabolites form. Key Words: HPLC/QTOF-MS/MS; Artemisia rupestris L.; Yizhihao granule; Uighur Medicine; rupestonic acid; metabolism
内容类型	学位论文
源URL	[http://ir.xjipc.cas.cn/handle/365002/4404]
专题	新疆理化技术研究所_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
推荐引用方式 GB/T 7714	顾冬雨. LC-MS研究一枝蒿药材及制剂的化学成分和一枝蒿酮酸的代谢产物[D]. 北京. 中国科学院研究生院. 2012.

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