荜茇的化学成分与抗ADP诱导的血小板凝集活性和抗HBV活性成分研究
其他题名CHEMICAL CONSTITUENTS AND ANTI-PLATELET AGGREGATION INDUCED BY ADP, ANTI-HBV ACTIVITIES OF PIPER LONGUM
刘文峰
学位类型硕士
导师陈纪军
2009-05-19
学位授予单位中国科学院昆明植物研究所
学位授予地点昆明植物研究所
学位专业药物化学
关键词荜茇 化学成分 酰胺类生物碱 抗adp诱导的血小板凝集活性 抗hbv活性
摘要本论文围绕抗ADP诱导的血小板凝集活性与抗乙肝病毒活性成分的发现,对荜茇(Piper longum)进行了较深入的化学成分分离。利用各种色谱分离技术,从荜茇中共分离得到55个化合物, 经波谱数据分析, 鉴定了它们的结构, 包括8个新化合物。新的天然产物2个。 化合物结构类型涉及酰胺类生物碱、倍半萜及其苷、降倍半萜及其苷、单萜及其苷等,分别为:荜茇眀碱 (piperlongumine, 1), N - 异丁基 - 2E, 4E, 8E - 十七烷三烯酰胺 (N - isobutyl - 2E, 4E, 8E - heptadecatrienamide, 2), N - 异丁基 - 2E, 4E - 十七烷二烯酰胺 (N - isobutyl - 2E, 4E - heptadecadienamide, 3), N - 异丁基 - 11 (3, 4 - 亚甲基二氧苯基) - 2E, 4E, 10E - 葵烷三烯酰胺 (N - isobutyl - 11 (3, 4 - methylenedioxyphenyl) - 2E, 4E, 10E - decatrienamide, 4), N - 异丁基 - 2E, 4E, 8E - 十九烷三烯酰胺 (N - isobutyl - 2E, 4E, 8E - nonadecatrienamide, 5), N - 异丁基 - 6 - 羟基 - 2E, 4E, 14Z - 十九烷三烯酰胺 (N - isobutyl - 6 - hydroxyl - 2E, 4E, 14Z -nonadecatrienamide, 6), 几内亚胡椒胺 (guineesine, 7), 1 - [1 - 羰基 - 5 (4 - 羟基苯基) - 2E, 4E - 戊二烯基] - 哌啶 (1 - [1 - oxo - 5 (4 - hydroxyphenyl) - 2E, 4E - pentadienyl] - piperidine, 8), 胡椒碱 (piperine, 9), 1 - [1 - 羰基 - 5 (3 - 甲氧基 - 4 - 羟基苯基) - 2E - 戊烯基] - 哌啶 (1 - [1 - oxo - 5 (3 - methoxyl - 4 - hydroxyphenyl) - 2E - pentenyl] - piperidine, 10), 苏式 - 1 - 羰基 - 5 (3, 4 - 亚甲基二氧苯基) - 2, 3 - 二羟基- 4E - 戊烯基- 哌啶 (erythro - 1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2, 3 - dihydroxy - 4E - pentenyl] - piperidine, 11), 赤式 - 1 - 羰基 - 5 (3, 4 - 亚甲基二氧苯基) - 2, 3 - 二羟基 - 4E - 戊烯基] - 哌啶 (threo - 1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2, 3 - dihydroxy - 4E - pentenyl] - piperidine, 12), 苏式 - 1 - [1 - 羰基 - 9 (3, 4 - 亚甲基二氧苯基) - 8, 9 - 二羟基 - 2E - 壬烯] - 哌啶 (erythro - 1 - [1 - oxo - 9 (3, 4 - methylenedioxyphenyl) - 8, 9 - dihydroxy - 2E - nonenyl] - piperidine, 13), 赤式 - 1 - [1 - 羰基 - 9 (3, 4 - 亚甲基二氧苯基) - 8, 9 - 二羟基 - 2E - 壬烯] - 哌啶 (threo - 1 - [1 - oxo - 9 (3, 4 - methylenedioxyphenyl) - 8, 9 - dihydroxy - 2E - nonenyl] - piperidine, 14), 1 - (1 - 羰基 - 2E - 二十烷烯基) - 哌啶 (1 - (1 - oxo - 2E - icosenyl) - piperine, 15), 1 - [1 - 羰基 - 5 (3, 4 - 亚甲基二氧苯基) - 2E, 4E - 戊二烯基] - 吡咯 (1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2E, 4E - pentadienyl] - pyrrolidine, 16), 1 - [1 - 羰基 - 5 (3, 4 - 亚甲基二氧苯基) - 2E - 戊烷烯基] - 吡咯 (1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2E - pentenyl] - pyrrolidine, 17), 1 - [1 - 羰基 - 9 (3, 4 - 亚甲基二氧苯基) - 2E, 8E -壬二烯基] - 吡咯 (1 - [1 - oxo - 9 (3, 4 - methylenedioxyphenyl) - 2E, 8E - nonadienyl] - pyrrolidine, 18 ), 3, 4 - 二羟基 - 1 - (3 - 苯丙基) - 哌啶 - 2 - 酮 (3, 4 - dihydroxy - 1 - (3 - phenylpropanoyl) - piperidine - 2 - one, 19), 胡椒内酰胺 A (piperolactam A, 20), 5, 6 -二氢 - 2 (1H) - 吡啶酮 (5, 6 - dihydro - 2 (1H) - pyridinone, 21), 苯丙酰胺 (3 - phenylpropanamide, 22), 3, 4 - 二羟基 - 2 - 哌啶酮 (3, 4 - dihydroxy - 2 - piperidinone, 23), 肌苷(inosine, 24), 5 - 羟基 -吡咯酮 (5 - hydroxy - pyridinone, 25), 核糖醇 (ribitol, 26), longamide A (27), longamide B (28), longamide C (29), longamide D (30), chabamide (31), nigramide R (32), nigramide