地黄活性物质与功能研究
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摘要
地黄Rehmannia glutinosa Libosch系玄参科地黄属植物,又名地髓,芑等。块根入药,现人工种植,现主产区在山西、河南等省。地黄由于加工炮制方式的不同分为鲜地黄、生地黄和熟地黄,具有清热、抗贫血和滋补等功效。现代科学研究证明地黄主要化学成分为糖类、环烯醚萜类、倍半萜类和苯乙醇苷类,具有降血糖、神经保护等多种生物活性。
本论文运用多种色谱技术和波谱技术,并结合化学方法,对鲜地黄进行了系统的化学成分研究,并对其粗提物及单体成分进行了药理活性筛选。
从鲜地黄的95%乙醇提取物中共分离鉴(测)定了110个化合物,结构分别为：地黄新苷A-K(1*-11*),jioglutin F (12*),也黄新萜A-F(13*-18*),1,4,5,6-四氢-1-甲基-6-氧代-3-吡啶乙酸(19*),梓醇(20),益母草苷A(21),myopor oside (22),桃叶珊瑚甙(23),单蜜力特苷24),5-deoxyantirrhinoside (25),二氢梓醇(26),myobontioside A (27),3'-O-β-D-glucopyranosyl-catalpol (28),蜜力特苷(29),地黄苷C(30),地黄苷A(31),5-deoxylamiol (32),去乙酰野芝麻苷(33),栀子新苷(34),8-表番木鳖酸(35),栀子酸(36),mussaenosidic acid(37),栀子新苷甲酯(38),栀子苷(39),8-表番木鳖碱(40),jioglutoside B(41),京尼平龙胆双糖苷(42),genipin1-O-α-L-rhamnopyranosyl (1→6)-β-D-glucopyranoside (43), genameside C (44),6-O-E-feruloyl ajugol (45),6-0-vanillate ajugol (46),6-O-p-hydroxybenzoyl ajugol (47),6-O-(4"-O-α-L-rhamn opyranosyl)vanilloyl ajugol (48),6-oxo-4'-(3-methoxyl-4-hydroxyphenylglycol-8")-feruloyl-ajugol (49-50),6-O-E-caffeoyl ajugol (51),6-0-.sec-hydroxyaeginetoy1ajugol (52), aeginetoyl ajugol5"-O-β-D-quinovoside (53),京尼平(54), jiogl utins D (55),6β-hydroxy-2-oxabicyclo[4.3.0]△8-9-nonen-l-one (56), jioglutins E (57),野菰酸(58), dihydroxy-β-ionone (59), rehmapicrogenin (60), trihydroxy-β-iononem (61), sec-hydroxyaeginetic acid (62), aeginetic acid5-O-β-D-quinov oside (63), neo-rehmannioside (64), dihydrophaseic acid4'-O-β-D-glucopyranosi de (65), rehmaionoside C (66),黑蒴苷(67), rehmaionoside A (68), rehmaion oside B (69), oxyrehmaionoside B (70),地黄苷(71), sculponiside (72),2-phe nylethyl-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside (73),阿克替甙(74),红景天苷(75),leucosceptoside A (76), jionoside D (77), deacyl-martynoside (78), jionosides A1(79), jionosidesB1(80),3,4-dihydroxy-β-phenethyl-O-α-L-rha mnopyranosyl-(1→3)-O-β-D-galacopyranosyl-(1→6)-4-O-caffeoyl-β-D-glucopyrano side (81),香草醛(82),1-(4-methy-2-furanyl)-2-(5-methyl-5-ethenyl-2-tetrahydrof uranyl)-propan-l-one (83),顺式细辛醚(84),丁香酚(85),异丁香酚甲酯(86),阿魏酸(87),苯甲酸(88),丁香酸(89),β-谷甾醇(90),腺苷(91),腺嘌呤(92), rhamnopyranosyl vanilloyl (93), syringicacid-4-O-a-L-rhamnopyranoside (94),2-methoxy-4-methylphenyl-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (95),葡萄糖(96),半乳糖(97),水苏糖(98),蔗糖(99),甘露三糖(100),棉子糖(101), yemuoside YM1(102-103),(7R,8S,7'R,8'S)-4,9,4',9'-tetrahydroxy-3,3'-dime thoxy-7,7'-epoxylignan9-O-β-D-glucopyranoside (104),1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (105), tachioside (106), isotachioside (107),丙烯酸(108),邻苯二甲酸二丁酯(109)。另外,首次分离得到梓醇苷元(110)。
