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题名: 五种药用植物的化学成分及其生物活性研究
作者: 马晓霞
学位类别: 博士
答辩日期: 2008-05-27
授予单位: 中国科学院昆明植物研究所
授予地点: 昆明植物研究所
导师: 杨崇仁
关键词: C-21甾体配糖体 ; 乙酰胆碱酯酶(AChE)模型 ; 抗真菌活性 ; 青阳参 ; 南山藤 ; 金瓜核 ; 萝藦科 ; 七叶莲 ; 幌伞枫 ; 五加科
学位专业: 植物学
中文摘要: 本论文对萝藦科三种植物青阳参(Cynanchum otophyllum),南山藤(Dregea volubilis),金瓜核(Dischidia esquirolii)和五加科两种植物七叶莲(Schefflera venulosa),幌伞枫(Heteropanax fragrans)进行了化学成分的研究,运用多种光谱和波谱学分析和化学方法鉴定了69个天然产物的结构,其中33个为新化合物,并对一些化学成分进行了乙酰胆碱酯酶抑制活性,抗真菌和抗病毒活性的筛选实验。 第一章 三种萝藦科植物的化学成分和活性研究 萝藦科植物中普遍存在的C-21甾体配糖体是一类以孕甾烷为母核的化合物,其C-11,C-12,C-20位羟基经常形成酯键,C-3位羟基与主要由α-去氧糖组成的糖链形成配糖体。这类化合物具有神经系统的生理活性,如抗惊厥,抗癫痫,抗忧郁等。它们的化学结构和生理功能与上个世纪九十年代兴起的神经甾体非常相似,由此推测,C-21甾体配糖体为一种植物来源的类神经甾体。由于神经细胞的一些特殊性质和神经系统的复杂调控机制,神经系统的疾病在治疗上还存在很大的问题。现代社会的生活压力导致精神疾患已逐渐上升为一种社会问题,人口老龄化这个世界性的难题也日趋突出。因此,神经系统疾病药物的研究已成为刻不容缓的科学任务。为了从植物中寻找这方面的有效药物,探讨作用机理,本论文建立了实验室操作性强的乙酰胆碱酯酶活性筛选模型,用于C-21甾体化合物的神经系统活性的初步评价。 从鹅绒藤属植物青阳参(Cynanchum otophyllum)的根中分离得到15个以青阳参甙元(qingyangshengenin)或告达亭(caudatin)为甙元的C-21甾体配糖体,其中12个为新化合物。这些C-21甾体配糖体的甙元稳定,糖链部分的组成和连接顺序变化丰富,糖链中糖基的数目3-7个不等,糖基的类型以α-去氧糖为主,包括加拿大麻糖,夹竹桃糖,毛地黄毒糖,黄花夹竹桃糖,末端常有1- 2个葡萄糖存在。在含有7个糖基的C-21甾体配糖体中,同时得到了D-和L-构型的加拿大麻糖。从青阳参总甙的酸水解产物中分离得到了告达亭和青阳参甙元。对分离到的15个C-21甾体配糖体和2个甙元进行了乙酰胆碱酯酶抑制活性的测定,但这些化合物都没有显示明显的体外抑制活性。本论文同时注意到抗癫痫药青阳参在植物资源方面的混杂问题,建立了HPLC的分析方法,对其近缘种及不同地区的药材样品进行了评价,发现其中一个民间称作青阳参的植物样品中基本不含青阳参甙元和告达亭。 从南山藤属植物南山藤(Dregea volubilis)的茎中分离得到25个化合物,包括20个C-21甾体配糖体,2个齐墩果酸型三萜化合物和3个并四氢呋喃型木脂素的配糖体,其中有17个新化合物和1个新的天然产物。C-21甾体化合物在该植物中含量丰富,三萜和木脂素类化合物则为首次从该属植物中分离得到。比较有意思的是,从采自云南墨江的南山藤茎中得到的C-21甾体化合物,其糖链组成相对固定,基本由两个加拿大麻糖和一个6-去氧-3-O-甲基-阿洛糖组成,而甙元的变化却很丰富。首先,母核部分根据C-17位甲基酮侧链还原与否以及C-8位是否有羟基取代,可以划分为四种类型。其次,C-11,C-12,C-20位的三个羟基出现了同时游离,一个游离,两个成酯,以及三个同时成酯的情况。再次,酯基的种类较多,除文献中常见的酯基基团外,还得到了一个新颖的酯基基团,命名为3-甲基戊酸酯。这些变化产生了大量新颖的C-21甾体化合物,与文献中从采自泰国的茎或采自印度的花中得到的化合物差别较大,表现出不同的生长环境和植物的不同部位次生代谢产物的分子多样性。对其中17个C-21甾体化合物进行了乙酰胆碱酯酶的抑制活性筛选,结果没有发现对AChE有明显的体外抑制活性的化合物。 从眼树莲属植物金瓜核(Dischidia esquirolii)新鲜的地上部分的甲醇提取物中分离得到11个化合物,其中2个为新化合物,并对1个已知化合物的文献报道数据进行了订正。金瓜核中没有得到C-21甾体类化合物,主要为氧化程度较高的三萜类成分,以乌苏酸型为主,也有齐墩果酸型存在。同时得到一个在茜草科(Rubiaceae)中广泛存在的金鸡纳酸类化合物,和一个天然来源的桉烷型倍半萜。值得注意的是,该植物中碳甙黄酮的含量较大,而这类成分在萝藦科植物的化学成分报道中较为罕见。对部分化合物进行了抗真菌和抗病毒的活性筛选,结果没有发现有活性的成分。 第二章 两种五加科植物的化学成分研究 深部真菌感染已经成为艾滋病和癌症患者等免疫力低下人群的主要死亡原因之一,而目前仍缺乏高效低毒的抗真菌药物。本项目与美国密西西比大学国家天然产物研究中心合作,采用与艾滋病和癌症相关的机会性感染病原体以及它们的抗性株系为筛选菌株模型,对所采集的五加科药用植物分不同部位和不同溶剂制备提取物,进行了抗真菌和抗微生物的活性筛选,结果发现七叶莲(Schefflera venulosa)和幌伞枫(Heteropanax fragrans)具有一定的抗真菌活性。 对鹅掌柴属植物七叶莲(S. venulosa)和幌伞枫属植物幌伞枫(H. fragrans)进行了化学成分的研究,得到18个化合物,主要是三萜皂甙,黄酮甙,木脂素配糖体,绿原酸衍生物等,其中有一个新的苯并呋喃型木脂素的配糖体,单体化合物的活性筛选工作将在后期进行。 第三章 萝藦科鹅绒藤属中的C-21甾体配糖体(综述) C-21甾体化合物的母核结构大致可分为经典的四元环骨架和变形骨架两大类型,本综述总结了这两大类型的C-21甾体化合物在鹅绒藤属植物中的分布规律,希望为化学分类学提供证据。同时总结了关于这两大类型化合物的现代药理学研究报道,为该科药用植物资源的开发利用提供科学依据。 以上研究成果已发表SCI论文两篇,待发表论文六篇。硕博连读期间参与了北京药物所张均田教授主编的《The Chemistry, Metabolism and Biological Activities of Ginseng》一书的写作,并为美国草药典(American Herbal Pharmacopoeia)撰写了三七(Panax notoginseng)专辑(Notoginseng Monograph)的部分章节。