V (33), 姜黄酮 ((R) - ( - ) - turmerone, 34), 3, 4 - dihydroxybiabola - 1, 10 - diene (35), eudesm - 4(15) - ene - 1β, 6α - diol (36), octahydro - 4 - hydroy - 3α - methyl - 7 - methylene - α - (1 - methylethyl) - 1H - indene - 1 - methanol (37), (+) - aphanamol I (38), 7 - epi - eudesm - 4 (15 ) - ene - 1β, 6β - diol (39), vomifoliol (40), (6S,9R)-roseoside (41), 胡椒醛 (3 - (3', 4' - methylenedioxophenyl) - propenal, 42), 胡椒酸(piperoic acid, 43), 胡椒酸甲酯 (methyl piperate, 44), 1 - (3, 4 - methylenedioxyphenyl) - 1E - tetradecene (45), 二去甲氧基姜黄素(bisdemethoxycurcumin, 46), 去甲氧基姜黄素 (demethoxycurcumin, 47), trans - cinnamyl - β - D - glucopyranoside (48), trans - cinnamyl - (6 - (3 - oxyl - 3 - methylpentanedioic acid)) - β - D - glucopyranoside (49), (1R, 2S, 4S, 5R) - angelicoidenol 2 - O - β - D - glucopyranoside (50), 5 - formyl - (1R, 2S, 4S, 5R) - angelicoidenol 2 - O - β - D - glucopyranoside (51), 丁四醇 (butane - 1, 2, 3, 4 - tetraol, 52), β - Lominaribiose (53), β-谷甾醇 (β - sitosterol, 54), 胡萝卜苷 (daucosterol, 55)。其中化合物13, 14, 19, 27, 28, 29, 30, 49为新化合物。化合物23和33为新的天然产物。 对分离得到的部分化合物进行了抗ADP诱导血小板凝集活性测试和体外抗HBV活性研究。研究结果表明:在浓度为0.71 mg/ml时,化合物3、4、7、14、16、27、28、29、30、31、32具有一定的抗ADP诱导的血小板凝集活性,其A (1′)(1分钟时的抑制率)和A (max)(5分钟内的最大抑制率)分别为: 70.13%、65.13%;77.78%、71.34%;46.76%、52.70%;88.71%、80.14%;57.93%、7.66%;100%、100%;73.62%、63.96%;100%、91.57%;100%、97.22%;61.04%、53.30%;71.02%、59.05%。 对部分化合物进行了体外抗HBV活性测试,研究表明: 化合物4, 5, 6, 7, 9, 13, 14, 15, 16, 17, 24, 29, 30, 32, 42对乙肝病毒表面抗原的分泌具有较强的抑制作用,同时化合物4, 5, 6, 7, 9, 13, 14, 15, 16, 29, 30, 32, 42对乙肝病毒e抗原的分泌也具有较强的抑制作用。 同时还总结了胡椒属酰胺类生物碱和荜茇的生物活性研究进展,综述了1997年至2008年12月发表的所有97个化合物。
其他摘要P. longum, a slender aromatic climber, is widely distributed in the tropical and subtropical regions in the world. The fruits of P. longum are employed for the treatment of an anodyne and stomach disease in China. Our preliminary study showed the ethanol extract of P. longum exhibited significant inhibitory activity on platelet aggregation induced by ADP, and anti-HBV activity on HBsAg and HBeAg secretion. During our research for biologically active secondary metabolites, 8 new compounds and 47 known compounds were isolated from P. longum. Based on spectral analyses (UV, IR, 1D, 2D NMR, MS) and comparison with reported literatures, the isolates were characterized as follows: piperlongumine (1), N - isobutyl - 2E, 4E, 8E - heptadecatrienamide (2), N - isobutyl - 2E, 4E - heptadecadienamide (3), N - isobutyl - 11 (3, 4 - methylenedioxyphenyl) - 2E, 4E, 10E - decatrienamide (4), N - isobutyl - 2E, 4E, 8E - nonadecatrienamide (5), N - isobutyl - 6 - hydroxyl - 2E, 4E, 14Z - nonadecatrienamide (6), guineesine (7), 1 - [1 - oxo - 5 (4 - hydroxyphenyl) - 2E, 4E - pentadienyl] - piperidine (8), piperine (9), 1 - [1 - oxo - 5 (3 - methoxyl - 4 - hydroxyphenyl) - 2E - pentenyl] - piperidine (10), erythro - 1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2, 3 - dihydroxy - 4E - pentenyl] - piperidine (11), threo - 1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2, 