| 题名 | 以一枝蒿酮酸为骨架的抗流感病毒候选化合物的合成及活性研究 |
| 作者 | 赵江瑜 |
| 学位类别 | 博士 |
| 答辩日期 | 2011-12-10 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 胡克林 |
| 关键词 | 一枝蒿酮酸 衍生物 合成 流感病毒 |
| 学位专业 | 有机化学 |
| 中文摘要 | 流感是流行性感冒的简称，是一种全球性的传染疾病，流感病毒是一种造成鸟类及哺乳动物患流行性感冒的单股负链的RNA病毒，在分类学上属于正黏液病毒科。流感在季节高发期可以全球范围传播，每年导致的死亡人数高达25~50万人，在一些高发季节死亡人数可达数百万。目前，应对流感的主要方式是流感疫苗和抗流感病毒药物，但是二者均存在不同程度的局限性。而且，2009年甲型H1N1流感的爆发再次引起全世界对流感病毒的高度重视，使得研究安全有效的抗流感病毒药物迫在眉睫。 新疆一枝蒿(Artemisia rupestris L.)为菊科蒿属植物，在新疆民间用药历史悠久，具有抗炎、抗过敏、抗肿瘤、增强免疫力、抗菌、保肝等生物活性。一枝蒿酮酸在新疆一枝蒿中含量丰富。鉴于其独特的倍半萜结构，本课题组率先对一枝蒿酮酸进行结构修饰，合成70个一枝蒿酮酸酰胺类衍生物和酯类衍生物，通过初步体外抗A, B型流感病毒和单纯Ⅰ,Ⅱ型疱疹病毒活性测试，从中筛选出4个抗A型流感病毒活性较好的一枝蒿酮酸衍生物。 在上述研究背景和研究基础上，我们继续对一枝蒿酮酸进行结构修饰，设计并合成59个一枝蒿酮酸羧基衍生物和30个一枝蒿酮酸类似物，所合成的衍生物均通过1H NMR, 13C NMR, IR, ESI-MS (HRMS)等分析方法进行表征。除此之外，还对它们进行初步的体外抗流感病毒活性测试。活性测试结果表明：化合物一枝蒿酮酸-(2,3,4-三-O-乙酰基)-b-D-木糖酯 (2d) 和一枝蒿酮酸-(2,3,6,2¢,3¢,4¢,6¢-七-O-乙酰基)-b-乳糖酯 (2g) 表现出良好的抗H3N2流感病毒活性 (2d: TC50=592.9 μM, IC50=0.35 μM, SI=1666.7; 2g: TC50=166.5 μM, IC50=0.21 μM, SI=801.1); 化合物一枝蒿酮酸-2-氯乙酯 (3) 具有一定的抗A、B型流感病毒活性 (H3N2: TC50=1669 μM, IC50=17.2 μM, SI=96.9; H1N1: IC50=27.8 μM, SI=60.0; B: TC50>3225 μM, IC50=358.4 μM, SI>9.0); 化合物一枝蒿酮酸-10-(4-苯基哌嗪基)-癸酯5g和一枝蒿酮酸-4-(4-甲基哌嗪基)-丁酯 (6c) 具有一定的抗H1N1流感病毒活性 (5g: TC50=456.2 μM, IC50=2.42 μM, SI=187.97; 6c: TC50=643.5 μM, IC50=10.25 μM, SI=62.79); 化合物一枝蒿酮酸-10-(4-甲基哌嗪基)-癸酯 (6g)表现出一定的抗H3N2和H1N1流感病毒活性 (H3N2: TC50=177.4 μM, IC50=5.23 μM, SI=33.95; H1N1: IC50=3.72 μM, SI=47.64); 化合物一枝蒿酮酸-5-(1H-1,2,4-三氮唑-1-基)-戊酯 (7d) 表现出一定的抗A、B型流感病毒活性 (H3N2: TC50=672.0 μM, IC50=17.3 μM, SI=38.90; H1N1: IC50=7.4 μM, SI=90.77; B: IC50=17.27 μM, SI=38.90); 化合物一枝蒿酮酸-8-(1H-1,2,4-三氮唑-1-基)-辛酯 (7f) 表现出一定的抗A、B型流感病毒活性 (H3N2: TC50=201.9 μM, IC50=5.20 μM, SI=38.84; H1N1: IC50=7.2 μM, SI=28.00; B: IC50=3.2 μM, SI=62.94); 化合物一枝蒿酮酸-10-(1H-1,2,4-三氮唑-1-基)-癸酯 (7g) 表现出强的抗H3N2和H1N1流感病毒活性 (H3N2: TC50=27.1 μM, IC50=0.97 μM, SI=28.07; H1N1: TC50=27.01 μM, IC50=0.42 μM, SI=65.0); 化合物一枝蒿酮酸-10-吗啡啉基-癸酯 (8g) 表现出一定的抗H1N1流感病毒活性 (TC50=15.1 μM, IC50=0.38 μM, SI=39.61); 化合物N-[3-(对氟苯基-异噁唑-5-基)-甲基]-一枝蒿酮酸酰胺 (11c) 表现出一定的抗H3N2流感病毒活性 (TC50=22.7 μM, IC50=1.0 μM, SI=20.83);化合物一枝蒿酮酸钾盐 (12b) 表现出一定的抗H3N2和H1N1流感病毒活性 (H3N2: TC50>3496.5 μM, IC50=213.1 μM, SI>16.41; H1N1: IC50=56.0 μM, SI>62.42); 化合物二氢一枝蒿酮酸对氯苯酰胺 (14) 表现出比母体化合物强的抗B型流感病毒 (TC50=71.4 μM, IC50=5.5 μM, SI=13.00); 化合物O-烯丙基四氢一枝蒿酮酸甲酯酮肟 (24e) 和戊酸酯 (27d) 具有一定的抗H1N1流感病毒 (24e: TC50=115.4 μM, IC50=4.27 μM, SI=27.04; 27d: TC50=1969.8 μM, IC50=83.15 μM, SI=23.69)。从中筛选出化合物2d, 2g, 7d和7g正在进行体内试验。 |
