远志和华南远志的化学成分及其生物活性研究
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摘要
远志为多年生草本植物细叶远志(Polygala tenuifolia Willd.)或卵叶远志(Polygala sibirica L.)的根,具有镇咳、祛痰、安定、益智、解毒消肿、补益强壮作用。远志的药理研究表明其能够明显改善由东莨菪碱引起的记忆障碍小鼠的记忆力,说明远志具有抗老年痴呆的作用。鉴于远志在临床上的良好效果和现代实验结果,我们认为极有可能从远志中发现具有改善学习记忆作用的先导化合物。为此我们以药理活性为指导,对远志进行了活性跟踪,并对有效部位进行了化学成分研究。远志根经95%乙醇回流提取,硅胶拌样,干燥后分别用氯仿、乙酸乙酯、丙酮和甲醇洗脱,得到4个洗脱部分。药理筛选结果表明:甲醇部分具有PC12细胞的保护作用。
对远志的甲醇部分和氯仿部分进一步以活性指导进行分离,运用硅胶、大孔树脂、凝胶Sephadex LH-20、中压液相色谱及高效制备液相色谱,分离得到46个化合物,通过UV、IR、1D NMR、2D NMR、MS等波谱分析及化学方法,鉴定了45个化合物的结构,包括16个三萜皂苷、13个寡糖多酯类、1个水杨酸类化合物、12个(口山)酮类化合物、1个甾醇类化合物、1个氨基酸和1个酯类化合物。其中7个三萜皂苷类化合物为新化合物,3个皂苷首次分离得到。
体外PC12细胞保护作用的研究表明,远志的甲醇部分和粗分后的含皂苷的PM6EF2和PM6EF6能提高模型组的PC12细胞的增殖率;皂苷类化合物1～16具有良好的活性PC12细胞作用(10~(-5)mol/L),其中化合物5,8,14,15的活性显著。对体外活性较强的2个皂苷组分和2个化合物(14和15)进行了学习记忆模型的体内实验,结果显示具有提高小鼠学习记忆的作用,化合物15的活性较强。
对远志皂苷在体内吸收和分布进行了探讨,发现远志皂苷能以原形进入血液,并结合对远志总皂苷LC-MS~n的研究结果从中指认了10个皂苷的结构。
华南远志(Polygala glomerata Lour.)为远志科远志属植物,主要分布于福建、广东、四川和云南,以全草入药。具有止咳、消积和活血散瘀的功效,主要用于治疗咳嗽胸痛、咽喉痛、肺痨、顿咳、小儿疳积、黄疸、痢疾、小儿麻痹后遗症、目赤、痈疽疖肿、跌打损伤等。通过药理筛选发现全草的95%乙醇提取物可促使PC12细胞分化,使细胞突起长度明显增加,即具有神经营养作用。为揭示华南远志药效的物质基础,根据药理筛选结果,对华南远志的95%乙醇提取物进行了系统的活性成分研究。在药理活性筛选指导下,利用大孔树脂、硅胶、凝胶Sephadex LH-20、中压液相色谱和高效制备液相色谱等多种技术和方法相结合,从华南远志的乙醇提取物中已分离得到46个化合物;并通过UV、IR、1DNMR、2D NMR、MS等波谱方法和化学方法相结合,鉴定了41个化合物的结构包括:三萜皂苷类6个,新皂苷1个(20);寡糖多酯类2个,(口山)酮类6个,新(口山)酮类5个(5～9,18),苯甲酮苷类5个,新苯甲酮苷类4个(1～4);远志醇衍生物4个均为新化合物(10～13);有机酸类化合物5个,4个为新化合物(14～17);黄酮类7个;木脂素类2个;其它类型的4个。其中有19个为新化合物。并根据其民间药用特点和远志属植物成分的活性报道,在抗肝炎、PC12细胞保护等药理模型上,对分离鉴定的主要成分进行了初步活性筛选。(口山)酮24和皂苷20,38,显示了PC12细胞的保护作用。化合物1-4,31有保肝活性。
根据质谱裂解规律和UV特征对华南远志的微量成分进行LC-MS~n研究,推测了16个微量成分可能的结构,包括6个黄酮苷、5个苯甲酮苷和5个(口山)酮苷。其中4个苯甲酮苷和1个(口山)酮苷为新化合物。
"Yuan Zhi",the roots of perennial herbaceous plant—Polygala tenuifolia Willd. in Polygalaceae family,has been playing an important role as traditional Chinese medicine having bioactivities including antitussive,expectorant,antipsychotic, cognitive improving,antidote,resolutive and tonic.The pharmacological studies on Yuan Zhi indicated its effect of anti-Alzheimer's disease based on its capability of obviously ameliorating the mice memory failure reduced by scopolamine in vivo. According to the satisfying remedial practice and modern experimental results,it is extremely promising to finding leading compounds for improving cognitive ability and memory.Therefore,following the bioactive values,we investigated the chemical constituents of the active parts from the extract of Polygala tenuifolia.The roots of P. tenuifolia were refluxed in 95%ethanol and concentrated,then the residue was eluted respectively by CHCl_3,EtOAc,acetone and MeOH after mixing with silica gel.The bioactivities of four elution fractions were evaluated,as a result the MeOH portion showed the protection of PC 12 from the glutamate and serum deficiency.