分离得到的110个化合物中,包括51个环烯醚萜(1*-12*,20-57,110),19个单萜、倍半萜和降倍半萜(13*-18*,58-70),10个苯乙醇苷(71-72,74-81)和30个其它类型化合物(19*,73,82-109)。其中化合物1*-19*为19个新化合物。
抗肿瘤方面,采用MTT法测定了地黄提取物各部位(图2-4-1)和97个单体化合物对五种人肿瘤细胞的抑制作用。结果显示地黄提取物各部位均无明显的抗肿瘤活性,单体化合物均没有表现出细胞毒活性(IC50>10μM)。
保肝和抗肝损伤方面,采用Fe2+-半胱氨酸诱导的肝微粒体脂质过氧化模型,测定地黄部分97个化合物的抗氧化活性。结果显示新化合物5在10-5M时表现一定的抗氧化活性(抑制率=23%)；同时,化合物51,76-77在10-5M也表现一定的抗氧化活性。采用扑热息痛(APAP)引起体外肝细胞损伤的保护模型,测定地黄部分97个化合物的肝保护活性。化合物71-72,74-75,79-80,100在10μM浓度下有一定的保护作用,活性与相同浓度的阳性对照药双环醇相当。以MTT法观察地黄提取物各部位对人肝细胞HL-7702细胞成活率的影响,结果显示,部位1,3,5,10-14有较明显的保肝活性,进一步考察显示化合物11,23,30,34,58,62,68,73,75,90,93,95有明显的保肝活性。
抗炎方面,采用给巴豆油致耳部炎症小鼠皮下注射相应受试物(100mg/kg)的方法,显示地黄提取物部位5,10,13,14可较明显的抑制小鼠耳肿胀,显示出一定的抗炎活性。单体化合物可以一定程度上抑制LPS诱导的细胞对NO的生成,与阳性对照地塞米松(浓度10-6M)相比,部分化合物在浓度10-5M显示出一定的活性
抗流感病毒方面,与阳性对照扎那米韦相比,地黄部分化合物对抗流感病毒神经氨酸酶均没有显示出活性。
镇静催眠和抗溃疡方面,采用戊巴比妥钠协同睡眠模型,小鼠腹腔注射给药测定地黄提取物各部位的镇静催眠作用,以入睡率为评价指标,地黄各部位均显示出一定的镇静催眠作用,但不强,与阳性对照安定相比差太多。采用测定H+-K+-ATP酶活性对地黄提取物各部位的抗溃疡活性进行评价,结果各部位均无明显抑制活性。
降血脂方面,地黄提取物各部位对降低甘油三酯活性均无较明显抑制活性。
神经保护方面,地黄提取物部位7在1、10μg/ml剂量下对去血清损伤PC12细胞均具有保护作用；部位13在10μg/ml下对鱼藤酮损伤具有保护作用；部位8,12对缺糖缺氧损伤的PC12细胞具有加重损伤作用。进一步测试显示化合物74,77,81和98在10μM浓度下对鱼藤酮损伤细胞具有保护作用。
调节钾通道作用方面,利用荧光膜电位法筛选出潜在钾通道阻断剂22个。
降血糖方面(体外),地黄提取物各部位对PTP1B酶均无较明显抑制活性。地黄提取物部位1有较明显的醛糖还原酶抑制活性,IC50在3.5μg/ml,化合物74有明显的醛糖还原酶抑制活性,IC50在2.68×10-7μM,其它化合物在浓度10-5μM抑制率均<69.4%。各部位在10μg/ml浓度下对FBPase1均无显著抑制作用,进一步显示各化合物在10μM浓度下对FBPase1均无显著抑制作用。地黄提取物各部位在40μg/ml浓度下对α-葡萄糖苷酶无显著抑制作用,化合物在浓度40μM对α-葡萄糖苷酶抑制率均<32.4%,无明显抑制活性。化合物51,74,77,81在浓度10μM对脂肪酶有明显的抑制活性。地黄提取物各部位对DPP-IV抑制活性均<13.0%,无较明显抑制活性。地黄提取物部位3和部位12对GK激活倍数接近阳性化合物。地黄提取物各部位对PPARy受体的激活倍数均<1.10,无较明显抑制PPARy转录活性。
降血糖方面(体内),梓醇在剂量50mg/kg和200mg/kg灌胃给药(每天一次,连续给药)对四氧嘧啶高血糖小鼠血糖在一定程度上有降低作用；腹腔注射(一次给药)对四氧嘧啶高血糖小鼠血糖无明显降低作用(50、200、300mg/kg);在50mg/kg和200mg/kg灌胃给药(每天一次,连续给药)对自发性2型糖尿病KKay小鼠血糖未见明显降低作用。
Rehmarnnia glutinosa Libosch (Scrophulariaceae) is indigenous to Mainland China, and the roots of this plant have been used in oriental medicine as an antianemic, an antipyretic, and a tonic. Due to the different processing methods, R. glutinosa is classified into three categories namely, fresh roots, dried roots, and steamed roots, which are used in different ways in traditional Chinese medicine. Previous phytochemical studies on the dried and steamed roots of R. glutinosa have led to the isolation and identification of iridoid glycosides, ionone glycosides, phenethyl alcohol glycosides, and several other components.
