肺形草抗H5N1禽流感活性成分研究
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摘要
高致病性禽流感（HPAI）给人类的健康造成巨大威胁，目前尚无特效治疗药物。从中草药中寻找高效低毒的抗HPAI的单体化合物是发现并研制抗HPAI药物的一条有效途径。本论文选择A/Tiger/Harbin/01/2002株简称（HAB/01）H5N1病毒感染犬肾细胞株（MDCK）为活性筛选模型，以细胞病变法（CPE）作为初步筛选的活性评价方法，对66种中草药进行体外抗病毒活性筛选，首次发现了7种抗H5N1病毒作用显著的中草药，其中肺形草活性最好。本论文决定对肺形草的化学成分及抗禽流感活性进行深入研究，希望发现具有抗禽流感活性的单体化合物，为抗禽流感药物的研制与开发奠定基础。
本论文通过AB-8大孔树脂柱色谱、重结晶、硅胶柱色谱、C18反相柱色谱、Sephadex LH-20柱色谱和PHPLC等手段分离纯化，从肺形草中分离得到了50个化合物，通过理化常数的测定、MS、1D和2D NMR（1H-1H COSY、HSQC、HMBC）等波谱分析，鉴定了其中41个化合物（包括1个混合物）的结构，其中有5个新化合物，鉴定的41个化合物的结构分别为：双蝴蝶苷C（1）、双蝴蝶苷D（2）、双蝴蝶苷E（3）、双蝴蝶苷F（4）、双蝴蝶苷G（5）、双蝴蝶苷B（6）、獐芽菜苷（7）、番木鳖酸（8）、8-表-金银花苷（9）、岩白菜素（10）、异牡荆素（11）、异牡荆素-7-O-鼠李糖（12）、异荭草素-7-O-鼠李糖（13）、肥皂草苷（14）、三叶豆苷-2′′-O-鼠李糖（15）、三叶豆苷（16）、8-羟基-1,2,6-三甲氧基呫吨酮（17）、1,7-二羟基-3,8-二甲氧基呫吨酮（18）、1,2,8-三羟基-5,6-二甲氧基呫吨酮（19）、1,3,7-三羟基-4-C-β-D-葡萄糖基呫吨酮（20）、大黄酚（21）、大黄素（22）、芦荟大黄素（23）、大黄素甲醚-8-O-β-D-葡萄糖苷（24）、1,3,8-三羟基-6-羟甲基蒽醌（25）、大黄素-8-O-β-D-葡萄糖苷（26）、大黄酚-8-O-β-D-葡萄糖苷（27）、芦荟大黄素-3（-羟甲基）-O-β-D-葡萄糖苷（28）、齐墩果酸（29）、熊果酸（30）、β-胡萝卜苷（31）、咖啡酸（32）、3,4-二羟基苯甲酸（33）、2-甲氧基苯酚（34）、4-羟基苯甲酸（35）、正三十四烷酸（36）、胸腺嘧啶脱氧核苷（37）、尿嘧啶核苷（38）、β-谷甾醇（39）、豆甾醇（40）、α-L-夹竹桃糖（41a）和β-D-加拿大麻糖（41b）。化合物1至5为5个新化合物（包括2个环烯醚萜四聚体、2个环烯醚萜二聚体、1个含有糖基的β-内酯），化合物9-10、12-16、21-29、31-38、40-41共26个化合物首次从该属分离得到；化合物7-8、20、30共4个化合物首次从该植物中分离得到。
从化合物结构类型看，包括环烯醚萜类化合物8个，黄酮类化合物8个，蒽醌类化合物8个，其它类化合物15个，其中化合物1和5是首次分离得到的裂环烯醚萜四聚体新化合物；化合物3是首次分离得到的含有糖基的β-内酯新化合物；化合物4是首次分离得到的裂环烯醚萜与生物碱相连接的新化合物；这些化合物丰富了天然产物的结构类型。对于已知化合物，本论文首次报道了化合物12和13的波谱数据。
通过细胞病变法（CPE）对分离得到的部分化合物进行抗H5N1病毒活性评价，结果发现异牡荆素（11）和化合物X有抗H5N1病毒活性，其中化合物X具有明显的抗H5N1病毒活性，药物浓度为37.5μg/mL时，CPE结果为“＋＋”，且有较好的剂量依赖关系，而且该单体化合物在肺形草中含量高，具有进一步研究开发的潜力，有望成为抗禽流感药物研究的新的先导化合物；化合物11具有一定的抗H5N1病毒活性，药物浓度为150μg/ml时，CPE结果为“+++”。
Highly pathogenic avian influenza（HPAI）causes a major threat to humans.Screening safe and effective anti-HPAI compounds in Chinese herbal medicinesprovides a large opportunity for the development of anti-HPAI drugs. In the dissertation,we selected66Chinese herbal medicines for anti-HPAI in vitro, employing the methodof MDCK cell cultures infected with H5N1subtype and using cytopathic effect (CPE) asactivity-evaluating method. Seven Chinese herbal medicines were found to have anti-HPAI activity during our experiments. Among them, the extract of Tripterospermumchinense showed the most prominent anti-HPAI activity, so our studies on chemicalconstituents and anti-HPAI activity of T. chinense has been processed deeply.