Bioassay-guided fractionation led to the isolation of 46 individual compounds,of which 45 were identified as 16 triterpenoid saponins,13 oligosaccharide polyesters,1 salicin,1 steroid,1 amine acid and 1 ester by spectroscopic methods including UV,IR, 1DNMR,2DNMR and MS etc as well as chemical experiments.Among them,seven triterpenoid saponins(1-7) were new and three other saponins were isolated from this plant for the first time.
Some compounds and residues were evaluated in search for substances with the neuroprotection effect against glutamate and serum deficiency and the data showed the PM6EF3 and PM6EF6(fraction riched in triterpenoid saponins) portions and compounds 1-16 could protect PC12 cell from serum deficiency and glutamate at the concentration of 10~(-5) mol/L,especially compounds 5,8,9,14 and 15 do better.In addition,the PM6EF3 and PM6EF6 portions exhibited moderate cognitive improving and cerebral protective effects in rats,compounds 14 and 15 also exhibited moderate cognitive improving and cerebral protective effects in rats.
The ADME of gross saponins were studied and the result indicated the saponins could be absorbed into blood in its own form without any modifying.The possible structures of 10 trace saponins were deduced from the serum by use of HPLC-MS/MS~n.
Polygala glomerata Lour.(Polygalaceae),widely distributed in the south of China including Fujian,Guangdong,Sichuan and Yunnan provinces,has traditionally been used as herbal medicine for the treatment of acute tonsillitis,tuberculosis, esophageal cancer,whooping cough,stomatitis and other inflammatory diseases such as myelitis and hepatitis pharyngitis etc.In pharmacological screen,the 95%EtOH extract showed protective effect against PC12 cell.Bioassay-guided fractionation led to the isolation 46 compounds through the combination of many isolating technologies and methods including macroporous resin column chromatography, silica gel column chromatography,Sephadex LH-20 column chromatography,mediate pressure liquid chromatography and preparative HPLC.In this thesis,41 structures were elucidated by spectroscopic and chemical methods.Among them,19 compounds were new,including a triterpenoid saponin(20),four benzophenone C-glucosides (1～4),six xanthone glucosides(5～9,18),four polygalytols(10～13) and the four remnants belonging to organic acids and asters respectively(14～17).
Some compounds were evaluated particularly for their neuroprotection and anti-hepatitis considering the using characteristic of this plant in folk and the properties reported about active constituents from the Polygalaceae genus in previous literatures.Compounds 20 and 38 showed neuroprotective effects against serum deficiency and glutamate at the concentration of 10~(-5)mol/L.Compounds 1～8 showed heapto lprotective function against D-GaiN-induced poisoning in WB-F344 cells.