The roots of R. glutinosa were investigated on their chemical constituents systematically by various kinds of chromatographic methods. The sructures of isolates were elucidated on the basis of spectroscopic analysis and chemical evidence. Some of them were assayed for their bioactivities.
110compounds were obtained from ethanolic extract of theair-dried roots of R. glutinosa. These compounds were identified as follows:rehmaglutoside A-K (1*-11*), jioglutin F (12*), frehmaglutoside A-F (13*-18*),1,4,5,6-tetrahydro-1-methyl-6-oxo-3-pyridineacetic acid (19*), catalpol (20), ajugol (21), myoporoside (22), aucubin (23), monomelittoside (24),5-deoxyantirrhinoside (25), dihydro catalpol (26), myobontioside A (27),3'-O-β-D-glucopyranosyl-catalpol (28), melittoside (29), rehmannioside C (30), rehmannioside A (31),5-deoxylamiol (32), lamiol (33), gardoside (34),8-epiloganic acid (35), geniposidic acid (36), mussaenosidic acid (37), gardoside methyl ester (38), geniposide (39),8-epiloganin (40), jioglutoside B (41), genipin-gentiobioside (42), genipin1-O-α-L-rhamnopyran-osyl (1→6)-β-D-glucopyranoside (43), genameside C (44),6-O-E-feruloyl ajugol (45),6-O-vanillate ajugol (46),6-O-p-hydroxybenzoyl ajugol (47),6-O-(4"-O-α-L-rhamnopyranosyl) vanilloyl ajugol (48),6-oxo-4'-(3-methoxyl-4-hydroxyphenylgly-col-8")-feruloyl ajugol (49-50),6-O-E-caffeoyl ajugol (51),6-O-sec-hydroxy-aeginetoyl ajugol (52), aeginetoyl ajugol5"-O-β-D-quinovoside (53), genipin (54), jioglutins D (55),6β-hydroxy-2-oxabicyclo[4.3.0]△"9-nonen-l-one (56), jioglutins E (57), aeginetic acid (58), dihydroxy-β-ionone (59), rehmapicrogenin (60), trihydroxy-β-iononem (61), sec-hydroxyaeginetic acid (62), aeginetic acid5-O-β-D-quinovoside (63), neo-rehmannioside (64), dihydrophaseic acid4'-O-β-D-glucopyranoside (65), rehmaionoside C (66), melasmoside (67), rehmaionoside A (68), rehmaionoside B (69), oxyrehmaionoside B (70), martynoside (71), sculponiside (72),2-phenylethyl-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside (73), acteoside,(74), salidroside (75), leucosceptoside A (76), jionoside D (77), deacyl-martynoside (78), jionoside A1(79), jionoside B1(80),3,4-dihydroxy-β-phenethyl-O-α-L-rhamnopyranosyl-(1→3)-O-β-D-galacopyranosyl-(1→6)-4-O-caffeoyl-β-D-glucopyra noside (81), vanillin (82),1-(4-methy-2-furanyl)-2-(5-methyl-5-ethenyl-2-tetrahydro-furanyl)-propan-l-one (83), cis-asarone (84), eugenol (85), isoeugenol methyl ether (86), ferulic acid (87), benzoic acid (88), syringic acid (89), β-sitosterol (90), adenosine (91), adenine (92), rhamnopyranosyl vanilloyl (93), syringicacid-4-O-a-L-rhamnopyranoside (94),2-methoxy-4-methylphenyl-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (95), glucose (96), galactopyranose (97), stachyose (98), sucrose (99), manninotriose (100), raffinose (101), yemuoside YM1(102-103),(7R,8S,7'R,8'S)-4,9,4',9'-tetrahydroxy-3,3'-dimethoxy-7,7'-epoxylignan9-O-β-D-gluc-opyranoside (104),1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (105), tachioside (106), isotachioside (107), acrylic acid (108), dibutyl phthalate (109), besides, the aglycone of catalpol (110) was also obtained.
