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两种大戟属植物和牛筋果的化学成分及其活性研究
袁文娟
学位类型博士
导师郝小江
2017-06-03
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
关键词月腺大戟 金刚纂 牛筋果 二萜 柠檬苦素 溶酶体
摘要

本论文对两种大戟属植物月腺大戟 (Euphorbia ebracteolata Hayata)、金刚纂 (Euphorbia antiquorum L.)、以及苦木科牛筋果属植物牛筋果 (Harrisonia perforata (Blanco) Merr.)的化学成分及生物活性进行了研究。利用各种分离技术,采用现代波谱学方法以及单晶X-衍射等技术,从上述三种植物中共分离鉴定了107个化合物,其中新化合物32个,包括2个异源二萜二聚体和3个新颖骨架的柠檬苦素类化合物。所鉴定的化合物结构类型以二萜和柠檬苦素为主。对分离得到的部分化合物进行了细胞毒活性筛选和诱导细胞凋亡机制的研究,以及促进溶酶体生成功能试验,抑制肿瘤干细胞,调控Nf-κB信号通路,抗炎活性以及抑制马铃薯晚疫菌菌丝体等多种生物活性的评价。第一章两种大戟科大戟属植物的化学成分和活性研究。从月腺大戟 (E. ebracteolata Hayata)中分离得到36个化合物,包括31个二萜类化合物,其中7个为新化合物, 化合物1和2是大戟科中首次分离得到的ent-abietane (Part A )与rosane (Part B)的异源二聚体,是通过Part A的14位与Part B的18'位间酯键连接而成,其中化合物2中的Part B单元发生了2'位与3'位的断裂,并推测了化合物1和2的生源途径。化合物1通过X射线单晶衍射数据获得其绝对构型。从金刚纂 (E. antiquorum L.)中分离得到29个化合物,包括23个二萜类化合物,其中6个新化合物; 以上两种植物分离得到的二萜涉及了多种骨架类型,包括二萜二聚体,松香烷型,玫瑰烷型,阿替生烷型,续随子烷型,海松烷型,巨大戟烷型,贝壳杉烷型。 我们对所获得二萜类化合物开展了体外细胞毒活性研究,其中化合物1, 2, 3, 7, 20对肿瘤细胞株显示出一定的细胞毒活性;特别是化合物1对肿瘤细胞株HL-60, SMMC-7721显示了较强的体外细胞毒活性,IC50值分别为2.61, 4.08 μM, 同时,该化合物对肿瘤干细胞株P6C显示出较强的抑制活性,IC50值达16.4 μM,并可抑制肿瘤干细胞株P6C的入侵、转移以及肿瘤球体的形成;机制研究发现化合物1能在浓度20 μM诱导细胞凋亡和坏死;HYX-3能够通过影响溶酶体转录因子的定位进而促进溶酶体的生成;评价了化合物1, 2, 3, 7, 20调控Nf-κB信号通路活性。第二章苦木科牛筋果属牛筋果植物的化学成分和生物活性研究。从牛筋果中分离得到化合物42个,涉及的化合物类型包括柠檬苦素、色原酮、木质素、C-21甾体、黄酮以及简单苯取代物等,其中新化合物19个,包括17个柠檬苦素类化合物,2个色原酮类化合物 (互为对映异构体)。化合物1和2是一对Z/E顺反异构体,具有新颖骨架的Nor-6,7-C-24型柠檬苦素类化合物,其中化合物1的绝对构型是通过X射线单晶衍射数据获得的。化合物3是具有新颖环系的C-25型柠檬苦素,文中按照结构特点及重排规律对牛筋果中的柠檬苦素类化合物进行归纳总结,推测了相应的柠檬苦素生源途径,并评价其体外细胞毒活性,一氧化氮 (NO)生成抑制剂活性,以及抑制马铃薯晚疫病原菌活性。 第三章综述了2013年至2016年大戟科大戟属植物的二萜类化学成分及生物活性研究进展。

其他摘要

This thesis investigated the chemical constituents and their biological activities of three species, including Euphoria ebracteolata Hayata, Euphorbia antiquorum L., and Harrisonia perforata (Blanco) Merr. By the means of chromatographic methods and spectroscopic elucidation in conjunction with single-crystal X-ray diffraction analysis, 107 compounds, including 32 new ones were identified. The results also highlighted with two abietane-rosane diterpenoid heterodimers and three novel nortriterpenoids with unprecedented skeleton or ring system. The involved compounds mainly include diterpenoids and limonoids. Most of compounds were assayed for their cytotoxicity, or approached on the mechanism of apoptosis, promoted lysosomal biogenesis, inhibited growth of tumor stem cells, inhibited on LPS-induced NO production in RAW 264.7 macrophages, Nf-κB signaling pathway, and inhibited on Potato late blight fungus.Chapters 1, phytochemistry investigations and biological screening on the two species of Euphorbia. Phytochemistry investigations on the roots of E. ebracteolata Hayata resulted in isolation of 36 compounds, including 7 new diterpenoids. To the best of our knowledge, compounds 1?2 are the first example of an abietane-rosane diterpernoid heterodimer from Euphorbiaceae, The two monomeric parts A and B were linked via the ester bond of C-14/C-18', and the absolute configuration of 1 was finally determined via single crystal X-ray diffraction, while C-2'?C-3' bond was proposed to cleave regarding 2, We also proposed their biosynthetic pathways. Phytochemistry investigations on E. antiquorum L. has led to isolate 29 compounds, including 6 new diterpenoids. Most diterpenoids isolated were assayed for their cytotoxicities against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7 and SW-480. Some diterpenoids showed cytotoxicities. Compound 1 showed antiproliferative activities against human tumor cells, HL-60 and SMMC-7721 with IC50 values of 2.61 and 4.08 μM, respectively, and the colorectal cancer stem cell, P6C, with IC50 value of 16.4 μM. Biological tests showed that compound 1 could induce significant apoptosis at 20 μM in SMMC-7721 cell lines using flow cytometry, exhibit inhibitory activities toward migration/invasion and tumorsphere formation of the P6C. Moreover, HYX-3 can promote the formation of lysosomes by influencing the location of lysosomal transcription factors. In addition, the effects of 1, 2, 3, 7, 20 on the tumor-assosicated Nf-κB signaling pathway were also evaluated with the Dual Luciferse Reporter Assay System. Chapters 2, phytochemistry investigations and biological screening on H. perforata (Blanco) Merr. resulted in isolation of 42 compounds, including 17 new linmonoids, and a pair of new chromone enantiomers. Compound 1 and 2 were a pair of Z/E isomer, with unprecedented Nor-6,7-C-24 skeleton, and the absolute configuration of compound 1 was finally determined via single crystal X-ray diffraction. Compound 3 was a novel skeleton of C-25 type limonoid. This thesis summarized the structural characteristics and the regularity of rearrangement limonoids in H. perforata (Blanco) Merr., plausible biosynthetic of new linmonoids pathways were also proposed. Moreover, the most of linmonoids isolated were assayed for their cytotoxic activity, inhibitory activities on LPS-induced NO production in RAW 264.7 macrophages, and inhibitory activities of Potato late blight fungus. Chapters 3, reviewed the advanced progress on the chemical constituents and biological activity of diterpenoids in the genus Euphorbia from 2013 to 2016.

文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4934
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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袁文娟. 两种大戟属植物和牛筋果的化学成分及其活性研究[D]. 北京. 中国科学院大学,2017.
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