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一枝蒿酮酸-2-苄基衍生物的合成及其生物活性研究
王新诚
Thesis Advisor黄国正
2017-06-03
Degree Grantor中国科学院大学
Place of Conferral北京
Degree Name硕士
Degree Discipline药物化学
Keyword一枝蒿酮酸 衍生物 合成 流感病毒
Abstract

对于季节性的流感大流行,人们能够依靠的除了自身免疫系统外,就只有抗病毒药物。从1999年开始,临床用于治疗流感的药物主要为神经氨酸酶抑制剂扎那米韦和奥塞米韦。但是2007年到2009年间出现了对奥塞米韦有免疫性的病毒(H1N1),对全人类健康产生了巨大的威胁。这一现象要求科研人员深入研究病毒抑制机理,不断开发出新的抗流感药物。新疆一枝蒿(Artemisia rupestris L.)为菊科蒿属植物,在新疆有着悠久的用药历史,在多个医疗领域有着明确的用药价值,多种以新疆一枝蒿为主要原料的药物已经上市,其抗病毒活性已在临床显现。一枝蒿酮酸是一种倍半萜,在新疆一枝蒿中含量丰富,是一枝蒿的主要活性成分。本课题组已经对其进行了大量的结构改造,取得了较好的结果。在此基础上,本论文选取新的位点,合成了20个全新的化合物并进行了结构表征,测试其体外抗甲(H1N1,H3N2)、乙型流感病毒活性。根据这些数据,讨论了一枝蒿酮酸2位结构改造的构效关系,为进一步获取活性更高、毒性更小的抗病毒分子指明了方向。在取得的活性数据中,3b,3c,3d,3e,3f,3g,3h,3i,3j,3k,3l,3p,3q,3r表现出了抗甲型流感病毒(H1N1)的活性,尤其是化合物 3b(IC50 = 0.82 mg·mL-1), 3c(IC50 = 0.82 mg·mL-1), 3j(IC50 = 1.43 mg·mL-1)具有比阳性对照物(达菲和利巴韦林)更强的活性。对于H3N2,只有3e,3l,3t表现出了一定的活性。对抗乙型流感,3i,3j,3k,3p,3q,3r表现出了与对照阳性化合物利巴韦林相近的活性。尤其值得注意的是,含氟化合物的活性普遍优于其它化合物。

Other Abstract

Antiviral agents play an important role in the control of seasonal influenza epidemics which people could rely on besides immune deficiency system. There are two approved neuraminidase inhibitors (NAIs) compounds available in the market: Zanamivir and Oseltamivir since 1999. However, the emergence of oseltamivir-resistant seasonal A(H1N1) viruses in 2007 present a severe threat to human health, and emphasize the need of a better understanding of the mechanisms of antivirals, the development of novel antiviral drugs. This article shares a series of compounds with potential antiviral activities, the synthesis and In vitro data.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. Our group members have done a lot structure modification on this molecule. On the basis of these works, author chose a new site, and synthesized a series of compounds and their structures were characterized. The activity against influenza A and B viruses were tested in vitro. According to these data, SAR of modification on the second carbon atom of methyl rupestonate was discussed, which could be served as a guidance to the pursue of lead compounds.Compounds 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3l, 3p, 3q, 3r have outstanding activity against influenza A viruses(H1N1) especially 3b(IC50= 0.82mg·mL-1), 3c(IC50 = 0.82mg·mL-1) and 3j (IC50 = 1.43mg·mL-1) were better than control groups (Ribavirin and Oseltamivir)。Only three compounds 3e, 3l, 3t showed positive effect against H3N2 virus but as expected. 3i, 3j, 3k, 3p, 3q, 3r had similar activities with control groups against influenza B virus, in which F atoms showed correlation.

Document Type学位论文
Identifierhttp://ir.xjipc.cas.cn/handle/365002/4997
Collection资源化学研究室
Recommended Citation
GB/T 7714
王新诚. 一枝蒿酮酸-2-苄基衍生物的合成及其生物活性研究[D]. 北京. 中国科学院大学,2017.
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