摘要
人参(Panax ginseng C.A.Meyer)为五加科(Araliaceae)人参属植物,主要分布在中国东北部,是传统的名贵中药,具有广泛的药理活性,不仅能强身壮体,还能治疗多种疾病。人参中发挥药理活性的物质基础主要是达玛烷型人参皂苷,其具有抗疲劳、延缓衰老、抑制肿瘤细胞生长、调节中枢神经系统、调节机体免疫力、改善心脑血管供血不足等功效。
为了寻找新的活性物质,本文对人参叶中的人参三醇组总皂苷提取物进行了化学成分研究,采用多种色谱方法(硅胶及ODS柱色谱等)分离得到14个化合物,通过理化常数、光谱数据分析以及化学方法鉴定了它们的结构,分别为20(R)-原人参三醇(20(R)-Protopanaxatriol,1),20(R)-Dammar-3β,6α,12β,20,25-pentol(2 ),Dammar-20(22),24-diene-3β,6α,12β-triol(3),20(S)-Dammar-25(26)-ene-3β,6α,12β,20,24(R)-pentol(4),3β,6α,12β-trihydroxy-22,23,24,25,26,27-hexanordammaran-20-one(5),人参皂苷Rh_4(ginsenoside Rh_4,6 ),20(R)-人参皂苷Rh_1(20(R)-ginsenoside Rh_1,7),20(S)-人参皂苷Rh_1(20(S)-ginsenoside Rh_1,8),3β,6α,12β-trihydroxy-22,23,24,25,26,27-hexanordammaran-20-one,6-O-β-D-glucopyranoside(9),20(R)-Dammar-3β,6α,12β,20,25-pentol,6-O-β-D-glucopyranoside(10),20(S)- Dammar-3β,6α,12β-triol-20,25-epoxy,6-O-β-D-glueopyranoside(11),20(R)-dammar-3β,6α,12β,20,25-pentol,6-O-(α-L-rhamnopyranosyl-(2→1)-O-β-D-glucopyranoside(12),20(R)-人参皂苷Rg_2(20(R)-ginsenoside Rg_2,13),20(S)-Dammar-24-ene,3β,6α,20-trihydroxy-12,23-epoxy,6,20-di-O-β-D-glucopyranoside(14)。其中化合物5,14为新化合物。
同时,采用HPLC法对人参叶中二醇组总皂苷提取物转化为人参皂苷Rg_3、Rh_2后产物中的人参皂苷Rg_3(R,S)、Rh_2(R,S)同时检测的方法学进行了研究。在色谱条件为乙腈:水:磷酸(44:56:0.028)、检测波长:203 nm、流量:1.0ml/min、柱温:20℃的条件下,Rg_3(R)、Rg_3(S)、Rh_2(R)、Rh_2(S)能够达到很好的分离:对线性、仪器精密度、样品的重现性、稳定性进行了考察,结果表明上述方法能稳定、可靠、快速的检测出转化产物中人参皂苷Rg_3(R,S)、Rh_2(R,S)的含量;此方法的建立,为进一步新药研发中对于人参皂苷Rg_3、Rh_2质量标准的方法学确立奠定了基础,也为人参皂苷的药效学评价提供了可靠依据。
肥胖病已成为日益严重的公众流行病,严重影响人们的健康和生活。目前,减肥药已成为研究热点,本课题组在前期对多种药用花的活性筛选中,发现沙生蜡菊花具有降脂的生物活性,故本论文对其化学成分和降脂活性进行了深入研究。
沙生蜡菊(Helichrysum arenarium(L.)MOENCH)为菊科(Compositae)蜡菊属(Helichrysum Mill.)多年生草本植物。广泛分布于欧洲北部、中部、东南部、苏联和蒙古,在我国主要分布于新疆北部。
沙生蜡菊在欧洲地区作为民间用药具有悠久的历史,主要作为利胆剂、利尿剂,并有驱毒的功效,花的汁液能够治疗消化系统疾病,如能刺激胃液分泌、调节胆汁分泌等。此外,还有抗炎的功效,用于治疗膀胱炎、关节炎、风湿病等症。文献报道其生物活性的物质基础是多酚类化合物,如黄酮类、酚酸等。
论文主要包括两部分内容:化学成分研究和降脂活性研究。
化学成分研究:为了明确沙生蜡菊花降脂活性的物质基础,对其化学成分进行了系统研究,通过硅胶柱色谱、ODS柱色谱、HPLC制备色谱从沙生蜡菊花的甲醇提取物中分离得到了68个化合物,并利用理化常数、光谱学手段(UV、IR、NMR、CD)以及化学方法鉴定了67个化合物的结构,分别为7-Hydroxy-5-methoxyphthalide-7-O-β-D-glucopyranoside(1),(2R,3R)-1-Phenyl-2,3-butanediol-2-O-β-D-glucopyranoside(2),Everlastoside A(3),5,7-Dihydroxyphthalide-7-O-β-D-glucopyranoside(4),东莨菪苷(Scopolin,5),丁香苷(Syringin,6),二氢丁香苷(Dihydrosyringin,7),Undulatoside