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两种新疆特有的翠雀属植物中二萜生物碱的研究
赵波
学位类型博士
导师阿吉艾克拜尔·艾萨
2015-06-01
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
关键词天山翠雀花 萨乌尔翠雀花 二萜生物碱 翠雀属 提取 纯化
摘要

天山翠雀花(Delphinium tianshanicum W. T. Wang)和萨乌尔翠雀花(Delphinium shawurense W .T. Wang)系毛茛科(Ranunculaceae)翠雀属(Delphinium)植物,分别分布于天山山脉南、北坡和萨乌尔山,属新疆特有民间药用植 物,《新疆药用植物志》记载天山翠雀花全草入药,能够祛风燥湿,止痛定惊,主治风湿痛、小儿惊风和跌打损伤;阿勒泰地区牧民则用萨乌尔翠雀花治疗风湿。但 是关于这两种植物的化学成分及活性研究尚未见系统报道。 数十年来,科研工作者们围绕着翠雀属植物中的特征成分二萜生物碱做了大量的研究,研究发现二萜生物碱具有镇痛、抗心律不齐、强心和抗肿瘤等多种药理活性, 并对其结构和活性之间的关系做了初步探讨。但是,由于二萜生物碱结构复杂,绝大多数伴随着强烈的毒性,这使得寻找高效低毒的二萜生物碱仍是当前研究的热点 和难点,而且其结构和活性之间的关系的研究仍停留在初级阶段。本论文以新疆特有的两种翠雀属植物天山翠雀花和萨乌尔翠雀花为研究对象,旨在从中寻找结构新 颖的二萜生物碱化合物,供药理活性筛选,以期能寻找到高效低毒的药物先导化合物,为明确其构效关系提供理论依据;并优化天山翠雀花中总二萜生物碱的提取纯 化工艺,为进一步的开发和利用新疆这一特有植物资源提供科学依据。具体工作如下: 1. 系统阐述了二萜生物碱的分类,药理活性,并对已报道的结构与活性之间的关系进行了归纳总结。 2. 开展了新疆特有的翠雀属植物资源调查及天山翠雀花和萨乌尔翠雀花中二萜生物碱成的系统研究: 从天山翠雀花中分离并鉴定出了15个二萜生物碱:tianshanisine (DT-1), tianshanine (DT-2), tianshanidine (DT-3), 6-dehydro-delcorine (DT-4), delbruninol (DT-5), blacknidine (DT-6), dehydroeldelidine (DT-7), ajacine (DT-8), lycoctonine (DT-9), delavaine A (DT-10), delavaine B (DT-11), lappaconitine (DT-12), vakhmatine (DT-13), delcorine (DT-14)和deltaline (DT-15),其中化合物DT-1~DT-3是新化合物,DT-4~ DT-13为首次从该植物中分离得到。从萨乌尔翠雀花中分离并鉴定出13个二萜生物碱:sharwuphinine B (DS-1), shawurenine A (DS-2), shawurenine B (DS-3), dictysine (DS-4), anthranoyllycoctonine (DS-5), delavaine A (DS-6), delavaine B (DS-7), deltaline (DS-8), delcorine (DS-9), shawuresine (DS-10), delbruline (DS-11), methyllycaconitine (DS-12)和lycoctonine (DS-13)。其中DS-1~DS-3为个新化合物,DS-4~DS-9为首次从该植物中分离得到。并用MTT比色法对分离得到的二萜生物碱的细胞毒性 进行了筛选,结果显示化合物delavaine (一对同分异构体delavaine A和delavaine B,即DS-6和DS-7的混合物)对人肺腺癌细胞 A549有很好的细胞毒性,化合物lappaconitine(DT-12)对人宫颈癌细胞HeLa 表现出一定的细胞毒性。 以上工作为进一步寻找高效低毒的二萜生物碱化合物,明确其构效关系提供了科学依据,并丰富了天山翠雀花和萨乌尔翠雀花化学成分研究内容,为两种药用植物的 药理研究和进一步开发利用新疆这一特色植物资源奠定了基础。 3. 完成了天山翠雀花中的有效成分-总生物碱进行了提取和大孔树脂纯化工艺研究: 以总生物碱含量为指标,确定了最佳提取工艺为:乙醇浓度90%,液料比为20倍,提取时间1小时,超声提取3次,得到天山翠雀花全草中总生物碱的含量为 6.2 mg/g。最佳大孔树脂纯化工艺为:乙醇提取浸膏用0.1% HCl溶解,稀释至0.2 g生药/mL,调节pH至5,上D101大孔树脂,上样流速为2 BV/h,上样量为8 BV,除杂用水为4 BV,洗脱剂为70%乙醇,洗脱剂用量为3 BV。纯化后总生物碱的含量从3.72%提高至34.03%。该工艺操作简单,安全可靠,对开发相关天山翠雀花经济产品具有指导意义。