3 - dihydroxy - 4E - pentenyl] - piperidine (12), erythro - 1 - [1 - oxo - 9 (3, 4 - methylenedioxyphenyl) - 8, 9 - dihydroxy - 2E - nonenyl] - piperidine (13), threo - 1 - [1 - oxo - 9 (3, 4 - methylenedioxyphenyl) - 8, 9 - dihydroxy - 2E - nonenyl] - piperidine (14), 1 - (1 - oxo - 2E - icosenyl) - piperine (15), 1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2E, 4E - pentadienyl] - pyrrolidine (16), 1 - [1 - oxo - 5 (3, 4 - methylenedioxyphenyl) - 2E - pentenyl] - pyrrolidine (17), 1 - [1 - oxo - 9 (3, 4 - methylenedioxyphenyl) - 2E,8E - nonadienyl] - pyrrolidine (18), 3, 4 - dihydroxy - 1 - (3 - phenylpropanoyl) - piperidine - 2 - one (19), piperolactam A (20), 5, 6 - dihydro - 2 (1H) - pyridinone (21), 3 - phenylpropanamide (22), 3, 4 - dihydroxy - 2 - piperidinone (23), inosine (24), 5 - hydroxy - pyridinone (25), ribitol (26), longamide A (27), longamide B (28), longamide C (29), longamide D (30), chabamide (31), nidramide R (32), nigramide V (33), (R) - ( - ) - turmerone (34), 3, 4 - dihydroxybiabola - 1, 10 - diene (35), eudesm - 4(15) - ene - 1β, 6α - diol (36), octahydro - 4 - hydroy - 3α - methyl - 7 - methylene - α - (1 - methylethyl) - 1H - indene - 1 - methanol (37), (+) - aphanamol I (38), 7 - epi - eudesm - 4 (15 ) - ene - 1β, 6β - diol (39), vomifoliol (40), (6S,9R)-roseoside (41), 3 - (3', 4' - methylenedioxophenyl) - propenal (42), piperoic acid (43), methyl piperate (44), 1 - (3, 4 - methylenedioxyphenyl) - 1E - tetradecene (45), bisdemethoxycurcumin (46), demethoxycurcumin (47), trans - cinnamyl - β - D - glucopyranoside (48), trans - cinnamyl - (6 - (3 - oxyl - 3 - methylpentanedioic acid)) - β - D - glucopyranoside (49), (1R, 2S, 4S, 5R) - angelicoidenol 2 - O - β - D - glucopyranoside (50), 5 - formyl - (1R, 2S, 4S, 5R) - angelicoidenol 2 - O - β - D - glucopyranoside (51), butane - 1, 2, 3, 4 - tetraol (52), β - Lominaribiose (53) , β - sitosterol (54), daucosterol (55). Among them, compounds 13, 14, 19, 27, 28, 29, 30, 49 were new ones, compounds 23 and 33 were new natural compounds. Anti-platelet aggregation bioassay showed compounds 3、4、7、14、16、27、28、29、30、31、32 had potent activities. The inhibitory ratios in 1 min and 5 min at the concentration of 0.71 mg/ml were 70.13%、65.13%;77.78%、71.34%;46.76%、52.70%;88.71%、80.14%;57.93%、7.66%;100%、100%;73.62%、63.96%;100%、91.57%;100%、97.22%;61.04%、53.30%;71.02%、59.05%, respectively. Anti-HBV study suggested compounds 4, 5, 6, 7, 9, 13, 14, 15, 16, 29, 30, 32, 42 exhibited inhibitory activities on HBsAg and HBeAg serections in Hep G2.2.15 cells. Furthermore, the amide alkaloids isolated from Piper species from 1997 to 2008 and bioactivities of P. longum were summarized.
页数105
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/470
专题昆明植物所硕博研究生毕业学位论文
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刘文峰. 荜茇的化学成分与抗ADP诱导的血小板凝集活性和抗HBV活性成分研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2009.
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