A(8),(E)-4-Hydroxybenzalacetone-3-O-β-D-glucopyranoside(9),Tortoside B(10),(2R)-Helichrysin(11 ),(2S)-Helichrysin(12),4-Allyl-2-methoxyphenyl 6-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(13 ),(2S)-柚皮素-7-O-β-D-吡喃葡萄糖苷((2S)-Naringenin-7-O-β-D-glucopyranoside,14),山奈酚-3-O-β-D-吡喃葡萄糖苷(Kaempferol-3-O-β-D-glucopyranoside,15),芹菜素-7-O-β-D-吡喃葡萄糖苷(Apigenin-7-O-β-D-glucopyranoside,16),木犀草素-7-O-β-D-吡喃葡萄糖苷(Luteolin-7-O-β-D-glucopyranoside,17),木犀草素-3′-O-β-D-吡喃葡萄糖苷(Luteolin-3′-O-β-D-glucopyranoside,18),地衣酚-β-D-吡喃葡萄糖苷(Orcinol-β-D-glucopyranoside,19),腺嘌呤核苷(Adenosine,20);Everlastoside B(21),Lcariside F2(22),p-Methoxyphenylethanol-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(23),3-Methylbutanol-1-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(24),淫羊藿次苷D1(Icariside D1,25),苯乙醇-β-巢菜糖苷(Phenethanot-β-vicianoside,26),(2R,3R)-1-Phenl-2,3-bunediol-2-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(27),3-(Z)-Hexenol-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(28),(7R,8S)-Dihydrodehydrodiconiferyl alcohol-4-O-β-D-Glucopyranoside(29),槲皮素-3-O-β-D-吡喃葡萄糖苷(Quercetin-3-O-β-D-glucopyranoside,30 ),Chalonaringenin-2'-O-β-D-glucopyranoside(31),(2R,3R)-二氢山柰酚.7-O-β-D-吡喃葡萄糖苷((2R,3R)-Dihydrokaempferol-7-O-β-D-glucoside,32),卞醇-β-巢菜糖苷(Benzylalcohol-β-vicianoside,33 ),Everlastoside C(34),Helicioside A(35),EverlastosideD(36),5,7-Dihydroxyphthalide-7-O-β-D-gentiobioside(37),苯甲酸-β-D-龙胆二糖苷(Benzoic acid-β-D-gentiobioside,38),(2S,3S)-1-Phenl-2,3-bunediol-2-O-β-D-glucopyranosyl-(1-6)-β-D-glucopyranoside(39),木犀草素-3-甲氧基-6-羟基-7-O-β-D-吡喃葡萄糖苷(Luteoiin-3-methoxyl-6-hydroxy-7-O-β-D-glucopyranoside,40),金鱼草素-6-O-β-D-吡喃葡萄糖苷(Aureusidin-6-O-β-D-glucpyranoside,41),黄芩素-7-O-β-D-吡喃葡萄糖苷(Scutellarein-7-O-β-D glucopyranoside,42),山柰酚-3-O-(3-β-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷(Kaempferol-3-O-(3-β-D-glucopyranosyl)-β-D-glucopyranoside,43),苯乙醇-β-D-龙胆二糖苷(Phenethanol-β-D-gentiobioside,44 ),Maltot-3-O-β-D-apiofuranosyl-(1-6)-O-β-D-glucopyranoside(45),(2R)-圣草素-5-O-β-D-吡喃葡萄糖苷((2R)-Eriodictyol-5-O-β-D-glucopyranoside,46 ),3-O-p-Coumaroylshikimicacid-4-O-β-D-glucopyranoside(47),(2R)-柚皮素-5-O-β-D-龙胆二糖苷((2R)-Naringenin-5-O-β-D-gentiobioside,48),(2S)-柚皮素-5-O-β-D-龙胆二糖苷((2S)-Naringenin-5-D-β-D-gentiobioside,49),木犀草素-6-羟基-7-O-β-D-吡喃葡萄糖苷(Luteolin-6-hydroxy-7-O-β-D-glucopyranoside,50),芹菜素-7-O-β-D-龙胆二糖苷(Apigenin-7-O-β-D-gentiobioside,51),斛皮素-3-O-芸香糖苷(Quercetin-3-O-rutinoside,52),山柰酚-3-O-β-D-龙胆二糖苷(Kaempferol-3-O-β-D-gentiobioside,53),2,4,6-Trihydroxylacetophenone-2,4-di-O-β-D-glucopyranoside(54),(2R)-柚皮素5,7-二氧-β-D吡喃葡萄糖苷((2R)Naringenin-5,7-di-O-β-D-glucopyranoside,55),(2S)-柚皮素-5.7-二氧-β-D吡喃葡萄糖苷((2S)-Naringenin-5,7-di-O-β-D-glucopyranoside,56),(2S)-柚皮素-5,4′-二氧-β-D-吡喃葡萄糖苷((2S)-Naringenin-5,4′-di-O-β-D-glucopyranoside,57),芹菜素-4′,7-二氧-β-D-吡喃葡萄糖苷(Apigenin-4′,7-di-O-β-D-glucopyranoside,58),山柰酚-3,4′-二氧-β-D-吡喃葡萄糖苷(Kaempferol-3,4′-di-O-β-D-glucopyranoside,59),Chalonaringenin-2′,4′-O-β-D-glucopyranoside(60),斛皮素-3,3′-二氧-β-D-吡喃葡萄糖苷(Quercetin-3,3′-di-O-β-D-glucopyranoside,61 ),Chalonaringenin-2′-O-β-D-gentiobioside(62),ArenariumosideⅡ(63),芹菜素-7-O-β-D-吡喃葡萄糖醛酸甲酯(Apigenin-7-O-β-D-glucopyranosiduronic acid methyl ester,64 ),ArenariumosideⅢ(65 ),Everlastoside E(66),ArenariumosideⅣ(67)。
其中化合物2、3、4、21、23、24、27、28、34、36、37、39、47、48、49、57、62、63、65、66、67为21个未见文献报道的新化合物,化合物1、5、6、7、8、9、10、13、14、18、19、20、22、25、26、29、32、33、35、38、40、41、42、43、44、45、46、50、51、52、54、55、56、58、59、60、61、64为从该属植物中首次分离得到的38个化合物,11为从该植物中首次分离得到的化合物。
降脂活性研究:1论文考察了沙生蜡菊花的甲醇提取物、乙酸乙酯萃取物、甲醇洗脱物及水层部分对小鼠肝脏细胞中脂肪含量的影响,结果表明甲醇提取物、乙酸乙酯萃取物、甲醇洗脱物均能显著降低小鼠肝脏中的脂肪含量,水层部分没有显著的作用。
2论文考察了沙生蜡菊花中的单体化合物1、11、12、14、15、16、31、45、47对小鼠肝脏中脂肪含量的影响,实验结果表明,化合物11、14、15、31、47具有显著的降脂作用,其中以31、47最为显著。由此推测沙生蜡菊花中发挥降脂活性的物质基础是黄酮、二氢黄酮、查耳酮以及酚酸类化合物。
3论文进一步考察了山柰酚-3-O-β-D-吡喃葡萄糖苷(15)及其苷元对小鼠内脏脂肪蓄积的影响,以小鼠体重、内脏脂肪含量以及血浆中甘油酸酯、总胆固醇、游离脂肪酸、葡萄糖的含量为考察指标,对比分析了糖苷与苷元的降脂活性,实验结果表明山柰酚-3-O-β-D-吡喃葡萄糖苷的降脂活性明显强于山柰酚。
Panax ginseng C.A.Meyer is an perennial herbal plant belonging to the Aralaceae family, which mainly distributes in the Northeast China,and has conspicuous pharmacologic action as a valuable traditional medicine.Panax Ginseng was used to enhance the health and treat the various diseases.According to the references,the dammarane-type panaxsaponins in Panax ginseng which were considered for the biological agents for lightening fatigue, delaying insenecence,anti-cancer,accommodating central nervous system,regulating immunity,improving insufficiency of blood in heart or brain.
