小红参抗肿瘤环肽及其作用机制研究 
范君婷 
学位类型博士
导师谭宁华 
2010-11
学位授予单位中国科学院研究生院
学位专业药物化学
摘要从天然产物尤其是植物中寻找抗肿瘤药物一直是国内外学者共同关注的热点。本论文围绕植物来源的抗肿瘤药物和植物环肽两方面开展研究。论文由四章组成:第一章通过肿瘤细胞毒活性筛选模型的引建及批量筛选,累计筛选化合物8835个,提取物3638个,发现活性化合物459个,活性提取物189个。根据筛选结果选择抗肿瘤活性较好且民间用于肿瘤治疗的茜草科茜草属植物小红参(Rubia yunnanensis (Franch.) Diels)作为进一步研究对象。第二章开展了系统的小红参环肽化学成分、生物活性、抗肿瘤作用机制及初步临床前研究。分离鉴定了18个环肽,其中2个新骨架环肽、7个新环肽,探讨了其四种类型环肽的生物合成途径。开展了18个环肽的11种肿瘤细胞株的体外细胞毒活性筛选,发现此类环肽具有很强的细胞毒活性,其中RA-V的IC50值约为10 nM。首次发现RA-V具有较好的抗I型疱疹病毒(HSV-1)活性。对活性最强的RA-V及其配糖体RA-XII开展了抗肿瘤作用机制研究,首次发现它们作用于NF-κB信号通路,能够抑制IκBα的磷酸化,进而抑制P65亚基的核转位,影响NO的生成,为该通路一类较强的新型天然抑制剂。还发现RA-V能有效抑制人脐静脉内皮细胞(HUVEC)和人微血管内皮细胞(HMEC)的增殖,可能通过抑制Erk信号通路影响周期相关调控蛋白的表达,使细胞周期阻滞在G2/M期,引起细胞凋亡。还可能通过抑制基质金属蛋白酶影响胞外基质降解,进而抑制细胞的迁移和成管作用。第三章开展了小红参其它化学成分和生物活性研究。分离鉴定了68个化合物,其中11个新乔木烷型三萜、4个新醌类。对其中61个化合物开展了3种肿瘤细胞株的细胞毒和2种菌株的抗菌活性筛选,首次发现乔木烷型三萜类化合物具有细胞毒活性,主要乔木烷型三萜rubiarbonol G和蒽醌2-methyl-1,3,6-trihydroxy-9,10-anthraquinone能明显诱导Hela细胞凋亡。第四章对茜草属植物的化学成分和生物活性研究进行了综述。以上研究工作为小红参环肽作为抗肿瘤药物的研发奠定了良好基础,并从多成分、多靶点协同作用的角度为小红参的质量控制和新药研发提供重要参考。
资助项目The search for new and efficient antitumor drugs from natural products, especially plants, has been the focus of scholars and researchers all over the world. The dissertation composed of four chapters and focused on antitumor drugs of plant origin and plant cyclopeptides research. The first chapter was about the establishment and application of cancer cell line assay. In total, 8835 compounds and 3638 extracts were tested against seven cell lines and the results indicated that 459 compounds and 189 extracts showed cytotoxicities. Based on these results, the plant Rubia yunnanensis (Franch.) Diels, which showed potential activity and has been used as a common herb to treat cancer, was selected for the further study. Chapter two, focused on the studies on chemistry, bioactivities, antitumor mechanism and preliminary pre-clinical research of cyclopeptides in R. yunnanensis. A phytochemical investigation on cyclopeptides constituents from this plant led to the isolation of 18 cyclopeptides, including 2 new ones with novel skeletons and 7 other new ones. The possible biosynthetic pathways for four types of rubiaceae-type cyclopeptides were also proposed. The 18 cyclopeptides were evaluated for their cyctotoxicities against 11 cancer cell lines and the result indicated that these cyclopeptides exhibited strong activities and RA-V showed best activities with IC50 values of approximately 10 nM. Moreover, RA-V was also found to exhibit anti I-type herpes simplex virus (HSV-1) activity for the first time. Thereafter, we carried out research on the antitumor mechanism of RA-V and its glycoside RA-XII. The results showed that they significantly inhibited TNF-α induced NF-κB signaling pathway. The phosphorylation of IκBα was down-regulated by them, which could inhibit the translocation of P65 and NO production in LPS and IFN-γ-induced RAW 264.7 murine macrophages. This is the first time it is being reported that RA-V and RA-XII are new natural NF-κB pathway inhibitors. Furthermore, from the anti-angiogenesis study, RA-V showed strong anti-proliferative activities in human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC). Further study on its mechanism indicated that RA-V could induce G2/M phase arrest and cell apoptosis by down-regulation of cell cycle regulatory protein and gene expression in extracellular signal-regulated kinase ½ (Erk ½) phosphorylation pathway. Moreover, RA-V could inhibit migration and tube formation of HUVEC and HMEC by inhibition of matrix metalloproteinase. The third chapter was about the studies on other chemical constituents of R. yunnanensis and their bioactivities. A phytochemical assessment of this plant resulted in the isolation of 68 compounds, including 11 new arborinane-type triterpenoids and 4 new quinones. Subsequently, 61 of them were evaluated for their cytotoxicities against three cancer cell lines, anti-Staphylococcus aureus and anti-Candida albicans activities. The results indicated that for the first time the arborinane-type triterpenoids exhibited cytotoxicities and also rubiarbonol G and 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone induced cell apoptosis in Hela cell line. The fourth chapter was a review on chemical constituents and bioactivities of genus Rubia plants. All the above-mentioned research work had laid a good foundation for quality control and multi-component, multi-target drug R&D of R. yunnanensis.
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/16190
专题昆明植物所硕博研究生毕业学位论文
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范君婷 . 小红参抗肿瘤环肽及其作用机制研究 [D]. 中国科学院研究生院,2010.
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