没食子单体化合物分离鉴定及其药理活性研究
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摘要
没食子为没食子蜂科(瘿蜂科)昆虫没食子蜂(Cynips gallae-tinctoriae Olivier)的幼虫,寄生于壳斗科植物没食子树( Quercus infectoria Olivier)幼枝上产生的虫瘿。没食子药用历史悠久,为维吾尔医常用药,具有固气,涩精,敛肺,止血之功效。本实验室前期研究表明,其粗提物具有较强的体外抑菌功能。本文在综述没食子化学成分及药理活性的研究进展基础上,对没食子的化学成分进行了系统研究,并对部分单体化合物进行药理活性实验。从没食子95%乙醇冷浸液中通过溶剂回流提取法及各种色谱分离手段(硅胶柱层析, TLC, Sephadex LH-20,ODS, MCI, HPLC)提取分离得到了12个化合物,通过1H-NMR、13C-NMR,HMQC、HMBC等波谱方法对其中9个化合物的结构进行鉴定,确定其结构分别为:没食子酸(1);间-二没食子酸(2);对-二没食子酸(3);没食子酸甲酯(4);没食子酸乙酯(5);1, 2, 3, 6-四-0-没食子酰基-β-D-葡萄糖( 6);1, 2, 3, 4, 6-五-0-没食子酰基-β-D-葡萄糖(7);1-O-没食子酰基- O-β-D-葡萄糖(8);1,6-二-0-没食子酰基- O-β-D-葡萄糖(9)。其中化合物对-二没食子酸(3)、没食子酸乙酯(5)、1-O-没食子酰基- O-β-D-葡萄糖(8)和1,6-二-0-没食子酰基- O-β-D-葡萄糖(9)均为首次从该植物中分离得到。对没食子化合物1, 2, 3, 6-四-0-没食子酰基-β-D-葡萄糖、没食子酸乙酯、没食子酸、没食子酸甲酯的部分药理活性进行了研究,结果表明:4种化合物对4种革兰氏阳性菌、3种革兰氏阴性菌和真菌白色念珠菌(ATCC10231)菌均具有体外抑菌活性,抑菌浓度为7.27-29.09μg/mL,其中化合物没食子酸、没食子酸甲酯、没食子酸乙酯对金黄色葡萄球菌(ATCC 25923)、仔猪副伤寒沙门氏菌(S.C 500)具有较强的抑菌活性,最小抑菌浓度为7.27μg/mL; 4种化合物对小鼠骨髓瘤SP2/0癌细胞具有较强的体外抗癌活性。细胞生长明显受到抑制,抑制作用呈浓度依赖关系,化合物1,4,5,6其IC50分别为:1.838mg/mL、1.221mg/mL、3.658mg/mL、3.035mg/mL;急性毒性试验结果表明没食子化合物没食子酸、没食子酸乙酯、1, 2, 3, 6-四-0-没食子酰基-β-D-葡萄糖LD50值无法做出,其最大安全耐受量倍数为137、151、157,相当于成人常用量的(0. 08g/kg·d - 1) 100倍以上,该剂量认为是安全可行的。没食子酸甲酯其半数致死剂量LD50为1.9004(g/kg), LD50可信限为1.821±1.984(g/kg),LD50的平均可信限为(1.9004±0.0815) g/kg,表明该化合物略有毒性,临床应用时要注意其毒性,其毒性机理有待进一步研究。
Turkish galls is produced by larvae of Gallic bee insects (Cynips gallae-tinctoriae Olivier), who are parasiticed in young branches of the Fagaceae Gallic tree (Quercus infectoria Olivier). Their female ovipositor stabs Gallic tree bud to make vegetation grow, in which its eggs are hatched into larvae. The larvae can secret enzyme-contained liquid, which can induce rapid transformation from starched to sugar in somatic cells of plants, and stimulate the plant meristem cells, then the neoplasm gradually grows into Turkish galls. Turkish galls is mainly produced in Mediterranean Sea, Turkey, Arabia, Iran, India, Greece and other places, especially in the largest production in Asia Minor; Turkish galls in Xinjiang province is mainly imported from Pakistan. Turkish galls has a long history of medicinal use, with a solid-gas, arresting seminal emission, astringing lung, the hemostasis. Previous studies in our laboratory indicated that its extract had a strong inhibitory function in vitro.
