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题名	粗根大戟和准噶尔大戟化学成分及其生物活性研究
作者	高洁
学位类别	博士
答辩日期	2016-06-03
授予单位	中国科学院大学
授予地点	北京
导师	阿吉艾克拜尔·艾萨
关键词	粗根大戟 准噶尔大戟 大环二萜 细胞毒活性 多药耐药逆转活性
学位专业	有机化学
中文摘要	大戟属（Euphorbia）是大戟科（Euphorbiaceae）中的一个大属，全球约有2000余种植物，广泛分布于热带及温带地区。大环二萜类化合物作为该属植物中的特征性成分，具有结构类型多变、生物活性多样的特点。粗根大戟（Euphorbia macrorrhiza C. A. Mey）为大戟属多年生草本植物，产于新疆阿勒泰地区，分布于俄罗斯和哈萨克斯坦，其挥发油和粗提物具有一定的抗肿瘤和抑菌活性，然而其物质基础尚未明确。本研究首次利用现代色谱分离技术和结构鉴定技术对粗根大戟的化学成分进行了研究，从其全草的丙酮提取物中分离并鉴定出22个单体化合物（21个为二萜类化合物），其中包括10个新化合物：macrorilones A-B (EM-1~EM-2), macroripremyrsinone A (EM-3), macrorilathyrones A-B (EM-4~EM-5), macrorieuphorones A-B (EM-6~EM-7) 和macroricasbalones A-C (EM-8~EM-10)，其余已知化合物均为首次从该种植物中分离得到。采用MTT法对分离得到的二萜类化合物（EM-1~EM-21）进行细胞毒活性筛选，结果表明其中10个化合物（EM-5~EM-8，EM-12~EM-14，EM-16，EM-18和EM-19）对人口腔鳞状细胞癌KB细胞及其长春新碱耐药株KBv200细胞表现出一定的细胞毒性（IC50为21.19~48.87 μM）。在肿瘤多药耐药（MDR）逆转活性实验中， 6个二萜类化合物（EM-5~EM-8, EM-12和EM-16）具有不同程度的MDR逆转活性（逆转倍数为4.17~43.63），其中EM-5可通过抑制P-糖蛋白（P-gp）介导的药物外排作用表现出最好的MDR逆转活性，且这种抑制作用具有浓度依赖性。准噶尔大戟（Euphorbia soongarica Boiss.）为大戟属多年生草本植物，产于新疆北部和甘肃西部，分布于中国、西西伯利亚至中亚和蒙古。其根部入药，具有逐水、消肿、散瘀的功效，在新疆地区也作为大戟的替代品使用。目前已报道的从准噶尔大戟中得到的化合物有50余个，主要为黄酮类、多酚类和三萜类化合物，但有关其生物活性的研究甚少，仅发现3个三萜类化合物具有一定的细胞毒性，而大戟属的特征成分——二萜类化合物并未见报道。因此，本研究针对准噶尔大戟的化学成分，特别是二萜类成分进行进一步研究。从准噶尔大戟全草丙酮提取物中分离并鉴定出29个单体化合物，其中新化合物11个，其余已知化合物均为首次从该种植物中分离得到。新化合物中包括5个二萜类化合物：soongaricones A-E (ESG-1~ESG-5)；3个降碳三萜类化合物：soongaricone F (ESG-6), soongaricone G (ESG-7) 和soongaricone I (ESG-9)；2个三萜类化合物：soongaricone H (ESG-8) 和soongaricone J (ESG-10) 以及1个1-茚酮类化合物 (soongaricone K, ESG-11)。细胞毒活性筛选（MTT法）结果表明其中8个化合物（ESG-2, ESG-5, ESG-7, ESG-8, ESG-10, ESG-15, ESG-21, ESG-25）对KB细胞和KBv200细胞均有一定的细胞毒性（IC50范围10.34~25.87 μM）。罗丹明123蓄积实验结果表明其中11个化合物（ESG-4~ESG-8, ESG-13, ESG-14, ESG-17, ESG-18, ESG-21和ESG-25）能够抑制P-gp介导的药物外排作用，从而显示出一定的多药耐药逆转活性。其中三萜类化合物ESG-8表现出最好的P-gp抑制活性（罗丹明123蓄积相对值为5.23）。
英文摘要	Euphorbia is the largest genus in the Euphorbiaceae family, comprising more than 2000 species, which is well known for the structural and bioactive diversity of its diterpenoid constituents. Euphorbia macrorrhiza C. A. Mey is mainly distributed in northwestern China, Russia and Kazakhstan. A previous study showed that the essential oil of its roots exhibited antimicrobial activity and cytotoxicity. However, the chemical constituents, especially the diterpenoid constituents, of this plant have not been reported. In the first part of this study, ten new diterpenoids, named macrorilones A–B (EM-1~EM-2), macroripremyrsinone A (EM-3), macrorilathyrones A–B (EM-4~EM-5), macrorieuphorones A–B (EM-6~EM-7) and macroricasbalones A–C (EM-8~EM-10), together with twelve known diterpenoids, were isolated from the whole plant of Euphorbia macrorrhiza C. A. Mey. Ten of the isolated compounds (EM-5~EM-8, EM-12~EM-14, EM-16 and EM-18~EM-19) were found to exhibit weak cytotoxicity against both KB and KBv200 cell lines with IC50 values ranging from 21.19 to 47.87 μM. Six of the isolated compounds (EM-5~EM-8, EM-12 and EM-16) showed multidrug resistance (MDR) reversal activity, among which macrorilathyrone B (EM-5) exhibited a remarkable inhibitory effect on P-gp-mediated drug exclusion.Euphorbia soongarica Boiss. is a perennial herb mainly distributed in northwestern China, Western Siberia to Central Asia and Mongolia. Its roots have long been used for treatment of venous hyperemia, edema and ascites in Chinese traditional medicine. Previous phytochemical investigations on E. soongarica afforded a number of flavonoids, polyphenols and triterpenoids, but few of them showed biological activities. To the best of our knowledge, the diterpenoid constituents of this species have not been characterized. In continuing the search for diverse and bioactive constituents from the genus Euphorbia, a phytochemical investigation was conducted on the whole plant of E. soongarica. As a result, 29 compounds, including 11 novel ones [five diterpenoids (soongaricones A-E, ESG-1~ESG-5), three nortrierpenoids (soongaricones F, J, I (ESG-6, 7, 9), two triterpenoids (soongaricones H, J (ESG-8, 10) and one 1-indanone (soongaricone K, ESG-11)], were isolated. Among these compounds, ESG-2, ESG-5, ESG-7, ESG-8, ESG-10, ESG-15, ESG-21 and ESG-25 showed cytotoxicity against both KB and KBv200 cell lines with the IC50 values ranging from 10.34 to 25.87 μM. In addition, the results of rhodamine-123 accumulation assay showed that compounds ESG-4~ESG-8, ESG-13, ESG-14, ESG-17, ESG-18, ESG-21 and ESG-25 exhibited inhibitory effect on P-gp-mediated drug exclusion, among which the triterpenoid ESG-8 showed the most potent inhibitory effect.
内容类型	学位论文
源URL	[http://ir.xjipc.cas.cn/handle/365002/4596]
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	高洁. 粗根大戟和准噶尔大戟化学成分及其生物活性研究[D]. 北京. 中国科学院大学. 2016.

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