Fifty constituents were separated through AB-8macroporous resin,recrystallisation, chromatography of silica gel, RP C18silica gel, Sephadex LH-20andPHPLC, and41of their structures were elucidated with physical and chemicalconstant, MS,1D and2D NMR (1H-1H COSY、HSQC、HMBC). There were5newcompounds. The structures of41compounds were as follows: tripterospermumcin C(1), tripterospermumcin D (1), tripterospermumcin E (3), tripterospermumcin F (4),tripterospermumcin G (5), tripterospermumcin B (6), sweroside (7), loganic acid (8),8-epi-kingiside (9), bergenin (10), isovitexin (11),7-O-rhamnopyranosyl-isovitexin(12),7-O-rhamnopyranosyl-isoorientin (13), saponarin (14),2′′-O-rhamnopyranosyl-trifoliside (15), trifoliside (16),8-hydroxy-1,2,6-trimethoxyxanthone (17),1,7-dihydroxy-3,8-dimethoxyxanthone (18),1,2,8-trihydroxy-5,6-dimethoxyxanthone(19), lancerin (20), chrysophanol (21), emodin (22), aloe emodin (23), physcion-8-O-β-D-glucopyranoside (24), citreorosein (25), emodin-8-O-β-D-glucopyranoside (26),emodin-8-O-β-D-glucopyranoside (27), aloe emodin-3-(hydroxymethyl)-O-β-D-glucopyranoside (28), oleanolic acid (29), ursolic acid (30), β-daucosterol (31),caffeic acid (32),3,4-dihydroxybenzoic acid (33),2-methoxyphenol (34),4-hydroxybenzoic acid (35), tetratriacontanoic acid (36), thymidine (37), urdin (38), β-sitosterol (39), stigmasterol (40), α-L-oleandrose (41a) and β-D-cymarose (41b).Compounds1,2,3,4and5were new compounds, including two iridoid tetramerswith four glucosides, two iridoid dimers with two glucosides, one β-lactone with aglucoside. Compounds9-10,12-16,21-29,31-38, and40-41were isolated from thegenus Tripterospermum for the first time. Compounds7-8,20, and30were isolatedfrom Tripterospermum chinense (Migo) H. Smith。for the first time.
From the perspective of chemical structures,41compounds include8iridoidglycosides,8flavones,8anthraquinones,15other structural types. Compounds1and5are the first isolation of secoiridoid tetramers with four glucosides. Compound3is the first isolation of β-lactone with a glucoside. Compound4is the first isolation ofsecoiridoid dimers with two glucosides, linkage to one alkaloids. These types ofcompounds increase structures of natural products. The NMR data of compounds12and13were reported for the first time.
