仙茅的化学成分与抗HBV活性研究
左爱学
学位类型博士
导师陈纪军
2010-05
学位授予单位中国科学院研究生院
学位专业药物化学
摘要本论文围绕抗乙型肝炎病毒(Hepatitis B virus, HBV)活性成分的发现,选择仙茅科(Hypoxidaceae)仙茅属植物仙茅(Curculigo orchioides Gaertn.)(Rhizoma Curculiginis)进行了较系统的化学成分研究。从仙茅的90%乙醇总提取物中分离鉴定了83个化合物,结构类型涉及酚及酚苷、环阿尔廷三萜醇及其苷、倍半萜、单萜、环二肽、苯丙素、木脂素、杂环类小分子等。其中新化合物26个,特别重要的是发现了3个结构新颖的酚苷二聚体orcinosides A-C(1-3),4个含有杂环的新颖的酚类小分子orcinosides I-K (9-11)和orcinol A(20),2个新的含有氯原子的酚苷类化合物orcinosides L – M(12-13),2个新的环阿尔廷三萜curculigosaponins N-O(25-26)和15个其它类新的酚类成分。本研究还首次从仙茅中分离鉴定了系列环二肽类成分,拓宽了仙茅的化学成分结构类型。采用含有HBV基因组的质粒转染Hep G 2.2.15细胞系测定化合物对乙肝病毒表面抗原 (HBsAg) 和e抗原 (HBeAg) 分泌的影响来评价其抗HBV活性,首次对从仙茅中分离得到部分的化合物进行了抗HBV活性研究,发现其中的酚苷二聚体、含有杂环和含氯原子的酚类成分、环肽等对HBsAg和HBeAg分泌具有抑制作用。其中新化合物orcinol B(21)活性较好,其抑制HBsAg 和HBeAg 的IC50值分别为2.22 mM、0.83 mM,对HBsAg 和HBeAg 的选择指数(Selective Index, SI)分别为1.75和4.66。具有杂环的新酚苷化合物orcinoside K(11)对HBsAg 和HBeAg 分泌的IC50值分别为2.17 mM和1.60 mM,对HBsAg 和HBeAg 的选择指数SI均大于1。含氯原子的酚苷化合物orcinoside M(13)对HBsAg的IC50值为1.38 mM,对HBeAg的IC50值为1.76 mM。化合物orcinoside E(5)和orcinol A(20)均对HBsAg显示出一定的抑制作用,其IC50值分别为1.85和3.51 mM。本研究不但深入地揭示了仙茅多种酚类新成分,还发现了系列酚苷类二聚体类化合物,杂环片段直接连接在酚类母核上延伸了碳原子的骨架或者杂环片段与母核取代基连接的新酚类以及环肽类成分,丰富了仙茅的化学成分结构类型。同时还发现其中一些化合物具有抗HBV活性,为拓宽仙茅的开发利用提供了新物质基础和研究线索。
资助项目In our continuing efforts to find anti - HBV (hepatitis B virus ) agents from natural sources, the chemical constituents of Curculigo orchioides Gaertn.were investigated intensively to result in the isolation and identification of 83 compounds from the 90% EtOH extract of rhizomers. The types of isolates involved in phenols and phenolic glycosides, cycloartenols and cycloartane saponins, monoterpenoids, sesquiterpenoids, cycolodipeptides, liglans, orcinosides A-C), four phenolic derivatives (orcinosides H-J and orcinol A) linked with heterocycle, and two phenolic glycosides (orcinosides K-L) contained chlorine atom, were elucidated based on spectroscopic methods (1H NMR, 13C NMR, HSQC, HMBC, COSY, ROESY, IR, MS, UV). Additionally, our investigation revealed the presence of C. orchioides for the first time. cyclic dipeptides from steroids, heterocycles, sugars, and fatty acids. Among them, 26 new compounds, including three novel dimeric phenol glycosides (Those findings enlarged the knowledge of chemical constituents from C. orchioides. The isolateswere evaluated for their anti-HBV activities in the HBV transfected Hep G 2.2.15 cell line in vitro. The results demonstrated that the phenolic glycoside dimers, phenolic derivatives linked with heterocycle, phenolic glycosides contained chlorine atom, and cyclic dipeptides had inhibitory action on the production of HBsAg and HBeAg. The most active compound, orcinol B (21), showed an IC50 value of 2.22 mM in inhibiting HBsAg secretion with a selectivity index (SI = 1.75) and an IC50 value of 0.83 mM (SI = 4.66) in inhibiting HBeAg secretion of the Hep G2.2.15 cells. Compound 11, possessed a heterocycle in the molecule, exhibited moderate inhibitory activities against HBsAg and HBeAg with IC50 value of 2.17 and 1.60 mM, respectively; T he compound 13, connected with two chlorine atom, showed an IC50 value of 1.38 mM in inhibiting HBsAg secretion and an IC50 value of 1.76 mM inhibiting HBeAg secretion of the Hep G2.2.15 cells. Compounds 5 and 20 showed potent anti-HBV activity, inhibiting HBsAg secretion with IC50 of 1.85 mM and 3.51 mM, respectively. Our extensive investigation on the chemical constituents of C. orchioides led to the isolation of phenolic glycoside dimers, phenolic dervatives linked with heterocycle, phenolic glycosides contained chlorine atom, and cyclic dipeptides from C. orchioides. To the best of our knowledge, it was the first time to investigate the anti - HBV activities of C. orchioides; it was also for the first time to report the phenolic dervatives from C. orchioides with anti-HBV activity. Up to now, no other documents reported the dimeric phenol glycosides from the family Hypoxidaceae except our latest paper. It was also found for the first time that the heterocycle moieties, existed as a substituent of phenolic glycosides in C. orchioides, characterized by the different linkage pattern for heterocycle with the C-atom in the phenolic glycosides, or with the substitutes in the phenolic glycosides. Those finding including phenolic glycoside dimers, phenolic dervatives linked with heterocycle, phenolic glycosides contained chlorine atom, and cyclo-dipeptides from C. orchioides provided fundamental substance for further exploring of C. orchioides.
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/16100
专题昆明植物所硕博研究生毕业学位论文
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左爱学. 仙茅的化学成分与抗HBV活性研究[D]. 中国科学院研究生院,2010.
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