其他摘要

Delphinium tianshanicum W. T. Wang and Delphinium shawurenseW. T. Wang, which are endemic to the Xinjiang of China, belonging to genus Delphinium (Ranunculaceae) plant, distributed in the north and south of the Tianshan Mountains and Sawuer Mountain, respectively, These two species are traditional Uighur medicinal plants, used for dispelling pathogenic wind and removing dampness, analgesic and anticonvulsant, treatment of rheumatism, convulsions in children and bruises. D. shawurense also be uesd to treat rheumatism by pastoralists in the Altay region. However, to date, the system research of their main active ingredient has not been reported. For decades, a vast range of studies about diterpenoid alkaloids, which are the characteristic ingredients of Delphinium plants, have been made. Many kinds of pharmacological activities had been found in diterpenoid alkaloids such as: analgesic, anti-arrhythmia, cardiac, anti-tumor, and so on. And these researches also made a preliminary discussion on the relationship between structure and activity. However, due to the complex structure and strong toxicity of diterpenoid alkaloids, the search for diterpenoid alkaloids with high efficiency and low toxicity is still hot and difficult point of natural products research, and the structure-activity relationship research remains in its infancy. In this dissertation, diterpenoid alkaloids from two kinds of Xinjiang unique plants D. tianshanicum and D. shawurense have been studied, the aim of this work was to provide some new diterpenoid alkaloids for pharmacological activity screening, and found some efficiency and low toxicity lead compounds for the drug, and meanwhile, toprovide a clear theoretical basis for exploring their structure-activity relationships. The extraction and purification process of the total diterpenoid alkaloids from D. tianshanicum have been conducted .All these work provide scientific basis for further scientific development and utilization of the unique resources in Xinjiang. 1. Classification, pharmacological activity, and structure-activity relationship of diterpenoid alkaloids were introduced. 2. Delphinium plants distribution of Xinjiang, and phytochemical investigation on the diterpenoid alkaloids from D. tianshanicum and D. shawurense were elaborated. Three new diterpenoid alkaloids, tianshanisine (DT-1), tianshanine (DT-2), tianshanidine (DT-3), together with twelve known diterpenoid alkaloids 6-dehydrodelcorine (DT-4), delbruninol (DT-5), blacknidine (DT-6), dehydroeldelidine (DT-7), ajacine (DT-8), lycoctonine (DT-9), delavaine A (DT-10), delavaine B (DT-11), lappaconitine (DT-12), vakhmatine (DT-13), delcorine (DT-14) and deltaline (DT-15), were isolated from D. tianshanicum, and compounds DT-4~DT-12 were isolated from the plant for the first time. Three new diterpenoid alkaloids, sharwuphinine B (DS-1), shawurenine A (DS-2), shawurenine B (DS-3), together with ten known diterpenoid alkaloids dictysine (DS-4), Anthranoyllycoctonine (DS-5), delavaine A (DS-6), delavaine B (DS-7), deltaline (DS-8), delcorine (DS-9), shawuresine (DS-10), delbruline (DS-11), methyllycaconitine (DS-12) and lycoctonine (DS-13), were isolated from D. shawurense. Compounds DS-4~DS-9 were isolated from the plant for the first time. All the compounds were assayed for their cytotoxicity by MTT assay. On the A549 cell line, delavaine (a pair of isomer, delavaine A and delavaine B; DS-6, DS-7) displayedsome cytotoxicity. On HeLa cell line, lappaconitine (DT-12) displayed a good cytotoxicity. This study not only provided a scientific evidence for further research about screening high efficiency and low toxicity diterpenoid alkaloids, exploring structure-activity relationships, but also enriched the chemical constituents of D. tianshanicum and D. shawurense, and established the foundation for the pharmacological research and further development and utilization of these endemic resources of medicinal plants in Xinjiang. On the basis of the chemical composition and folk medicinal effects, the process of extraction and purification method of total alkaloids from D. tianshanicum was established with total alkaloids content as an indicator. The optimal extraction process conditions were ultrasonic extract 3 times by 20 BV of 90% ethanol. Using this method, the extraction rate of total alkaloids was 6.2 mg/g. The optimal purification process conditions were dryness of the extraction dissolved and diluted to 0.2 g crude drug/ mL with 0.1% HCl, adjusted pH to 5, subjected to the D101 macroporous resin column. The flow rate was 2 BV/h, and solution treatment capacity was 8 BV. After washing with 4 BV water, 70% ethanol was used as eluent, and the eluent volume was 3 BV at the flow rate 2 BV/h. After purification, total alkaloids content increased to 34.03% from 3.72%. This method was simple, safe and reliable. It provided profound guiding significance for economic products development of D. tianshanicum.

文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4235
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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赵波. 两种新疆特有的翠雀属植物中二萜生物碱的研究[D]. 北京. 中国科学院大学,2015.
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