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题名: 一枝蒿酮酸衍生物的合成及体外抑流感病毒和单纯疱疹病毒活性研究
作者: 雍建平
答辩日期: 2008-11-22
导师: 阿吉艾克拜尔·艾萨
专业: 有机化学
授予单位: 中国科学院研究生院
授予地点: 北京
学位: 博士
关键词: 一枝蒿酮酸 ; 一枝蒿酮酸衍生物 ; 合成 ; 体外抗流感病毒活性 ; 抗单纯疱疹病毒活性
摘要: 流感病毒是一种单股负链的RNA病毒,它引起的流行性感冒传染性强、发病率高,涉及面广,死亡率高。据统计,全球每年有1 亿人患病,25~50 万人死亡,我国每年流感发病率为10~20%;流感对人类的生存造成了莫大的威胁,尤其是2003 年以来禽流感在亚洲地区的持续爆发和向全世界的不断扩散引起了全世界对流感的关注,目前临床上用来预防和治疗流感的措施主要是药物治疗和疫苗。由于流感疫苗的研究速度相对较慢,疫苗只有和正在传播的流感病毒亚型相配对时才有效,此外流感疫苗对无免疫应答的老年人和幼儿的保护作用很小;另外,临床上用来预防和治疗流感病毒(禽流感) 的最有效药物奥斯它韦已经对流感病毒H5N1 产生了耐药性,因此迫切需要开发新结构的预防和治疗流感病毒的药物,尤其从天然产物中寻找新的抗病毒先导化合物,进而对其进行结构修饰,合成me—too药将成为必然。新疆一枝蒿在新疆民间沿用已久,具有抗炎﹑抗病毒﹑解蛇毒﹑保肝等活性,其中一枝蒿酮酸是从一枝蒿中分离得到的含多官能团的一种结构独特的倍半萜。由于倍半萜具有广泛的药理活性,因此我们对此单体化合物做了初步的体外抗A, B 型流感病毒和单纯I﹑II 型疱疹病毒活性研究,结果表明此单体化合物对B 型流感病毒具有较强的抑制活性 (TC50=1044.4 μmol/L, IC50=115.7 μmol/L, SI=9.0)。为了提高一枝蒿酮酸的抗病毒活性,根据受体 (流感病毒神经氨酸酶)理论,我们对此单体化合物进行了结构修饰,共设计合成了未见文献报道的含芳香环(1a~1u)﹑手性氨基酸酯(2a~2g)﹑手性氨基醇(3a~3f)﹑氨基酸(4a~4f)片断的一枝蒿酮酸的酰胺类衍生物和一枝蒿酮酸酯类(5a~5z-n, n=0~6)衍生物,共70 多个。所合成的化合物均经IR, 1H NMR, ESI-MS 等分析方法进行了表征,并对所合成的化合物进行了初步的体外抗流感病毒和单纯I,II型疱疹病毒活性研究。结果表明: 化合物1f 同时具有较强的抗I 型疱疹病毒活性 (TC50=200 μmol/L, IC50=17.7 μmol/L, SI=11.3) 和II型疱疹病毒活性 (TC50=200 μmol/L, IC50=20.7 μmol/L, SI=9.7); 化合物5i, 5j, 5k, 5l, 5q, 5r, 5v, 5w 具有较强的抗流感病毒活性,其中化合物5i, 5l, 5q, 5r, 5w 同时对A, B 型流感病毒均有较强的抑制活性,5l 相对具有较强的抑制活性和安全性,其抗A, B型流感病毒的活性数据分别为:TC50=189.5 μmol/L, IC50=29.4 μmol/L, SI=6.4;TC50=189.5 μmol/L, IC50=24.9 μmol/L, SI=7.6。化合物5j, 5k, 5v, 5x, 5z-6 对A 型流感病毒均有较强的抑制活性,而且化合物5j (TC50=18.9 μmol/L, IC50=0.5 μmol/L, SI=32.7)显示出比阳性药奥司米(Oseltamivir)(TC50>1219.5 μmol/L, IC50=5.1 μmol/L, SI>242.7)有更强的抑制A 型流感病毒活性,但是毒性相对较高;化合物5x, 5z-6 对A 型流感病毒相对具有较强的抑制活性,其抑制A 型流感病毒的活性数据分别为:TC50=240.5 μmol/L, IC50=19.1 μmol/L, SI=12.6; TC50=119.3 μmol/L, IC50=13.4 μmol/L, SI=14.3。从以上化合物中优选出了活性高、安全性高的化合物5j(一枝蒿酮酸对叔丁基苯酚酯), 5l(一枝蒿酮酸对乙酰氨基苯酚酯), 5x(一枝蒿酮酸对氯苯酚酯), 5z-6(一枝蒿酮酸对甲基苯酚酯) 正在进行体内试验,对其药代、毒理、安全性等进行初步筛选。本文的研究结果:发现了具有抗A, B 型流感病毒和单纯I, II 型疱疹病毒活性的新化合物,是对抗病毒药物研究的有益探索。为抗病毒药物的筛选提供了新的候选化合物,为一枝蒿酮酸构效关系的研究提供了丰富的数据,对后续工作的深入开展奠定了良好基础。
英文摘要:
Influenza virus is one kind of RNA viruses. Nowadays, the high incidence of flu, and the morbidity and mortality of epidemic influenza is substantial. It is reported that 100,000,000 people in the world was infected influenza virus and 250,000-500,000 people died from the flu per year. The incidence of flu in our state arrived between ten percent to twenty percent and the flu has caused the serieous threaten to the human’s survival. Especially, in recent years, the persistence of H5N1 avian influenza virus in many Asian countries, its diffusion globally and its ability to cause fatal infections in humans have raised serious concerns about a global flu pandemic. Today, the strategies taken for protection against and treatment of influenza are inoculating the flu vaccinia earlier or using anti-flu drugs later. But the vaccinia developed slowly than the subflu-virus variated, and the vaccinia can only take effect while it is matching the subflu-virus being spreaded. In addition, the vaccinia can’t well protect for the young and the old persons. Oseltamivir has been orally used for protection against and treatment of influenza, and regarded as the effective drug in clinical. But it is reported that it has been resistant to the H5N1 avain