英文摘要: This dissertation mainly focused on the chemical investigation on five plants from Asclepiadaceae and Araliaceae families: Cynanchum otophyllum, Dregea volubilis, Dischidia esquirolii, Schefflera venulosa, and Heteropanax fragrans. Through various chromatographic methods, 69 natural products were isolated, including 33 new ones. Their structures were determined on the basis of detailed spectroscopic analyses and chemical methods. The AChE inhibitory, anti-fungal and anti-virus activities of some compounds were studied. Moreover, the plant resources of C. otophyllum were evaluated by HPLC analysis. Chapter 1 The chemical constituents of three plants of Asclepiadaceae and their bioactivities C-21 steroidal glycosides occurred commonly in the plants of Asclepiadaceae family. These kind of natural steroids possess a pregnane skeleton and some activities on nervous system, such as antiepilepsy and antidepression. Their structures and functions are so similar to those of neurosteroids that they are presumed to be a kind of neurosteroids-like compounds from plants. The total glycosides from Cynanchum otophyllum (Chinese name: Qingyangshen) have been used for the clinical treatment of epilepsy for more than twenty years in China, and the quality of this phytomedicine was not so stable these years because of the confusion of the original plant materials. Phytochemical studies on the roots of C. otophyllum collected in the northwest of Yunnan province led to the isolation of 15 C-21 steroidal glycosides, including 12 new compounds. The glycosides had qingyangshengenin or caudatin as aglycones and various compositions of sugars, consisting of 3-7 sugar units. The sugar units contained cymarose, oleandrose, digitoxose, thevetose, and glucose. A pair of optically isomeric sugars, D- and L-cymarose was obtained. The aglycones, qingyangshengenin and caudatin were isolated from the acidic hydrolysate of the total glycosides as well. Both the glycosides and aglycones were submitted to the AChE inhibitory assay in vitro, and no obvious activity was observed. Accounting for the problem of plant resources, a HPLC analysis method was established for the quality control of the medicinal materials of Qingyangshen. It is found that one botanical sample known as Qingyangshen by local people contained neither qingyangshengenin nor caudatin. Dregea volubilis was reported to contain plenty of C-21 steroidal glycosides. By the utilization of open column chromatography and preparative or semi-preparative HPLC, 20 C-21 steroidal glycosides, including 15 new ones were isolated from the stems of D. volubilis collected in Mojiang, Yunnan province. It is interesting that the C-21 steroidal glycosides from D. volubilis possessed a relative stable sugar chain, mostly consisted of two cymarose and one 6-deoxy-3-O-methyl allose. However, the aglycones exhibited a molecular diversity, which may result from the different living environments. The aglycones of these C-21 steroidal glycosides can be devided into four types according to the reduction of the side chain at C-17 and the hydroxyl substitution at C-8. The hydroxyl groups at C-11, C-12 and C-20 can form the ester groups in different ways of