升麻属植物化学成分及其体外抗肿瘤活性研究 
年寅 
学位类型博士
导师邱明华 
2010-11
学位授予单位中国科学院研究生院
学位专业植物学
摘要升麻属植物的化学成分及其生物活性一直是国际上研究的热点。我国升麻属(Cimicifuga)植物资源丰富,但是对其研究与使用却远远跟不上国际步伐。为了充分开发利用国内丰富的资源,本课题组自2003年以来一直对升麻属植物的化学成分,特别是其中的9,19-环阿尔廷型三萜类成分及其生物活性进行研究,并在国内率先发现了一些具有潜在抗肿瘤活性的升麻三萜类化合物。为了进一步从升麻属植物中寻找结构新颖、活性突出的抗肿瘤先导化合物,在前人工作的基础上,本论文选取了云南香格里拉地区的云南升麻(C. yunnanensis)的根茎和绿升麻(C. foetida)的地上部分,贵州黑石头镇的绿升麻(C. foetida)的根茎以及辽宁省清远县的兴安升麻(C. dahurica)和大三叶升麻的根茎(C. heracleifolia)为实验材料,运用多种分离材料、分离手段和有机化学反应方法,结合现代波谱分析技术,从中分离鉴定化合物148个次,不重复的有105个,其中94个为9,19-环阿尔廷型三萜,44个为新化合物,类型涉及Cimigenol型 Hydroxyshengmanol型、Shengmanol型、Acteol型、Dahurinol型、Cimicidol型以及比较新颖的C-3和C-4位开裂和C-15和C-16位开裂类型。剩下11个为常见的色酮、谷甾醇、齐墩果烷型三萜类化合物以及一个麦角甾醇类型的新化合物。对分离得到的三萜类化合物在体外进行了对人肝癌细胞株HepG2,人乳腺癌细胞MCF-7以及人结肠癌细胞株HT-29等15种人肿瘤细胞株生长抑制活性的筛选,发现了40个有活性的化合物,其中三个从云南升麻(C. yunnanensis)中分离得到的活性成分对耐药性乳腺癌细胞株R-MCF-7有显著的抑制作用,其活性与阳性对照物紫杉醇相当。通过机理研究发现这三个化合物可以上调P53和Bax基因的表达,继而导致线粒体膜电位的消失,引起caspase-7的激活,最后引发细胞凋亡,从而使癌细胞死亡。此外,从绿升麻(C. foetida)的根茎中分离得到一系列对人肝癌细胞株HepG2有选择性抑制活性的化合物,活性超过了阳性对照品顺铂,申请了国家发明专利。最后我们还对Cimigenol型活性成分进行了构效关系方面的总结,发现该类化合物要产生活性的关键点之一就是化合物的头端或者是末端需要有双键或者是羰基这样的疏水性基团取代羟基。在论文的最后,我们比较全面地综述了升麻属植物在世界范围内的种源分布与使用情况,并且对其中环阿尔廷型三萜类化合物的结构及其抗更年期综合症、抗骨质疏松和抗肿瘤的活性进行了全面的阐述。
资助项目Chemical constituents and bioactivities research on Cimicifuga species have been became an international hotspot. There are abundant plant resources of this genus in China, however the step of exploitation is far fall behind the western world. In an attempt to fully utilize our domestic resources, our research group has been studying on the chemical constituents and their bioactivities, specially 9,19-cyclolanostanetriterpenes of this genus, since 2003. As a result, several cycloartane triterpenoids with potential anti-tumor activities were obtained for the first time in China. For further searching anti-tumor lead compounds with novel structures and more potent activities, in this thesis,the roots of C. yunnanensis and the aerial parts of C. foetida, which collected from Shangrila County in Yunnan Province, the roots of C. foetida, which collected from Heishitou Town in Guizhou Province and the roots of C. dahurica and C. heracleifolia, which collected from Qingyuan County in Liaoning Province were used as experimental materials and total 105 compounds were isolated and identified by different spectroscopic and chemical methods. Among these 105 compounds, there are 94 9,19-cyclolanostanetriterpenes,including 44 new constituents. All these new compounds can be categorized as Cimigenol-type, Shengmanol-type, Hydroxyshengmanol-type, Acteol-type, Dahurinol-type, Cimicidol-type, and 3,4-Seco-type, 15,16-Seco-type, which were very novel. The left 11 compounds are normal Chromones, sitosterols, oleanane triterpenes and a new Ergostane-type steoid. The isolated 9,19-cyclolanostane compounds were tested for their cytotoxicities against 15 human carcinoma cell lines, which included human hepatoma cell line HepG2, human breast carcinoma cell line MCF-7, human colorectal carcinoma cell line HT-19 and so on. 40 compounds showed activities and three of them, which isolated from C. yunnanensis exhibited as potent activities as positive control Taxol. Mechanism research indicated that these three compounds can increase the expression of p53 and bax, which led to the loss of mitochondrial potential and then resulted in the activation of caspase-7 and induced apoptosis of MCF-7. In addition, a series of compounds which isolated from the roots of C. foetida showed selective significant cytotoxicity (potent than positive controlcisplatin) against the human HepG2 cell line and a domestic patent was applied for these compounds. A conclusion of the structure-activity relationships of Cimigenol-type compounds were proposed: one of the key point for anti-tumor activities is at least one side of the compound has hydrophobic groups such as carbonyl, double bond substitute hydroxyl groups. At the end of this thesis, a comprehensive review about the distribution and utilization of the Cimicifuga genus worldwide, the structures of 9,19-cyclolanostanetriterpenes and their anti-climacteric syndrome, anti-osteoporotic and anti-tumor activities were gave.
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/16068
专题昆明植物所硕博研究生毕业学位论文
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年寅 . 升麻属植物化学成分及其体外抗肿瘤活性研究 [D]. 中国科学院研究生院,2010.
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