Among the isolated one hundred and ten compounds, there were fifty-one iridoid and iridoid glycosides (1*-12*,20-57,110), nineteen monoterpene and sesquiterpenes and nor sesquiterpenes (13*-18*,58-70), ten phen ethyl alcohol glycosides (71-72,74-81) and thirty other components (19*,73,82-109). Nineteen compounds (1*-19*) were new compounds.
The crude extracts and ninety-seven compounds obtained from the roots of R. glutinosa were tested for their cytotoxicity against five human tumor cell lines by MTT method. However, all were inactive for all cell lines used (IC50>10μM is defined as "inactive").
By the model of inhibiting the production of lipid peroxide induced by Fe2+-Cys system in the liver microsomal, ninety-seven compounds were evaluated for their antioxidant activities and compounds5,51,76-77exhibited weak activities. Compounds71-72,74-75,79-80and100exhibited moderate hepatoprotecti-ve activities against APAP-induced HepG2cell damage. They were also bioassayed for their hepatoprotective activities against D-galactosamine induced toxicity in HL-7702cells, using the hepatoprotective activity drug bicyclol as the positive control, fractions1,3,5,10-14exhibited moderated hepatoprotective activities, and compounds11,23,30,34,58,62,68,73,75,90,93and95exhibited pronounced hepatoprotective activities.
Fractions5,10,13and14exhibited anti-inflammatory activities in vivo. Th e inhibitory effects of the isolates against nitric oxide (NO) production in mou seperitoneal macrophages were examined. Some compounds inhibited NO elevat ion at a concentration of10μM.
All ninety-seven compounds were inactive for anti influenza virus NA (neuramidinase) tested model.
All crude extracts exhibited weak sedative-hypnotic activites and were inactive in inhibiting H+-K+-ATPase activity.
All crude extracts were inactive in decreasing triglyceride level.
The protective activities of the crude extracts and compounds against neuroto xicity induced by serum deprivation in PC12cells were investigated by the M TT method. The results showed that serum deprivation induced significant inhi-bition of MTT reduction. Fraction7increased cell viability at a concentration of1μg/ml and10μg/ml, respectively. Furthermore, compounds74,77,81and98exhibited protective activity on cell damage induced by nicouline at a conc-entration of10μM, indicating that they may be effective in neurodegenerative disorders.
It has been found22possible potassium channel inhibitors by detecting fluorescent membrane potential in PC12cells.
For antidiabetic bioactivities, all crude extracts exhibited weak activities in inhibiting PTP1B (protein-tyrosine phosphatase-1B) and FBPasel. Fraction1and compound74possesed obvious inhibition agaist aldose reductase, with IC50values of3.5μg/ml and2.68×10-7μM, respectively, and other compounds showed inhibitory rates less than69.4%at a concentration of10μM. All crude extracts exhibited weak activities in inhibiting a-glucosidase at a concentration of40μg/ml and all compounds tested showed inhibitory rates less than32.4%at a concentration of40μM. Compounds51,74,77and81exhibited pronounced activities in inhibiting lipidase on a concentration of10μM. All crude extracts exhibited weak activities in inhibiting DPP-IV and PPARγ transcription. Fractions3and12exhibited significant GK (glucokinase) enzymatic activity, which was comparative to the positive control. Further more, in vivo, compound20exhibited weak antihyperglycemic activity at a concentration of200mg/kg on hyperglycemic mice induced by alloxan by intragastric administration, but no significant activity at a concentration of300mg/kg by intraperitoneal injection. In T2DM Kkay mice model, compound20exhibited no significant activity at a concentration of200mg/kg by intragastric administration.