combination. Furthermore, there are various ester groups in these compounds, and a novel one named 3-methylvaleryl was discovered. Meanwhile, 3 new lignan glycosides and 2 known triterpene were obtained; these kinds of compounds were isolated from the plants of Dregea genus for the first time. Most of the C-21 steroidal glycosides were valuated for the in vitro AChE inhibitory activity and no positive results were observed. Eleven compounds were isolated from Dischidia esquirolii, including two new ones. The structure of a known compound was revised by detailed NMR studies. The phytochemical studies revealed that the fresh aerial parts of D. esquirolii mainly contained pentacyclic triterpenes of high oxidization degree and flavonoids. It is interesting that a quinovic acid glycoside which commonly occurred in Rubiaceae family and C-glycoside flavonoids of macro-quantity which are really rare in Asclepiadaceae family were found in this plant. Some of the compounds were submitted to the anti-fungal and anti-virus bioassay and no potent ingredients were found. Chapter 2 The chemical constituents of two plants of Araliaceae Opportunistic fungal infections, mainly resulting from Candida, Cryptococcus, and Aspergillus, are life threatening in immuno-deficient patients with cancer, AIDS, diabetes, or organ transplant, etc. The current antifungal drugs have different side-effects in clinical treatment. It is of great importance to find new antifungal agents from natural products with high efficiency and little toxicity. Some medical plants of Araliaceae family were used to treat fungal infections according to the ancient medicine records. Different extracts of some plants were prepared and submitted to initial anti-fungal bioassay. The results revealed that the water-soluble part of Schefflera venulosa and the fruits of Heteropanax fragrans have potential antifungal activities. Systematic phytochemical studies on S. venulosa and H. fragrans led to the isolation of 1 novel and 17 known compounds including triterpenoids, flavonoids, lignans, polyphenols, diterpenoids, and etc. The further antifungal activity screening work of the isolated compounds will be carried out in American National Center for Natural Products Research, School of Pharmacy, University of Mississippi. Chapter 3 Review: C-21 steroidal glycosides in Cynanchum (Asclepiadaceae) The aglycone of C-21 steroidal glycosides can be divided into two kinds: the normal four-ring pregnane skeleton and the abnormal pregnane skeleton arising from a high oxidization degree. Both of them were contained in the plants of Cynanchum genus. A summary concerned the distribution and modern pharmacological studies of these two types was given here to provide evidences for the chemotaxonomy investigation and the utilization of medicinal plants of Cynanchum.
语种: 中文
内容类型: 学位论文
URI标识: http://ir.kib.ac.cn/handle/151853/394
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五种药用植物的化学成分及其生物活性研究.马晓霞[d].中国科学院昆明植物研究所,2008.20-25
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