| 英文摘要 | Influenza, commonly referred to as the flu, is an highly contagious disease caused by RNA viruses of the family Orthomyxoviridae that affects birds and mammals. The influenza spreads around the world in seasonal epidemics, resulting in the deaths of between 250,000 and 500,000 people annually, up to millions in some pandemic years. Influenza vaccine and anti-influenza drugs are two main options to prevent and treat influenza, however, both of them show some disadvantages. Moreover, worldwide spread of influenza virus A (H1N1) in 2009 again emphasized the urgency for rapidly developing safe and effective antiviral drugs. Artemisia rupestris L. (Chinese name is Yizhihao) is a well-known traditional Chinese medicinal plant in Xinjiang used for antiallergic, antitumour, antiinflammatory and detoxification. Rupestonic acid is the main active ingredient of Artemisia rupestris L. In the previous work of our group, more than 70 rupestoric amide derivatives and rupestoric ester derivatives have been synthesized and in vitro assayed against influenza A, B viruses and HSV-1, HSV-2. Four compounds were chosen as the potent active compounds against influenza A. On the basis of the above study and in continuation of our search for antiviral active compounds, in this thesis, 59 rupestonic acid carboxyl derivatives and 30 rupestonic acid analogues were designed and synthesized. Their structures have been confirmed by 1H NMR, 13C NMR, IR, ESI-MS (HRMS). In addition, they were in vitro evalued for their potency against influenza A (H3N2 and H1N1) and B. The preliminary test results showed that compoundsrupestoric-(2,3,4-tri-O-acetyl)-β-D-xylosyl ester(2d) and rupestoric acid-(2,3,6,2¢,3¢,4¢,6¢-hepta-O-acetyl)-lactosyl ester(2g) exhibited excellent activity against influenza H3N2 (2d: TC50=592.9 μM, IC50=0.35 μM, SI=1666.7; 2g: TC50=166.5 μM, IC50=0.21 μM, SI=801.1); compound rupestoric-2-chloroethyl ester (3) possessed potential activity against A and B (H3N2: TC50=1669 μM, IC50=17.2 μM, SI=96.9; H1N1: IC50=27.8 μM, SI=60.0; B: TC50>3225 μM, IC50=358.4 μM, SI>9.0); compounds rupestoric-10-(4-phenyl-piperazinyl)-decyl ester(5g) andrupestoric-4-(4-methyl -piperazinyl)-butyl ester(6c) showed good inhibitive activity against influenza H1N1 (5g: TC50=456.2 μM, IC50=2.42 μM, SI=187.97; 6c: TC50=643.5 μM; IC50=10.25 μM, SI=62.79); compounds rupestoric acid-10-(4-methyl-piperazinyl)-decyl ester(6g) possessed higher activity against influenza H3N2 and H1N1 (H3N2: TC50=177.4 μM, IC50=5.23 μM, SI=33.95; H1N1: IC50=3.72 μM, SI=47.64); compoundrupestoric-5-(1H-1,2,4-triazol-1-yl)-pentyl ester (7d) exhibited promising activity against influenza A and B (H3N2: TC50=672.0 μM, IC50=17.3 μM, SI=38.90; H1N1: IC50=7.4 μM, SI=90.77; B: IC50=17.27 μM, SI=38.90); compoundrupestoric-8-(1H-1,2,4-triazol)-octyl ester (7f) showed higher activity against influenza A and B (H3N2: TC50=201.9 μM, IC50=5.20 μM, SI=38.84; H1N1: IC50=7.2 μM, SI=28.00; B: IC50=3.2 μM, SI=62.94); compoundrupestoric-10-(1H-1,2,4-triazol-1-yl)-decyl ester(7g) possessed higher activity against influenza H3N2 and H1N1 (H3N2: TC50=27.1 μM, IC50=0.97 μM, SI=28.07; H1N1: TC50=27.01 μM, IC50=0.42 μM, SI=65.0); compounds rupestoric-10-morpholinyl- decyl ester(8g) showed higher activity against influenza H1N1 (TC50=15.1 μM, IC50=0.38 μM, SI=39.61); N-[3-p-fluoro-phenyl-isoxazol-5-yl)-methyl] rupestonic acid amide(11c) possessed moderateactivity against influenza H3N2 (TC50=22.7 μM, IC50=1.0 μM, SI=20.83); compound rupestoric potassium (12b) exhibited better activity against influenza H3N2 and H1N1 (H3N2: TC50>3496.5 μM, IC50=213.1 μM, SI>16.41; H1N1: IC50=56.0 μM, SI>62.42); compound dihyro rupestoric p-chloro benzenyl amide (14)showed better activity against B influenza virus than parent compound (TC50=71.4 μM, IC50=5.5 μM, SI=13.00); compound O-allyl tetrahydro rupestoric methyl ester ketone oxime (24e)andamyl ester (27d) showed better activity against H1N1 influenza virus than parent compound (24e: TC50=115.4 μM, IC50=4.27 μM, SI=27.04; 27d: TC50=1969.8 μM, IC50=83.15 μM, SI=23.69). The in vivo activities against influenza virus of compounds 2d, 2g, 7d and 7g selected from above were carrying out. |
| 内容类型 | 学位论文 |
| 源URL | [http://ir.xjipc.cas.cn/handle/365002/4444]  |
| 专题 | 新疆理化技术研究所_资源化学研究室 |
| 作者单位 | 中国科学院新疆理化技术研究所 |
| 推荐引用方式 GB/T 7714 | 赵江瑜. 以一枝蒿酮酸为骨架的抗流感病毒候选化合物的合成及活性研究[D]. 北京. 中国科学院研究生院. 2011. |
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