本论文运用多种色谱技术和波谱技术,并结合化学方法,对鲜地黄进行了系统的化学成分研究,并对其粗提物及单体成分进行了药理活性筛选。
从鲜地黄的95%乙醇提取物中共分离鉴(测)定了110个化合物,结构分别为：地黄新苷A-K(1*-11*),jioglutin F (12*),也黄新萜A-F(13*-18*),1,4,5,6-四氢-1-甲基-6-氧代-3-吡啶乙酸(19*),梓醇(20),益母草苷A(21),myopor oside (22),桃叶珊瑚甙(23),单蜜力特苷24),5-deoxyantirrhinoside (25),二氢梓醇(26),myobontioside A (27),3'-O-β-D-glucopyranosyl-catalpol (28),蜜力特苷(29),地黄苷C(30),地黄苷A(31),5-deoxylamiol (32),去乙酰野芝麻苷(33),栀子新苷(34),8-表番木鳖酸(35),栀子酸(36),mussaenosidic acid(37),栀子新苷甲酯(38),栀子苷(39),8-表番木鳖碱(40),jioglutoside B(41),京尼平龙胆双糖苷(42),genipin1-O-α-L-rhamnopyranosyl (1→6)-β-D-glucopyranoside (43), genameside C (44),6-O-E-feruloyl ajugol (45),6-0-vanillate ajugol (46),6-O-p-hydroxybenzoyl ajugol (47),6-O-(4"-O-α-L-rhamn opyranosyl)vanilloyl ajugol (48),6-oxo-4'-(3-methoxyl-4-hydroxyphenylglycol-8")-feruloyl-ajugol (49-50),6-O-E-caffeoyl ajugol (51),6-0-.sec-hydroxyaeginetoy1ajugol (52), aeginetoyl ajugol5"-O-β-D-quinovoside (53),京尼平(54), jiogl utins D (55),6β-hydroxy-2-oxabicyclo[4.3.0]△8-9-nonen-l-one (56), jioglutins E (57),野菰酸(58), dihydroxy-β-ionone (59), rehmapicrogenin (60), trihydroxy-β-iononem (61), sec-hydroxyaeginetic acid (62), aeginetic acid5-O-β-D-quinov oside (63), neo-rehmannioside (64), dihydrophaseic acid4'-O-β-D-glucopyranosi de (65), rehmaionoside C (66),黑蒴苷(67), rehmaionoside A (68), rehmaion oside B (69), oxyrehmaionoside B (70),地黄苷(71), sculponiside (72),2-phe nylethyl-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside (73),阿克替甙(74),红景天苷(75),leucosceptoside A (76), jionoside D (77), deacyl-martynoside (78), jionosides A1(79), jionosidesB1(80),3,4-dihydroxy-β-phenethyl-O-α-L-rha mnopyranosyl-(1→3)-O-β-D-galacopyranosyl-(1→6)-4-O-caffeoyl-β-D-glucopyrano side (81),香草醛(82),1-(4-methy-2-furanyl)-2-(5-methyl-5-ethenyl-2-tetrahydrof uranyl)-propan-l-one (83),顺式细辛醚(84),丁香酚(85),异丁香酚甲酯(86),阿魏酸(87),苯甲酸(88),丁香酸(89),β-谷甾醇(90),腺苷(91),腺嘌呤(92), rhamnopyranosyl vanilloyl (93), syringicacid-4-O-a-L-rhamnopyranoside (94),2-methoxy-4-methylphenyl-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (95),葡萄糖(96),半乳糖(97),水苏糖(98),蔗糖(99),甘露三糖(100),棉子糖(101), yemuoside YM1(102-103),(7R,8S,7'R,8'S)-4,9,4',9'-tetrahydroxy-3,3'-dime thoxy-7,7'-epoxylignan9-O-β-D-glucopyranoside (104),1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (105), tachioside (106), isotachioside (107),丙烯酸(108),邻苯二甲酸二丁酯(109)。另外,首次分离得到梓醇苷元(110)。