In order to find new active agent from this plant,the chemical study of the extract of panoxatriol saponins of the leaves of Panax ginseng was carried out.By various methods of isolation(silica gel column chromatography,ODS gel column chromatography ),14 compounds were isolated.By means of spectroscopic analysis and physiochemical properties, they were identified as 20(R)-Protopanaxatriol(1),20(R)-Dammar-3β,6α,12β,20,25-pentol (2),Dammar-20(22),24-diene-3β,6α,12β-triol(3),20(S)-Dammar-25(26)-ene-3β,6α,12β.20, 24(R)-pentol(4),3β,6α,12β-trihydroxy-22,23,24,25,26,27-hexanordammaran-20-one(5), ginsenoside Rh_4(6),20(R)-ginsenoside Rh_1(7),20(S)-ginsenoside Rh_1(8), 3β,6α,12β-trihydroxy-22,23,24,25,26,27-hexanordammaran-20-one,6-O-β-D-glucopyranosid e(9),20(R)-Dammar-3β,6α,12β,20,25-pentol,6-O-β-D-glucopyranoside(10),20(S)-Dammar -3β,6α,12β-triol-20,25-epoxy,6-O-β-D-glucopyranoside(11),20(R)-dammar-3β,6α, 12β,20,25-pentol,6-O-(α-L- rhamnopyranosyl-(2→1)-O-β-D-glucopyranoside(12), 20(R)-ginsenoside Rg_2(13),20(S)-Dammar-24-ene,3β,6α,20-trihydroxy-12,23-epoxy,6,20-di-O -β-D-glucopyranoside(14),respectively.Among them,compound 5 and 14 were new compounds.
Meanwhile,the study of the quality determination methods on ginsenoside Rg_3(R,S) and Rh_2(R,S) which were transformed from the extract of panoxadiol saponins in the leaves of Panax ginseng by HPLC was carried out.Rg_3(R),Rg_3(S),Rh_2(R),Rh_2(S) can reach the standard of chromatograms separation under the chromatograms conditions which mobile phase was CH_3CN-H_2O-H_3PO_4(44:56:0.028),the detection wavelength was 203nm,the flow rate was 1.0ml/min,room temperature.The results of studied on the precision of constancy, reproduction quality and constancy of sample showed this method was accurate,sensitive, stable which could be used for the quality control the contents of ginsenoside Rg_3(R,S), Rh_2(R,S),and the establishment of this method was the substructure for the new drug study about ginsenosides Rg_3,Rh_2 and the evaluation of pharmacodynamics,
Now adiposis is an increasingly serious public epidemic disease,and threaten human being's health and normal life.During the prophase course of our active screening studies on some medicinal flowers,we found that the methanolic extract of the flowers of Helichrysum arenarium has the conspicuous activity to anti-obesity,the further study on the chemical constituents and the activity of reducing grease of Helichrysum arenarium were carried out.
The inflorescence of Helichrysum arenarium(L.) MOENCH(Helichrysi flos syn. Stoechados flos) is a native perennial herbal plant of the Asteraceae family.And mainly distributes in the northern,southern and central region of Europe.In China,it mainly grows in north of Xin-jiang Province.
In Europe,the therapeutic application of Helichrysum arenarium(L.) MOENCH has been used as a folk medicine due to its choleretic,diuretic,and detoxify function for long time. The sap of its flos could be used to treat the disease of digestive system,such as stimulating the gastric secretion,adjusting the bilifaction and gallbladder disorders and so on.In addition, the flos also showed the anti-inflammatoty activity,and it was used to treat cystitis,arthritis, rheumatism.Literatures reported the active ingredients of Helichrysi flos were mainly phenolics such as flavonoids,phenolic acids.
The thesis contained the studies on the chemical constituents and the activity of reducing grease.
The study on the chemical constituents:For the purpose of finding the chemical constituents with the bioactivity in Helichrysi flos,the further chemical study on its MeOH extract was carried out.By various methods of isolation(silica gel column,ODS gel column, HPLC),68 compounds were isolated,and by the methods of physico-chemical property,and spectrographic analysis,67 compounds were identified as 7-Hydroxy-5-methoxyphthalide,7-O-β-D-glucopyranoside(1),(2R,3R)-1-Phenyl-2,3-butane diol-2-O-β-D-glucopyranoside(2),Everlastoside A(3),5,7-Dihydroxyphthalide-7-O-β-D-glucopyranoside (4),Scopolin(5),Syringin(6),Dihydrosyringin(7),Undulatoside