At present, the study on Turkish galls is limited to its pharmacology and its extracts. Research showed that Turkish galls has a wide range of pharmacological effects, for example the crude extract had a better antimicrobial effect on Staphylococcus aureus, Salmonella choleraesuis and E. coli in vitro. At present, some researches reported the chemical composites of Turkish galls, but they were particularly prevalent in the small and medium-polarity polar pars. There is few study on its active composites. Based on the previous related studies, we systematically studied the chemical composition of Turkish galls, determined the structure of some monomer of and did some pharmacological experiments on them. Our study provides scientific evidence for the development and utilization of Turkish galls, and its quality standards.
In this study, we overviewed the progress of chemical constituents and pharmacological research about Turkish galls. The chemical constituents of Turkish galls were separated by using silica gel, SephadexLH-20 column chromatography, preparative thin-layer chromatography and HPLC. After that, we obtained 12 compounds and their structures were identified by physiochemical properties and 1H-NMR, 13C-NMR, HMQC, HMBC and other spectroscopic methods. The compounds obtained were identified to be gallic acid (1);m-digallic acid (2); p-digalloyl acid (3); methyl gallate (4);ethyl gallate (5);1,2,3, 6-tetra-0-galloyl-β-D-glucose(6);1,2,3,4,6-penta-0-galloyl-β-D-glucose(7),1-0-galloyl-β-D-glucose(8),and1,6-di-0-galloyl-β-D-glucose(9), p-digalloyl acid, Ethyl gallate, 1-0-galloyl-β-D-glucose,and 1,6-di-0-galloyl-β-D-glucose were isolated from this plant for the first time. Some pharmacological activities of 1,2,3, 6-tetra-0-galloyl-β-D-glucose, gallic acid, methyl gallate, and ethyl gallate were studied, and the results of pharmacological experiments indicated that four kinds of compounds had antibacterial activity on four Gram-positive bacteria, three kinds of gram-negative bacteria and fungi Candida albicans (ATCC10231) strains in vitro. The inhibitory concentration was 7.27-29.09μg/mL. Among them, gallic acid compounds, methyl gallate, ethyl gallate against Staphylococcus aureus (ATCC25923), and Salmonella paratyphi piglets (S.C 500) had strong antibacterial activity, and the minimum inhibitory concentration was 7.27μg/mL. All compounds had strong anti-tumor activity to small mouse myeloma SP2 / 0 cells in vitro. They significantly inhibited the growth of mouse cell, and the effect of inhibition was concentration-dependent.The IC50 of compound1,4, 5, 6 were1.838mg/mL, 1.221mg/mL, 3.658mg/mL, and 3.035mg/mL, respectively. The acute toxicity test results showed that the LD50 value of compound gallic acid, ethyl gallate, and 1, 2, 3, 6-d-0-galloyl-β-D-glucose could not be obtained. The maximum tolerated dose in multiples of security were the 137,151 and 157, which were 100 times higher than the dose of adults commonly used (0. 08g/kg ? d - 1), so they are safe and feasible. LD50 of methyl gallate was 1.9004 (g / kg), and confidence limit of LD50 was 1.821±1.984 (g / kg). The average confidence limit LD50 was the (1.9004±0.0815) g / kg, which indicated that the compounds were slightly toxic, so attentions should be paid in its clinical application. Its mechanism of toxicity remains to be further studied.