分离得到的110个化合物中,包括51个环烯醚萜(1*-12*,20-57,110),19个单萜、倍半萜和降倍半萜(13*-18*,58-70),10个苯乙醇苷(71-72,74-81)和30个其它类型化合物(19*,73,82-109)。其中化合物1*-19*为19个新化合物。
抗肿瘤方面,采用MTT法测定了地黄提取物各部位(图2-4-1)和97个单体化合物对五种人肿瘤细胞的抑制作用。结果显示地黄提取物各部位均无明显的抗肿瘤活性,单体化合物均没有表现出细胞毒活性(IC50>10μM)。
保肝和抗肝损伤方面,采用Fe2+-半胱氨酸诱导的肝微粒体脂质过氧化模型,测定地黄部分97个化合物的抗氧化活性。结果显示新化合物5在10-5M时表现一定的抗氧化活性(抑制率=23%)；同时,化合物51,76-77在10-5M也表现一定的抗氧化活性。采用扑热息痛(APAP)引起体外肝细胞损伤的保护模型,测定地黄部分97个化合物的肝保护活性。化合物71-72,74-75,79-80,100在10μM浓度下有一定的保护作用,活性与相同浓度的阳性对照药双环醇相当。以MTT法观察地黄提取物各部位对人肝细胞HL-7702细胞成活率的影响,结果显示,部位1,3,5,10-14有较明显的保肝活性,进一步考察显示化合物11,23,30,34,58,62,68,73,75,90,93,95有明显的保肝活性。
抗炎方面,采用给巴豆油致耳部炎症小鼠皮下注射相应受试物(100mg/kg)的方法,显示地黄提取物部位5,10,13,14可较明显的抑制小鼠耳肿胀,显示出一定的抗炎活性。单体化合物可以一定程度上抑制LPS诱导的细胞对NO的生成,与阳性对照地塞米松(浓度10-6M)相比,部分化合物在浓度10-5M显示出一定的活性
抗流感病毒方面,与阳性对照扎那米韦相比,地黄部分化合物对抗流感病毒神经氨酸酶均没有显示出活性。
镇静催眠和抗溃疡方面,采用戊巴比妥钠协同睡眠模型,小鼠腹腔注射给药测定地黄提取物各部位的镇静催眠作用,以入睡率为评价指标,地黄各部位均显示出一定的镇静催眠作用,但不强,与阳性对照安定相比差太多。采用测定H+-K+-ATP酶活性对地黄提取物各部位的抗溃疡活性进行评价,结果各部位均无明显抑制活性。
降血脂方面,地黄提取物各部位对降低甘油三酯活性均无较明显抑制活性。
神经保护方面,地黄提取物部位7在1、10μg/ml剂量下对去血清损伤PC12细胞均具有保护作用；部位13在10μg/ml下对鱼藤酮损伤具有保护作用；部位8,12对缺糖缺氧损伤的PC12细胞具有加重损伤作用。进一步测试显示化合物74,77,81和98在10μM浓度下对鱼藤酮损伤细胞具有保护作用。
调节钾通道作用方面,利用荧光膜电位法筛选出潜在钾通道阻断剂22个。
降血糖方面(体外),地黄提取物各部位对PTP1B酶均无较明显抑制活性。地黄提取物部位1有较明显的醛糖还原酶抑制活性,IC50在3.5μg/ml,化合物74有明显的醛糖还原酶抑制活性,IC50在2.68×10-7μM,其它化合物在浓度10-5μM抑制率均<69.4%。各部位在10μg/ml浓度下对FBPase1均无显著抑制作用,进一步显示各化合物在10μM浓度下对FBPase1均无显著抑制作用。地黄提取物各部位在40μg/ml浓度下对α-葡萄糖苷酶无显著抑制作用,化合物在浓度40μM对α-葡萄糖苷酶抑制率均<32.4%,无明显抑制活性。化合物51,74,77,81在浓度10μM对脂肪酶有明显的抑制活性。地黄提取物各部位对DPP-IV抑制活性均<13.0%,无较明显抑制活性。地黄提取物部位3和部位12对GK激活倍数接近阳性化合物。地黄提取物各部位对PPARy受体的激活倍数均<1.10,无较明显抑制PPARy转录活性。
降血糖方面(体内),梓醇在剂量50mg/kg和200mg/kg灌胃给药(每天一次,连续给药)对四氧嘧啶高血糖小鼠血糖在一定程度上有降低作用；腹腔注射(一次给药)对四氧嘧啶高血糖小鼠血糖无明显降低作用(50、200、300mg/kg);在50mg/kg和200mg/kg灌胃给药(每天一次,连续给药)对自发性2型糖尿病KKay小鼠血糖未见明显降低作用。
Rehmarnnia glutinosa Libosch (Scrophulariaceae) is indigenous to Mainland China, and the roots of this plant have been used in oriental medicine as an antianemic, an antipyretic, and a tonic. Due to the different processing methods, R. glutinosa is classified into three categories namely, fresh roots, dried roots, and steamed roots, which are used in different ways in traditional Chinese medicine. Previous phytochemical studies on the dried and steamed roots of R. glutinosa have led to the isolation and identification of iridoid glycosides, ionone glycosides, phenethyl alcohol glycosides, and several other components.