On the basis of the mass spectroscopy characteristics of benzophenone C-glucosides and xanthone glucosides,the fractions containing those compounds were investigated by HPLC-MS/MS~n.As a result,the possible structures of sixteen trace compounds were deduced,in which five were new compounds.
对远志的甲醇部分和氯仿部分进一步以活性指导进行分离,运用硅胶、大孔树脂、凝胶Sephadex LH-20、中压液相色谱及高效制备液相色谱,分离得到46个化合物,通过UV、IR、1D NMR、2D NMR、MS等波谱分析及化学方法,鉴定了45个化合物的结构,包括16个三萜皂苷、13个寡糖多酯类、1个水杨酸类化合物、12个(口山)酮类化合物、1个甾醇类化合物、1个氨基酸和1个酯类化合物。其中7个三萜皂苷类化合物为新化合物,3个皂苷首次分离得到。
体外PC12细胞保护作用的研究表明,远志的甲醇部分和粗分后的含皂苷的PM6EF2和PM6EF6能提高模型组的PC12细胞的增殖率;皂苷类化合物1～16具有良好的活性PC12细胞作用(10~(-5)mol/L),其中化合物5,8,14,15的活性显著。对体外活性较强的2个皂苷组分和2个化合物(14和15)进行了学习记忆模型的体内实验,结果显示具有提高小鼠学习记忆的作用,化合物15的活性较强。
对远志皂苷在体内吸收和分布进行了探讨,发现远志皂苷能以原形进入血液,并结合对远志总皂苷LC-MS~n的研究结果从中指认了10个皂苷的结构。
华南远志(Polygala glomerata Lour.)为远志科远志属植物,主要分布于福建、广东、四川和云南,以全草入药。具有止咳、消积和活血散瘀的功效,主要用于治疗咳嗽胸痛、咽喉痛、肺痨、顿咳、小儿疳积、黄疸、痢疾、小儿麻痹后遗症、目赤、痈疽疖肿、跌打损伤等。通过药理筛选发现全草的95%乙醇提取物可促使PC12细胞分化,使细胞突起长度明显增加,即具有神经营养作用。为揭示华南远志药效的物质基础,根据药理筛选结果,对华南远志的95%乙醇提取物进行了系统的活性成分研究。在药理活性筛选指导下,利用大孔树脂、硅胶、凝胶Sephadex LH-20、中压液相色谱和高效制备液相色谱等多种技术和方法相结合,从华南远志的乙醇提取物中已分离得到46个化合物;并通过UV、IR、1DNMR、2D NMR、MS等波谱方法和化学方法相结合,鉴定了41个化合物的结构包括:三萜皂苷类6个,新皂苷1个(20);寡糖多酯类2个,(口山)酮类6个,新(口山)酮类5个(5～9,18),苯甲酮苷类5个,新苯甲酮苷类4个(1～4);远志醇衍生物4个均为新化合物(10～13);有机酸类化合物5个,4个为新化合物(14～17);黄酮类7个;木脂素类2个;其它类型的4个。其中有19个为新化合物。并根据其民间药用特点和远志属植物成分的活性报道,在抗肝炎、PC12细胞保护等药理模型上,对分离鉴定的主要成分进行了初步活性筛选。(口山)酮24和皂苷20,38,显示了PC12细胞的保护作用。化合物1-4,31有保肝活性。
根据质谱裂解规律和UV特征对华南远志的微量成分进行LC-MS~n研究,推测了16个微量成分可能的结构,包括6个黄酮苷、5个苯甲酮苷和5个(口山)酮苷。其中4个苯甲酮苷和1个(口山)酮苷为新化合物。
"Yuan Zhi",the roots of perennial herbaceous plant—Polygala tenuifolia Willd. in Polygalaceae family,has been playing an important role as traditional Chinese medicine having bioactivities including antitussive,expectorant,antipsychotic, cognitive improving,antidote,resolutive and tonic.The pharmacological studies on Yuan Zhi indicated its effect of anti-Alzheimer's disease based on its capability of obviously ameliorating the mice memory failure reduced by scopolamine in vivo. According to the satisfying remedial practice and modern experimental results,it is extremely promising to finding leading compounds for improving cognitive ability and memory.Therefore,following the bioactive values,we investigated the chemical constituents of the active parts from the extract of Polygala tenuifolia.The roots of P. tenuifolia were refluxed in 95%ethanol and concentrated,then the residue was eluted respectively by CHCl_3,EtOAc,acetone and MeOH after mixing with silica gel.The bioactivities of four elution fractions were evaluated,as a result the MeOH portion showed the protection of PC 12 from the glutamate and serum deficiency.
