海菜花化学成分研究和Telekin的结构改造

	海菜花化学成分研究和Telekin的结构改造
	曾政权
导师	李顺林
关键词	天然产物、海菜花、天名精、倍半萜内酯、结构修饰 Natural Products, Ottelia acuminata, Carpesium abrotanoides L., Sesquiterpene lactone, Structural modification
摘要	天然产物由于其独特的骨架结构和多样的生物活性，在有机化学和药物开发中起着重要作用。目前，77%获批上市的小分子药物，其来源都可以追溯至天然产物及其衍生物或类似物。我国地域辽阔，有着多样的植物类群，尤其是在西北和西南地区，由于其独特的自然生态环境，孕育了许多珍稀的植物资源，因此，对天然产物的研究与利用有着得天独厚的优势。本论文包括两部分工作：第一部分工作选用产自我国云南地区的药食同源类植物——海菜花为研究对象，首次对其进行系统的植物化学研究，并对其有效成分进行生物活性测试。第二部分工作，关于我国传统药用植物天名精量丰成分Telekin的结构改造研究，对所得到的衍生物进行体外抗肿瘤活性测试，并对活性显著化合物的作用机制进行初步探究。第一部分工作的具体研究内容：1）海菜花的化学成分研究，以采自云南省大理白族自治州洱源县东湖湿地的海菜花（Ottelia acuminata）全草为研究对象。综合利用正相、反相、凝胶等柱层析手段，从海菜花中共分离鉴定40个化合物，其中新化合物7个。化合物类型包括黄酮、甾醇、二芳基庚烷、吲哚生物碱、脂肪酸、二烯酮类、糖苷类等，上述化合物均为首次从海菜花中分离得到。2）海菜花中部分化合物的生物活性研究，分离得到的两个二芳基庚烷类化合物（1和3）具有一定抗氧化活性。化合物7和8（二烯酮类化合物）有显著的体外抗肿瘤活性，其中化合物8在HL60细胞系中其IC50 = 0.024±0.003 μM，明显优于阳性对照药顺铂。第二部分工作的具体研究内容：1）关于我国传统药用植物天名精中量丰成分Telekin（一种倍半萜内酯化合物）的结构改造研究。首先，利用其A环环外双键易重排的特性，以对甲苯磺酸为催化剂，换用不同的反应溶剂得到不同的重排产物，并初步推测了其反应机理，接着采用氧化等策略对重排产物进一步修饰。此外，我们对该化合物结构中C环进行水解，发现水解产物的体外抗肿瘤活性远远低于Telekin，由此证实Telekin上C环的α, β-不饱和内酯片段是使其具有体外抗肿瘤活性的关键结构。2）选择HL-60、A-549、SMMC-7721、MCF-7、SW-480这五株不同组织来源的细胞株，对合成的17个Telekin衍生物进行体外抗癌活性的初筛实验，筛选出6个具有显著抗肿瘤活性的化合物，其中化合物h效果尤为显著（在SMMC-7721细胞系中，其IC50 = 5.07±0.03 μM，肿瘤抑制效果是Telekin的3倍）。进一步，我们又对化合物h进行了初步的作用机理探究，通过细胞凋亡、线粒体膜电位、细胞周期等实验，发现化合物h通过诱导肿瘤细胞线粒体膜电位降低，从而促进肿瘤细胞凋亡，阻滞细胞周期在G2/M期。; Natural products are complex and varied in structure, and most of them possess diverse biological activities, which have potential applications for drug research and development. Currently, 77% of drugs approved for marketing can be traced back to natural products and their derivatives or analogues. Therefore，natural products have been extensively studied as a source of drug-lead structures. In addition, the vast territory of China has nurtured the rich botanical resources, especially in the north-western and south-western regions, which, due to their unique natural ecological environment, possess many unique medicinal plants, and thus, have great advantages for the research and utilization of natural products. This thesis consists of two sections: the first section chose Ottelia acuminata, which are abundant in Yunnan, China, as the subject of study. We have carried out the first systematic phytochemical study and the related biological activity research on them. The second section was to design and synthesis of Telekin derivatives. Telekin is a volume-rich ingredient in Carpesium abrotanoides L., a traditional Chinese medicinal plant. Cytotoxic activities of these derivatives against five human cancer cell lines were evaluated, and the results indicated that six compounds exhibited strong tumor inhibitory activity. The specific studies in the first section include: The chemical composition of Ottelia acuminata was investigated by using the whole herb of Ottelia acuminata, which was harvested from Dali Bai Autonomous Prefecture, Yunnan Province. A total of 40 compounds were isolated and identified from Ottelia acuminata, combination of normal-phase, reversed-phase and gel chromatography, including 7 new compounds. These 40 compounds, including flavonoids, sterols, diarylheptanoids, indole alkaloids, fatty acids, dienones, glycosides and others were isolated and identified from Ottelia acuminata for the first time. 2) We investigated the biological activity of some of the chemical components isolated from Ottelia acuminata. Firstly, the diarylheptanoids were evaluated for antioxidant activity, and two compounds with certain antioxidant activity were screened. After evaluating the in-vitro antitumor activity of the dienone, Compounds 7 and 8 showed significant in vitro antitumour activity, with compound 8 having an IC50 = 0.024 ± 0.003 μM in the HL60 cell line, which was more potent than positive control drug, cisplatin. The specific studies in the second section include: 1) Structural modification of Telekin, a sesquiterpene lactone compound isolated from the traditional medicinal plant Carpesium abrotanoides L. in China, was performed. Firstly, several rearrangement products were obtained by modifying the exo double bond in A-ring under acidic conditions. The rearrangement reaction mechanism was also briefly speculated. Then further modifications were carried out by using various strategies. The hydrolysis product was found to have much lower an
语种	中文
	2022-05
学位授予单位	中国科学院大学
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75150
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	曾政权. 海菜花化学成分研究和Telekin的结构改造[D]. 中国科学院大学,2022.

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