Anti-H5N1activities of compounds11and X has been discovered by CPEactivity assay. At the effective dose of37.5μg/mL, compound X did not showapparent toxicity to cell viability, metabolism or proliferation, which exhibited apotent anti-influenza virus activity in MDCK cell cultures infected with H5N1subtyp.Compound X might become a new leading natural compound for the systhesis anddevelopment of new anti-HPAI drugs. At the effective dose of150μg/mL, compound11did not show apparent toxicity to cell viability, metabolism or proliferation, whichexhibited a potent anti-influenza virus activity in MDCK cell cultures infected withH5N1subtype.
本论文通过AB-8大孔树脂柱色谱、重结晶、硅胶柱色谱、C18反相柱色谱、Sephadex LH-20柱色谱和PHPLC等手段分离纯化，从肺形草中分离得到了50个化合物，通过理化常数的测定、MS、1D和2D NMR（1H-1H COSY、HSQC、HMBC）等波谱分析，鉴定了其中41个化合物（包括1个混合物）的结构，其中有5个新化合物，鉴定的41个化合物的结构分别为：双蝴蝶苷C（1）、双蝴蝶苷D（2）、双蝴蝶苷E（3）、双蝴蝶苷F（4）、双蝴蝶苷G（5）、双蝴蝶苷B（6）、獐芽菜苷（7）、番木鳖酸（8）、8-表-金银花苷（9）、岩白菜素（10）、异牡荆素（11）、异牡荆素-7-O-鼠李糖（12）、异荭草素-7-O-鼠李糖（13）、肥皂草苷（14）、三叶豆苷-2′′-O-鼠李糖（15）、三叶豆苷（16）、8-羟基-1,2,6-三甲氧基呫吨酮（17）、1,7-二羟基-3,8-二甲氧基呫吨酮（18）、1,2,8-三羟基-5,6-二甲氧基呫吨酮（19）、1,3,7-三羟基-4-C-β-D-葡萄糖基呫吨酮（20）、大黄酚（21）、大黄素（22）、芦荟大黄素（23）、大黄素甲醚-8-O-β-D-葡萄糖苷（24）、1,3,8-三羟基-6-羟甲基蒽醌（25）、大黄素-8-O-β-D-葡萄糖苷（26）、大黄酚-8-O-β-D-葡萄糖苷（27）、芦荟大黄素-3（-羟甲基）-O-β-D-葡萄糖苷（28）、齐墩果酸（29）、熊果酸（30）、β-胡萝卜苷（31）、咖啡酸（32）、3,4-二羟基苯甲酸（33）、2-甲氧基苯酚（34）、4-羟基苯甲酸（35）、正三十四烷酸（36）、胸腺嘧啶脱氧核苷（37）、尿嘧啶核苷（38）、β-谷甾醇（39）、豆甾醇（40）、α-L-夹竹桃糖（41a）和β-D-加拿大麻糖（41b）。化合物1至5为5个新化合物（包括2个环烯醚萜四聚体、2个环烯醚萜二聚体、1个含有糖基的β-内酯），化合物9-10、12-16、21-29、31-38、40-41共26个化合物首次从该属分离得到；化合物7-8、20、30共4个化合物首次从该植物中分离得到。
从化合物结构类型看，包括环烯醚萜类化合物8个，黄酮类化合物8个，蒽醌类化合物8个，其它类化合物15个，其中化合物1和5是首次分离得到的裂环烯醚萜四聚体新化合物；化合物3是首次分离得到的含有糖基的β-内酯新化合物；化合物4是首次分离得到的裂环烯醚萜与生物碱相连接的新化合物；这些化合物丰富了天然产物的结构类型。对于已知化合物，本论文首次报道了化合物12和13的波谱数据。
通过细胞病变法（CPE）对分离得到的部分化合物进行抗H5N1病毒活性评价，结果发现异牡荆素（11）和化合物X有抗H5N1病毒活性，其中化合物X具有明显的抗H5N1病毒活性，药物浓度为37.5μg/mL时，CPE结果为“＋＋”，且有较好的剂量依赖关系，而且该单体化合物在肺形草中含量高，具有进一步研究开发的潜力，有望成为抗禽流感药物研究的新的先导化合物；化合物11具有一定的抗H5N1病毒活性，药物浓度为150μg/ml时，CPE结果为“+++”。
Highly pathogenic avian influenza（HPAI）causes a major threat to humans.Screening safe and effective anti-HPAI compounds in Chinese herbal medicinesprovides a large opportunity for the development of anti-HPAI drugs. In the dissertation,we selected66Chinese herbal medicines for anti-HPAI in vitro, employing the methodof MDCK cell cultures infected with H5N1subtype and using cytopathic effect (CPE) asactivity-evaluating method. Seven Chinese herbal medicines were found to have anti-HPAI activity during our experiments. Among them, the extract of Tripterospermumchinense showed the most prominent anti-HPAI activity, so our studies on chemicalconstituents and anti-HPAI activity of T. chinense has been processed deeply.