Turkish galls is produced by larvae of Gallic bee insects (Cynips gallae-tinctoriae Olivier), who are parasiticed in young branches of the Fagaceae Gallic tree (Quercus infectoria Olivier). Their female ovipositor stabs Gallic tree bud to make vegetation grow, in which its eggs are hatched into larvae. The larvae can secret enzyme-contained liquid, which can induce rapid transformation from starched to sugar in somatic cells of plants, and stimulate the plant meristem cells, then the neoplasm gradually grows into Turkish galls. Turkish galls is mainly produced in Mediterranean Sea, Turkey, Arabia, Iran, India, Greece and other places, especially in the largest production in Asia Minor; Turkish galls in Xinjiang province is mainly imported from Pakistan. Turkish galls has a long history of medicinal use, with a solid-gas, arresting seminal emission, astringing lung, the hemostasis. Previous studies in our laboratory indicated that its extract had a strong inhibitory function in vitro.
At present, the study on Turkish galls is limited to its pharmacology and its extracts. Research showed that Turkish galls has a wide range of pharmacological effects, for example the crude extract had a better antimicrobial effect on Staphylococcus aureus, Salmonella choleraesuis and E. coli in vitro. At present, some researches reported the chemical composites of Turkish galls, but they were particularly prevalent in the small and medium-polarity polar pars. There is few study on its active composites. Based on the previous related studies, we systematically studied the chemical composition of Turkish galls, determined the structure of some monomer of and did some pharmacological experiments on them. Our study provides scientific evidence for the development and utilization of Turkish galls, and its quality standards.
In this study, we overviewed the progress of chemical constituents and pharmacological research about Turkish galls. The chemical constituents of Turkish galls were separated by using silica gel, SephadexLH-20 column chromatography, preparative thin-layer chromatography and HPLC. After that, we obtained 12 compounds and their structures were identified by physiochemical properties and 1H-NMR, 13C-NMR, HMQC, HMBC and other spectroscopic methods. The compounds obtained were identified to be gallic acid (1);m-digallic acid (2); p-digalloyl acid (3); methyl gallate (4);ethyl gallate (5);1,2,3, 6-tetra-0-galloyl-β-D-glucose(6);1,2,3,4,6-penta-0-galloyl-β-D-glucose(7),1-0-galloyl-β-D-glucose(8),and1,6-di-0-galloyl-β-D-glucose(9), p-digalloyl acid, Ethyl gallate, 1-0-galloyl-β-D-glucose,and 1,6-di-0-galloyl-β-D-glucose were isolated from this plant for the first time. Some pharmacological activities of 1,2,3, 6-tetra-0-galloyl-β-D-glucose, gallic acid, methyl gallate, and ethyl gallate were studied, and the results of pharmacological experiments indicated that four kinds of compounds had antibacterial activity on four Gram-positive bacteria, three kinds of gram-negative bacteria and fungi Candida albicans (ATCC10231) strains in vitro. The inhibitory concentration was 7.27-29.09μg/mL. Among them, gallic acid compounds, methyl gallate, ethyl gallate against Staphylococcus aureus (ATCC25923), and Salmonella paratyphi piglets (S.C 500) had strong antibacterial activity, and the minimum inhibitory concentration was 7.27μg/mL. All compounds had strong anti-tumor activity to small mouse myeloma SP2 / 0 cells in vitro. They significantly inhibited the growth of mouse cell, and the effect of inhibition was concentration-dependent.The IC50 of compound1,4, 5, 6 were1.838mg/mL, 1.221mg/mL, 3.658mg/mL, and 3.035mg/mL, respectively. The acute toxicity test results showed that the LD50 value of compound gallic acid, ethyl gallate, and 1, 2, 3, 6-d-0-galloyl-β-D-glucose could not be obtained. The maximum tolerated dose in multiples of security were the 137,151 and 157, which were 100 times higher than the dose of adults commonly used (0. 08g/kg ? d - 1), so they are safe and feasible. LD50 of methyl gallate was 1.9004 (g / kg), and confidence limit of LD50 was 1.821±1.984 (g / kg). The average confidence limit LD50 was the (1.9004±0.0815) g / kg, which indicated that the compounds were slightly toxic, so attentions should be paid in its clinical application. Its mechanism of toxicity remains to be further studied.
引文
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