influenza virus. Thus it is an urgent demand to find new inhibitors, especially promote to find new and more active inhibitors from the natural products, then modifying its structure and synthesizing me-too drugs. Artemisia rupestris L. (chinese name is Yizhihao) is one kind of Chinese traditional herbal medicines, long been used in folk of Xinjiang of China. It is known to be effective as antiallergic, antitumour, antiinflammatory, and detoxification reagents. Rupestonic acid is a sesquiterpene with mutifunctional groups, isolated from Artemisia rupestris L. Sesquiterpene always exhibit considerable biological activities. Thus we assayed the rupestonic acid against herpes simplex tpye I virus(HSV-I, VR733), herpes simplex tpye II virus(HSV-II, SAV) and influenza A3/Jifang/90/15, B/Jifang/97/13 viruses. The results showed that it exhibited higher activity against influenza B virus(TC50=1044.4 μmol/L, IC50=115.7 μmol/L, SI=9.0). In order to improve ruptstonic acid’s biological activities, according to the connection between the drug and the recipient(neurominidase). In this paper, we modified rupestonic acid and synthesized over 70 rupestonic acid derivatives, containing aromatic ring (1a~1u), chiral amino acid ester (2a~2g), chiral amino ethanol (3a~3f), amino acid (4a~4f) rupestonic acid amide derivatives and rupestonic acid ester derivatives (5a~5z-n, n=0~6). All derivatives have been confirmed by the methods of IR, 1HNMR, ESI-MS spectra datas. All derivatives were preliminarily assayed in vitro against HSV-1, HSV-2 and influenza A, B viurses. The results showed that compound 1f possessed higher inhibitive activities both to HSV-I (TC50=200 μmol/L, IC50=17.7 μmol/L, SI=11.3) and HSV-II (TC50=200 μmol/L, IC50=20.7 μmol/L, SI=9.7); Compounds 5i, 5j, 5k, 5l, 5q, 5r, 5v, 5w showed higher inhibitive flu-virus activity, the compound 5i, 5l, 5q, 5r, 5w showed dural inhibitive activities both to influenza A and B virus, 5l is comparatively more active and safer among the active compounds(5i, 5l, 5q, 5r, 5w), and the inhibition against influeza A and B are TC50=189.5 μmol/L, IC50=29.4 μmol/L, SI=6.4; TC50=189.5 μmol/L, IC50=24.9 μmol/L, SI=7.6 respectively. Compounds 5j, 5k, 5v, 5x, 5z-6 showed higher inhibitive activity to influenza A viurs, and 5j is more active (TC50=18.9 μmol/L, IC50=0.5 μmol/L, SI=32.7) than the positive drug(Oseltamivir)(TC50>1219.5 μmol/L, IC50=5.1 μmol/L, SI>242.7), but unfortunately, the toxicity is also higher than the Oseltamivir’s. The in vivo activities against influenza virus of compounds 5j, 5l, 5x, 5z-6 selected from above are carrying out. In this study, we found the lead compounds of anti-influenza and anti-HSV. Thus providing the novel candidates for anti-viral drug screen. In addition, providing the abundent datas for studying the structure relationship of rupestonic acid, and building up the good foundation for the further study of rupestonic acid.
内容类型: 学位论文
URI标识: http://ir.xjipc.cas.cn/handle/365002/3555
Appears in Collections:资源化学研究室_学位论文

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作者单位: 中国科学院新疆理化技术研究所

Recommended Citation:
雍建平. 一枝蒿酮酸衍生物的合成及体外抑流感病毒和单纯疱疹病毒活性研究[D]. 北京. 中国科学院研究生院. 2008.
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