The roots of R. glutinosa were investigated on their chemical constituents systematically by various kinds of chromatographic methods. The sructures of isolates were elucidated on the basis of spectroscopic analysis and chemical evidence. Some of them were assayed for their bioactivities.
110compounds were obtained from ethanolic extract of theair-dried roots of R. glutinosa. These compounds were identified as follows:rehmaglutoside A-K (1*-11*), jioglutin F (12*), frehmaglutoside A-F (13*-18*),1,4,5,6-tetrahydro-1-methyl-6-oxo-3-pyridineacetic acid (19*), catalpol (20), ajugol (21), myoporoside (22), aucubin (23), monomelittoside (24),5-deoxyantirrhinoside (25), dihydro catalpol (26), myobontioside A (27),3'-O-β-D-glucopyranosyl-catalpol (28), melittoside (29), rehmannioside C (30), rehmannioside A (31),5-deoxylamiol (32), lamiol (33), gardoside (34),8-epiloganic acid (35), geniposidic acid (36), mussaenosidic acid (37), gardoside methyl ester (38), geniposide (39),8-epiloganin (40), jioglutoside B (41), genipin-gentiobioside (42), genipin1-O-α-L-rhamnopyran-osyl (1→6)-β-D-glucopyranoside (43), genameside C (44),6-O-E-feruloyl ajugol (45),6-O-vanillate ajugol (46),6-O-p-hydroxybenzoyl ajugol (47),6-O-(4"-O-α-L-rhamnopyranosyl) vanilloyl ajugol (48),6-oxo-4'-(3-methoxyl-4-hydroxyphenylgly-col-8")-feruloyl ajugol (49-50),6-O-E-caffeoyl ajugol (51),6-O-sec-hydroxy-aeginetoyl ajugol (52), aeginetoyl ajugol5"-O-β-D-quinovoside (53), genipin (54), jioglutins D (55),6β-hydroxy-2-oxabicyclo[4.3.0]△"9-nonen-l-one (56), jioglutins E (57), aeginetic acid (58), dihydroxy-β-ionone (59), rehmapicrogenin (60), trihydroxy-β-iononem (61), sec-hydroxyaeginetic acid (62), aeginetic acid5-O-β-D-quinovoside (63), neo-rehmannioside (64), dihydrophaseic acid4'-O-β-D-glucopyranoside (65), rehmaionoside C (66), melasmoside (67), rehmaionoside A (68), rehmaionoside B (69), oxyrehmaionoside B (70), martynoside (71), sculponiside (72),2-phenylethyl-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside (73), acteoside,(74), salidroside (75), leucosceptoside A (76), jionoside D (77), deacyl-martynoside (78), jionoside A1(79), jionoside B1(80),3,4-dihydroxy-β-phenethyl-O-α-L-rhamnopyranosyl-(1→3)-O-β-D-galacopyranosyl-(1→6)-4-O-caffeoyl-β-D-glucopyra noside (81), vanillin (82),1-(4-methy-2-furanyl)-2-(5-methyl-5-ethenyl-2-tetrahydro-furanyl)-propan-l-one (83), cis-asarone (84), eugenol (85), isoeugenol methyl ether (86), ferulic acid (87), benzoic acid (88), syringic acid (89), β-sitosterol (90), adenosine (91), adenine (92), rhamnopyranosyl vanilloyl (93), syringicacid-4-O-a-L-rhamnopyranoside (94),2-methoxy-4-methylphenyl-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (95), glucose (96), galactopyranose (97), stachyose (98), sucrose (99), manninotriose (100), raffinose (101), yemuoside YM1(102-103),(7R,8S,7'R,8'S)-4,9,4',9'-tetrahydroxy-3,3'-dimethoxy-7,7'-epoxylignan9-O-β-D-gluc-opyranoside (104),1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (105), tachioside (106), isotachioside (107), acrylic acid (108), dibutyl phthalate (109), besides, the aglycone of catalpol (110) was also obtained.