A(8), (E)-4-Hydroxybenzalacetone-3-O-β-D-glucopyranoside(9),Tortoside B(10), (2R)-Helichrysin(11),(2S)-Helichrysin(12),4-Allyl-2-methoxyphenyl 6-O-β-D-apiofurano syl(1-6)-β-D-glucopyranoside(13),(2S)-Naringenin-7-O-β-D-glucopyranoside(14), Kaempferol-3-O-β-D-glucopyranoside(15),Apigenin-7-O-β-D-glucopyranoside(16), Luteolin-7-O-β-D-glucopyranoside(17),Luteolin-3'-O-β-D-glucopyranoside(18), Orcinol-β-D-glucopyranoside(19),Adenosine(20),Everlastoside B(21),Lcariside F2(22), p-Methoxyphenyleth-anol-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(23),3-Methyl butanol-1-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside(24),Icariside D1(25), Phenethanol-β-vicianoside(26),(2R,3R)- 1-Phenl-2,3-bunediol-2-O-β-D-apiofuranosyl-(1-6)-β-Dglucopyranoside(27),3-(Z)-Hexenol-O-β-D-apiofuranosyl-(1-6)-β-D-glucopyranoside (28),(7R,8S)-Dihydrodehydrodiconiferyl alcohol-4-O-β-D-Glucopyranoside(29), Quercetin-3-O-β-D-glucopyranoside(30),Chalonaringenin-2'-O-β-D-glucopyranoside(31), (2R,3R)-Dihydrokaempferol-7-O-β-D-glucoside(32),Benzylalcohot-β-vicianoside(33), Everlastoside C(34),Helicioside A(35),Everlastoside D(36), 5,7-Dihydroxyphthalide-7-O-β-D-gentiobioside(37),Benzoic acid-β-D-gentiobioside(38), (2S.3S)-1-Phenl-2,3-bunediol-2-O-β-D-glucopyranosyl-(1-6)-β-D-glucopyranoside(39), Luteolin-3-methoxyl-6-hydroxy-7-O-β-D-glucopyranoside(40),Aureusidin-6-O-β-D-glucpyranoside (41),Scutellarein-7-O-β-D glucopyranoside(42),Kaempferol-3-O-(3-β-D-glucopyranosyl) -β-D-glucopyranoside(43),Phenethanol-β-D-gentiobioside(44),Maltol-3-O-β-D-apiofuranosyl-(1-6)-O-β-D-glucopyranoside(45)(2R)-Eriodictyol-5-O-β-D-gluco pyranoside(46),3-O-p-Coumaroylshikimicacid-4-O-β-D-glucopyranoside(47), 2R)-Naringenin-5-O-β-D-gentiobioside(48),(2S)-Naringenin-5-O-β-D-gentiobioside(49), Luteolin-6-hydroxy-7-O-β-D-glucopyranoside(50),Apigenin-7-O-β-D-gentiobioside(51), Quercetin-3-O-rutinoside(52),Kaempferol-3-O-gentiobioside(53),2,4,6-Trihydroxylaceto phenone-2,4-di-O-β-D-glucopyranoside(54),(2R)-Naringenin-5,7-di-O-β-D-glucopyranoside (55),(2S)-Naringenin-5,7-di-O-β-D-glucopyranoside(56),(2S)-Naringenin-5,4'-di-O-β-D -glucopyranoside(57),Apigenin-4',7-di-O-β-D-glucopyranoside(58),Kaempferol-3,4'-di-O-β-D-glucopyranoside(59),Chalonaringenin-2',4'-O-β-D-glucopyranoside(60), Quercetin-3,3'-di-O-β-D-glucopyranoside(61),Chalonaringenin-2'-O-β-D-gentiobioside(62), ArenariumosideⅡ(63),Apigenin-7-O-β-D-glucopyranosiduronic acid methyl ester(64), ArenariumosideⅢ(65),Everlastoside E(66),ArenariumosideⅣ(67).
Among them,compound 2,3,4,21,23,24,27,28,34,36,37,39,47,48,49,57,62,63, 65,66,67 were 21 new compounds,and compound 1、5、6、7、8、9、10、13、14、18、 19、20、22、25、26、29、32、33、35、38、40、41、42、43、44、45、46、50、51、52、54、55、56、58、59、60、61、64 were 38 comopounds isolated from Helichrysum for the first time,and compound 11 were isolated from Helichrysum arenarium for the first time.
The study on the activity of reducing grease:1 The result of study on MeOH extract, EtOAc layer,MeOH eluted and H_2O eluted of Helichrysi flos on the neutral fat of primary culture liver cells in mice showed that MeOH extract,EtOAc layer,MeOH eluted had the noticeable activity of degrading the content of neutral fat of primary culture liver cells of mice.
2 The same study on the compound 1,11,12,14,15,16,31,45,47 were valuated respectively,and the results indicated that the compound 11,14,15,31,47 had the marked activity of reducing grease,and among them,compound 31,47 showed the most conspicuous activity.On the above analysis,it could be concluded that the flavone, flavonone,chalcone and acids were the main constituents with bioactivity in Helichrysi flos.
3 The study of the effect of compound 15 and its aglycone on the visceral lipopexia in mice was carried out,and investigated the weight,viscero-fat and the contents of glycerinate (TG),total cholesterol(TC),free fatty acids and glucose in blood plasma of mice,and the results of the glucoside showed better activity on reducing grease than that of aglycone.
引文
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