Bioassay-guided fractionation led to the isolation of 46 individual compounds,of which 45 were identified as 16 triterpenoid saponins,13 oligosaccharide polyesters,1 salicin,1 steroid,1 amine acid and 1 ester by spectroscopic methods including UV,IR, 1DNMR,2DNMR and MS etc as well as chemical experiments.Among them,seven triterpenoid saponins(1-7) were new and three other saponins were isolated from this plant for the first time.
Some compounds and residues were evaluated in search for substances with the neuroprotection effect against glutamate and serum deficiency and the data showed the PM6EF3 and PM6EF6(fraction riched in triterpenoid saponins) portions and compounds 1-16 could protect PC12 cell from serum deficiency and glutamate at the concentration of 10~(-5) mol/L,especially compounds 5,8,9,14 and 15 do better.In addition,the PM6EF3 and PM6EF6 portions exhibited moderate cognitive improving and cerebral protective effects in rats,compounds 14 and 15 also exhibited moderate cognitive improving and cerebral protective effects in rats.
The ADME of gross saponins were studied and the result indicated the saponins could be absorbed into blood in its own form without any modifying.The possible structures of 10 trace saponins were deduced from the serum by use of HPLC-MS/MS~n.
Polygala glomerata Lour.(Polygalaceae),widely distributed in the south of China including Fujian,Guangdong,Sichuan and Yunnan provinces,has traditionally been used as herbal medicine for the treatment of acute tonsillitis,tuberculosis, esophageal cancer,whooping cough,stomatitis and other inflammatory diseases such as myelitis and hepatitis pharyngitis etc.In pharmacological screen,the 95%EtOH extract showed protective effect against PC12 cell.Bioassay-guided fractionation led to the isolation 46 compounds through the combination of many isolating technologies and methods including macroporous resin column chromatography, silica gel column chromatography,Sephadex LH-20 column chromatography,mediate pressure liquid chromatography and preparative HPLC.In this thesis,41 structures were elucidated by spectroscopic and chemical methods.Among them,19 compounds were new,including a triterpenoid saponin(20),four benzophenone C-glucosides (1～4),six xanthone glucosides(5～9,18),four polygalytols(10～13) and the four remnants belonging to organic acids and asters respectively(14～17).
Some compounds were evaluated particularly for their neuroprotection and anti-hepatitis considering the using characteristic of this plant in folk and the properties reported about active constituents from the Polygalaceae genus in previous literatures.Compounds 20 and 38 showed neuroprotective effects against serum deficiency and glutamate at the concentration of 10~(-5)mol/L.Compounds 1～8 showed heapto lprotective function against D-GaiN-induced poisoning in WB-F344 cells.
On the basis of the mass spectroscopy characteristics of benzophenone C-glucosides and xanthone glucosides,the fractions containing those compounds were investigated by HPLC-MS/MS~n.As a result,the possible structures of sixteen trace compounds were deduced,in which five were new compounds.
引文
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