Among the isolated one hundred and ten compounds, there were fifty-one iridoid and iridoid glycosides (1*-12*,20-57,110), nineteen monoterpene and sesquiterpenes and nor sesquiterpenes (13*-18*,58-70), ten phen ethyl alcohol glycosides (71-72,74-81) and thirty other components (19*,73,82-109). Nineteen compounds (1*-19*) were new compounds.
The crude extracts and ninety-seven compounds obtained from the roots of R. glutinosa were tested for their cytotoxicity against five human tumor cell lines by MTT method. However, all were inactive for all cell lines used (IC50>10μM is defined as "inactive").
By the model of inhibiting the production of lipid peroxide induced by Fe2+-Cys system in the liver microsomal, ninety-seven compounds were evaluated for their antioxidant activities and compounds5,51,76-77exhibited weak activities. Compounds71-72,74-75,79-80and100exhibited moderate hepatoprotecti-ve activities against APAP-induced HepG2cell damage. They were also bioassayed for their hepatoprotective activities against D-galactosamine induced toxicity in HL-7702cells, using the hepatoprotective activity drug bicyclol as the positive control, fractions1,3,5,10-14exhibited moderated hepatoprotective activities, and compounds11,23,30,34,58,62,68,73,75,90,93and95exhibited pronounced hepatoprotective activities.
Fractions5,10,13and14exhibited anti-inflammatory activities in vivo. Th e inhibitory effects of the isolates against nitric oxide (NO) production in mou seperitoneal macrophages were examined. Some compounds inhibited NO elevat ion at a concentration of10μM.
All ninety-seven compounds were inactive for anti influenza virus NA (neuramidinase) tested model.
All crude extracts exhibited weak sedative-hypnotic activites and were inactive in inhibiting H+-K+-ATPase activity.
All crude extracts were inactive in decreasing triglyceride level.
The protective activities of the crude extracts and compounds against neuroto xicity induced by serum deprivation in PC12cells were investigated by the M TT method. The results showed that serum deprivation induced significant inhi-bition of MTT reduction. Fraction7increased cell viability at a concentration of1μg/ml and10μg/ml, respectively. Furthermore, compounds74,77,81and98exhibited protective activity on cell damage induced by nicouline at a conc-entration of10μM, indicating that they may be effective in neurodegenerative disorders.
It has been found22possible potassium channel inhibitors by detecting fluorescent membrane potential in PC12cells.
For antidiabetic bioactivities, all crude extracts exhibited weak activities in inhibiting PTP1B (protein-tyrosine phosphatase-1B) and FBPasel. Fraction1and compound74possesed obvious inhibition agaist aldose reductase, with IC50values of3.5μg/ml and2.68×10-7μM, respectively, and other compounds showed inhibitory rates less than69.4%at a concentration of10μM. All crude extracts exhibited weak activities in inhibiting a-glucosidase at a concentration of40μg/ml and all compounds tested showed inhibitory rates less than32.4%at a concentration of40μM. Compounds51,74,77and81exhibited pronounced activities in inhibiting lipidase on a concentration of10μM. All crude extracts exhibited weak activities in inhibiting DPP-IV and PPARγ transcription. Fractions3and12exhibited significant GK (glucokinase) enzymatic activity, which was comparative to the positive control. Further more, in vivo, compound20exhibited weak antihyperglycemic activity at a concentration of200mg/kg on hyperglycemic mice induced by alloxan by intragastric administration, but no significant activity at a concentration of300mg/kg by intraperitoneal injection. In T2DM Kkay mice model, compound20exhibited no significant activity at a concentration of200mg/kg by intragastric administration.
引文
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