Fifty constituents were separated through AB-8macroporous resin,recrystallisation, chromatography of silica gel, RP C18silica gel, Sephadex LH-20andPHPLC, and41of their structures were elucidated with physical and chemicalconstant, MS,1D and2D NMR (1H-1H COSY、HSQC、HMBC). There were5newcompounds. The structures of41compounds were as follows: tripterospermumcin C(1), tripterospermumcin D (1), tripterospermumcin E (3), tripterospermumcin F (4),tripterospermumcin G (5), tripterospermumcin B (6), sweroside (7), loganic acid (8),8-epi-kingiside (9), bergenin (10), isovitexin (11),7-O-rhamnopyranosyl-isovitexin(12),7-O-rhamnopyranosyl-isoorientin (13), saponarin (14),2′′-O-rhamnopyranosyl-trifoliside (15), trifoliside (16),8-hydroxy-1,2,6-trimethoxyxanthone (17),1,7-dihydroxy-3,8-dimethoxyxanthone (18),1,2,8-trihydroxy-5,6-dimethoxyxanthone(19), lancerin (20), chrysophanol (21), emodin (22), aloe emodin (23), physcion-8-O-β-D-glucopyranoside (24), citreorosein (25), emodin-8-O-β-D-glucopyranoside (26),emodin-8-O-β-D-glucopyranoside (27), aloe emodin-3-(hydroxymethyl)-O-β-D-glucopyranoside (28), oleanolic acid (29), ursolic acid (30), β-daucosterol (31),caffeic acid (32),3,4-dihydroxybenzoic acid (33),2-methoxyphenol (34),4-hydroxybenzoic acid (35), tetratriacontanoic acid (36), thymidine (37), urdin (38), β-sitosterol (39), stigmasterol (40), α-L-oleandrose (41a) and β-D-cymarose (41b).Compounds1,2,3,4and5were new compounds, including two iridoid tetramerswith four glucosides, two iridoid dimers with two glucosides, one β-lactone with aglucoside. Compounds9-10,12-16,21-29,31-38, and40-41were isolated from thegenus Tripterospermum for the first time. Compounds7-8,20, and30were isolatedfrom Tripterospermum chinense (Migo) H. Smith。for the first time.
From the perspective of chemical structures,41compounds include8iridoidglycosides,8flavones,8anthraquinones,15other structural types. Compounds1and5are the first isolation of secoiridoid tetramers with four glucosides. Compound3is the first isolation of β-lactone with a glucoside. Compound4is the first isolation ofsecoiridoid dimers with two glucosides, linkage to one alkaloids. These types ofcompounds increase structures of natural products. The NMR data of compounds12and13were reported for the first time.
Anti-H5N1activities of compounds11and X has been discovered by CPEactivity assay. At the effective dose of37.5μg/mL, compound X did not showapparent toxicity to cell viability, metabolism or proliferation, which exhibited apotent anti-influenza virus activity in MDCK cell cultures infected with H5N1subtyp.Compound X might become a new leading natural compound for the systhesis anddevelopment of new anti-HPAI drugs. At the effective dose of150μg/mL, compound11did not show apparent toxicity to cell viability, metabolism or proliferation, whichexhibited a potent anti-influenza virus activity in MDCK cell cultures infected withH5N1subtype.
引文
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