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新疆道地药材中二萜生物碱核磁规律与高乌甲素体外代谢
海力马依·海米提
学位类型硕士
导师侯雪玲
2016-06-03
学位授予单位中国科学院大学
学位授予地点北京
学位专业材料工程
摘要

二萜生物碱主要存在于毛茛科(Ranunculeceae)乌头属(Aconitum)和翠雀属(Delphinium)植物中,具有广泛而显著的生物活性与药用价值。60年代以来,随着现代波谱技术特别是核磁共振技术在结构分析中的广泛应用,二萜生物碱的研究得到了迅速发展。氢溴酸高乌甲素是从毛茛科乌头属植物中提取分离得到的一种二萜类生物碱,属于拉巴乌头碱(Lappaconitine)。根据二萜生物碱的结构差异,一般将其分为C18-二萜生物碱、C19-二萜生物碱、C20-二萜生物碱和双二萜型。我们的民族药创新研究团队对新疆道地药材进行了多年的研究,从几种翠雀属植物(天山翠雀花和萨乌尔翠雀花)和乌头属植物(多根乌头和白喉乌头)中分离得到了一系列二萜类生物碱,本论文对这些二萜类生物碱的1H-NMR和13C-NMR数据进行整理,总结了该类化合物的结构与核磁共振谱数据之间的规律,初步对氮杂缩醛等特殊结构单元的1H-NMR和13C-NMR化学位移值范围进行了归纳,为建立二萜类生物碱的核磁共振谱数据库打下基础,并为今后能通过NMR识别技术发现新的二萜类生物碱提供了方向。另外,对这些化合物的活性筛选结果进行了归纳,发现其中一些化合物对人宫颈癌HeLa细胞株和人肺腺癌A549细胞株表现出较好的细胞毒活性。采用肝微粒体孵育体系的体外代谢研究方法,对氢溴酸高乌甲素的代谢过程及代谢产物结构进行了研究,建立了灵敏、快速的液相色谱-串联质谱 (HPLC-MS)的检测方法。体外代谢研究结果表明:氢溴酸高乌甲素在肝微粒体孵化体系的作用下进行了去甲基化、酯水解、单氧化、O-去甲基并单氧化、酰胺键水解并O-去甲基等多种代谢过程,生成了8种类型共计14种代谢产物。此研究结果,对今后该类化合物中活性成分的发现、结构改造以及给药途径和剂型的选择等提供了重要的依据。

其他摘要

Diterpenoid alkaloids mainly exist in the Ranunculeceae plants of Delphinium, Aconitum and Consolida, and have significant biological activities and medicinal value . Since 1960, with the development of modern technology, especially the widely use of NMR spectroscopy in structural analysis, research of diterpene alkaloids has been developing rapidly. Hydrobromide lappaconitine is one of the most important diterpenoid alkaloid with so many biological activities, which is isolated from Aconitum (Aconitum sinomoutanum nakai).Depending on the structure, diterpenoid alkaloids were classified into four categories: the C18-, C19-, C20-and double diterpenoidalkaloids. In recent years, our national drug innovation research team which focused on Xinjiang genuine medicinal materials had isolated some diterpenoid alkaloids, from several Delphinium genus plant (Delphinium tianshanicum W, Wang and Delphinium shawurense W, Wang), Aconitum plants (Aconitum karakolicum Rapaics and Aconitum leucostomum Vorosch). In this paper, the 1H-NMR and 13C-NMR data of these alkaloids were collected, based on their 1H-NMR and 13C-NMR data, the relationships of the structures and NMR data were studied. These works will help us to lay the foundation on building the NMR spectrum database of diterpenoid alkaloid compounds and to provide a new direction for discovering new diterpenoid alkaloid compounds by the NMR recognition technology. Antitumor activities of the isolated diterpenoid alkaloids showed that some compounds had good cytotoxicity against human cervical cancer HeLa cell lines and human lung adenocarcinoma A549 cell lines. By liver microsomes incubation system, the in vitro metabolic processes and metabolites of hydrobromide lappaconitine were studied. In this research,a sensitive and rapid liquid chromatography-mass spectrometry (HPLC-MS) detection method was established. Totally 14 metabolites were determined in hepatic microsomal incubation system, including the metabolites of hydrobromide lappaconitine by demethylation, ester hydrolysis, oxidation , single O- demethylation and oxidation, hydrolysis of the amide bond and O- demethylation chemical reaction. Study of the metabolic processes and metabolites of lappaconitine hydrobromide will provide important references for discovery of active ingredient, structural modification and route of administration.

文献类型学位论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4552
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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海力马依·海米提. 新疆道地药材中二萜生物碱核磁规律与高乌甲素体外代谢[D]. 北京. 中国科学院大学,2016.
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