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Thesis Advisor阿吉艾克拜尔·艾萨
Degree Grantor中国科学院大学
Place of Conferral北京
Degree Name博士
Degree Discipline有机化学
Keyword阿纳其根 天山堇菜 瘤果黑种草籽 生物碱 生物合成途径

生物碱是广泛分布于自然界中的一类含氮有机化合物。其骨架结构丰富多样,生物活性广泛而显著, 因而备受科学家们的关注。近年来,有关生物碱的分离纯化、 化学合成、 生物合成以及活性机理研究已逐步成为研究的热点。本论文以三种维药经典药材: 阿纳其根( 菊科植物罗马除虫菊 Anacyclus pyrethrum (L) DC 的干燥根)、 比那夫西( 天山堇菜 Viola tianshanica Maxim 的干燥全草) 和斯亚旦( 瘤果黑种草 Nigella glandulifera Freyn 的干燥种子) 为研究对象,综合利用现代分离纯化技术对其总生物碱进行了系统的分析分离纯化,并利用现代波谱技术( 1D、 2D-NMR, HRESIMS, ECD, UV)对分离得到的生物碱化合物进行了详细的结构表征, 共鉴定了 57 个生物碱化合物,其中新化合物50 个,包括 21 个新骨架化合物(拥有 8 种新骨架类型),并对这些生物碱类化合物进行生物活性筛选。从阿纳其根中分离纯化并鉴定了 27 个生物碱化合物,其中新化合物 24 个( AP1-AP16,含 8对对映异构体),包括 9个新骨架化合物( AP4, (+)-AP8/(-)-AP8,(+)-AP9/(-)-AP9, (+)-AP10/(-)-AP10, (+)-AP11/(-)-AP11),拥有新骨架类型 4 种。并对分离得到的这 27 个生物碱化合物分别进行 5 型磷酸二酯酶(PDE5) 抑制活性和 Menin-MLL1 蛋白蛋白相互作用阻断活性筛选,结果表明这些生物碱化合物对 PDE5 均无抑制活性,而对 Menin-MLL1 蛋白蛋白相互作用有较弱的阻断作用,其中(-)-AP6、 (+)-AP10、 (+)-AP13 在 20 μM 浓度下对 Menin-MLL1 蛋白蛋白相互作用的阻断活性均大于 40%。从天山堇菜全草中分离纯化并鉴定了 26 个生物碱化合物,其中新化合物 24个( VT3-VT15,含 11 对对映异构体),包括 12 个新骨架化合物( (+)-VT3/(-)-VT3,(+)-VT4/(-)-VT4, (+)-VT5/(-)-VT5, (+)-VT6/(-)-VT6, (+)-VT7/(-)-VT7, (+)-VT9/(-)-VT9),拥有新骨架类型 4 种。 并对这 26 个生物碱化合物进行Menin-MLL1蛋白蛋白相互作用阻断活性筛选,结果表明这些生物碱化合物对 Menin-MLL1蛋白蛋白相互作用的阻断活性较弱,但总体上比阿纳其根中的化合物略强,其中(-)-VT4 和(-)-VT7 在 20 μM 浓度下对 Menin-MLL1 蛋白蛋白相互作用的阻断活性接近 50%,说明这些化合物在结构上对于急性白血病药物的设计和开发具有一定的借鉴意义。 从瘤果黑种草籽中分离纯化并鉴定了 4 个生物碱化合物( NG1-NG4),其中新化合物 2 个(NG1-NG2)。并对这 4 个生物碱化合物进行了蛋白酪氨酸磷酸酶( PTP1B)抑制活性筛选,结果表明化合物 NG1 具有较强的 PTP1B 抑制活性( IC50 = 3.65 ±0.08 μM),说明该化合物可作为降糖药先导化合物进行进一步的研究。另外,对分离得到的生物碱化合物的结构进行系统的归纳分析,发现绝大部分的化合物属于哌啶类生物碱。同时,在推导这些化合物的生物合成前体的过程中发现这些哌啶类生物碱化合物在生源上并非来源于经典的赖氨酸途径,它们的氮源极有可能来源于甘氨酸或丙氨酸脱羧途径,也可能来源于酶催化的转氨作用。该研究成果不仅丰富了哌啶类生物碱家族的骨架类型,同时也为化学生物学家们在哌啶类生物碱生源途径方面的研究提供了一些新的思考和借鉴。

Other Abstract

Alkaloids, an indispensable member of the natural products family, are a class of nitrogen-containing organic compounds that widely distributed in nature. They have been found to display a variety of skeletons and a wide range of significant bioactivities, which attracts scientists to carry out a series of related researches concerning separation and purification, chemical synthesis, biosynthesis and pharmacological studies.This thesis mainly focus on the isolation, structure elucidation, plausible biosynthetic pathway and bioactive investigation of the alkaloid constituents of three kinds of commonly used herbs in Uygur medicine, Anacyclus pyrethrum, Viola tianshanica and Nigella glandulifera, aiming at finding alkaloids with novel structures and significant bioactivities from these three medicinal plants.A total of 27 alkaloids were isolated from Anacyclus pyrethrum, among which 24 were new alkaloids (AP1-AP16, including eight pairs of enantiomers), and nine of them [AP4, (+)-AP8/(-)-AP8, (+)-AP9/(-)-AP9, (+)-AP10/(-)-AP10, (+)-AP11/ (-)-AP11] possessed four types of new skeletons. All of these alkaloids were evaluated for their potential activities of inhibiting the type 5 phosphodiesterase (PDE5) and of interfering the menin?mixed lineage leukemia 1 (MLL1) protein?protein interaction. The results showed that these alkaloids have no inhibitory activity against PDE5, but exhibited weak inhibitory activity on menin?MLL1 protein?protein interaction at the initial concentration of 20 μM.A total of 26 alkaloids were obtained from Viola tianshanica, among which 24 were new alkaloids (VT3-VT15, including 11 pairs of enantiomers), and 12 of them [(+)-VT3/(-)-VT3, (+)-VT4/(-)-VT4, (+)-VT5/(-)-VT5, (+)-VT6/(-)-VT6, (+)-VT7/ (-)-VT7, (+)-VT9/(-)-VT9] displayed four kinds of novel skeletons. These alkaloids showed weak inhibitory activity on menin?MLL1 protein?protein interaction at the initial concentration of 20 μM, among which the optically pure enantiomers, (-)-VT4 and (-)-VT7, exhited the inhibition rate closed to 50%.Four alkaloids (NG1-NG4) were separated from Nigella glandulifera, among which two were new compounds (NG1-NG2). These alkaloids were measured for the protein tyrosine phosphatase 1B (PTP1B) inhibitory activity, and the results showed that only NG1 exhibited potent inhibitory activity with an IC50 value of 3.65 ± 0.08 μM.In addition, it is noticed that most of the isolated alkaloids belong to the piperidine alkaloid family. The hypothetical biosynthetic precursors of these piperidine alkaloids hint that they are not derived from the classical lysine pathway, but are most likely to be originated from the decarboxylation of glysine or alanine, or from enzyme-catalyzed transamination.Undoubtedly, the discovery of these alkaloids not only enriches the piperidine alkaloid family, but also provides a new inspiration concerning the biogenesis of piperidine alkaloids.

Document Type学位论文
Recommended Citation
GB/T 7714
陈其宾. 三种维药经典药材生物碱类成分及其生物活性研究[D]. 北京. 中国科学院大学,2017.
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