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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
| dc.contributor.author | Yu-Cheng Liu | en |
| dc.contributor.author | 劉宥承 | zh_TW |
| dc.date.accessioned | 2021-06-16T08:47:57Z | - |
| dc.date.available | 2018-09-02 | |
| dc.date.copyright | 2013-09-02 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-08-20 | |
| dc.identifier.citation | 1. WHO
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/59067 | - |
| dc.description.abstract | 流行性感冒（influenza）為一種急性呼吸道疾病，由流感病毒所引起，發病快速，在歷史上爆發過的全球性疫情不勝枚舉，特別是近幾年來的H5N1 的禽流感以及H1N1的新型流感最為嚴重。瑞樂沙及克流感為治療流感最主要的兩種藥物，以病毒的神經胺酸酶作為抑制目標。神經胺酸酶在病毒的生命週期扮演很重要的角色，從演化的角度來看，不同亞型的神經胺酸酶可依照其相似程度分成兩大群：包含N1、N4、N5、N8 的group-1 以及包含N2、N3、N6、N7、N9 的 group-2，group-1 的神經胺酸酶在構型上多出了一個可結合空間，稱為150-cavity。因此我們以150-cavity 為目標，設計新型抗流感藥物。另一方面，當病人感染流感時，病毒所引發的嚴重發炎反應會產生許多嚴重併發症如肺炎，提高了病患的致死率。因此，我們設計出新型雙標靶（dual-target）藥物，結合抗流感藥物以及抗發炎藥物，希望在治療流感藥物上能有更好的成效。
之前本實驗室已經開發出瑞樂沙磷衍生物的合成方法，我們在此進一步合成中間體26，並針對不同目標來做化學結構上的修飾。我們已經成功合成出化成物34以及化合物39，期望此類新型雙標靶藥物能夠抑制發炎反應並同時具有抗病毒療效，目前生物活性測試正在進行中。 另一方面，以group-1的神經胺酸脢為抑制目標的化合物42和43目前還在和成階段，未來希望對於疫情嚴重的H5N1能夠有很有的抑制效果。 | zh_TW |
| dc.description.abstract | Influenza is a severe viral infection of respiratory system. The outbreaks of worldwide H5N1 avian influenza and the new type pandemic H1N1 human flu have heightened the
threat of public health. Zanamivir and oseltamivir are the main anti-influenza drugs targeting the neuraminidase (NA) of influenza virus. NA plays an important role in the life cycle of influenza viruses. There are two phylogenetically distinct groups of NAs of influenza A viruses: group-1 NAs include the N1, N4, N5, and N8 subtypes, and group-2 NAs include the N2, N3, N6, N7, and N9 subtypes. The group-1 NA contains a flexible loop and a cavity, so-called “150-cavity” near the binding pocket S2. Based on this rationale, we designed new inhibitors, which targeted 150-cavity of group-1 NA for better inhibitory activity. On the other hand, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. We explored the novel dual-target bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. Our research group has developed the zanamivir phosphonate congeners, which have better inhibitory activities. In this study I synthesized the pivotal intermediate compound 26, and further modified the C4-substituent for two specific aims. We successfully synthesized compounds 34 and 39 by conjugating the phosphono-zanamivir with anti-inflammatory agents as new dual-target drugs against influenza viruses. The bioactivity of compounds 34 and 39 is currently under investigation. We also designed the phosphono-zanamivir derivatives 42 and 43 having additional bindings to the 150-cavity of group-1 NAs. The synthetic work is in progress. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T08:47:57Z (GMT). No. of bitstreams: 1 ntu-102-R00223159-1.pdf: 15441807 bytes, checksum: b208faf514d3df54290a8f9d3577fc57 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 中文摘要 ......................................................................................................................... I
Abstract ......................................................................................................................... III 目錄 ............................................................................................................................... V 表目錄 ....................................................................................................................... VIII 圖目錄 .......................................................................................................................... IX 流程目錄 .................................................................................................................... XII 簡稱用語對照表 ....................................................................................................... XIII 第一章 緒論 .................................................................................................................. 1 第一節 流行性感冒病毒與人類 .......................................................................... 1 第二節 流感病毒簡介 .......................................................................................... 3 2－1 流感病毒種類及介紹 .......................................................................... 3 2－2 流感病毒的生命週期 .......................................................................... 5 2－3 流感病毒表面兩個重要的膜蛋白 ...................................................... 8 2－3－1 血球凝集素（Hemagglutinin，HA） .................................. 8 2－3－2 神經胺酸酶（Neuraminidase，NA） ................................ 10 2－4 離子通道蛋白（M2 ion-channel） ................................................. 12 第三節 流感藥物的開發 .................................................................................... 13 3－1 M2 離子通道抑制劑（M2 ion channel inhibitor） ........................ 13 VI 3－2 血球凝集素抑制劑（hemagglutinin inhibitor） ............................ 15 3－3 神經胺酸酶抑制劑（neuraminidase inhibitor） ............................ 16 3－3－1 Zanamivir 的開發 .............................................................. 18 3－3－2 Zanamivir 的修飾以及改進 .............................................. 20 3－3－3 Oseltamivir 的開發 ........................................................... 23 3－3－3 Peramivir 的開發 .............................................................. 26 3－3－4 流感病毒的抗藥性 ............................................................ 28 3－3－5 零流感（Tamiphosphor）的發展 ..................................... 32 第四節 發炎反應與藥物 .................................................................................... 34 4－1 抗發炎藥物的開發 .......................................................................... 35 4－2 Naproxen 和Ibuprofen ..................................................................... 38 第五節 多標靶治療（Multi-target therapy） .................................................... 39 第六節 抗流感以及抗發炎合併治療 ................................................................ 42 第二章 結果與討論 .................................................................................................... 44 第一節 研究背景與目的 .................................................................................... 44 第二節 Phosphono-zanamivir 衍生物的合成 .................................................... 47 第三節 設計雙標靶抗流感藥物 ........................................................................ 50 3－1 設計概念 .......................................................................................... 50 3－2 雙標靶藥物的合成 .......................................................................... 52 3－2－1 Ibuprofen 衍生物的合成 ................................................... 52 VII 3－2－2 Naproxen 衍生物的合成 ................................................... 56 3－3 離體培養活性測試 .......................................................................... 57 3－3－1 活性測試方法 .................................................................... 57 3－3－2 抗流感活性測試結果與討論 ............................................ 59 3－4 結論 .................................................................................................. 61 第四節 針對流感病毒上N1 開放式構型選擇性合成神經胺酸酶抑制劑 ..... 62 4－1 設計概念 .......................................................................................... 62 4－2 化合物44、45 的合成 .................................................................... 67 4－3 結論 .................................................................................................. 73 第五節 總結 ........................................................................................................ 74 第三章 實驗部分 ........................................................................................................ 77 第一節 General Part ............................................................................................ 77 第二節 Procedures of Bioassay ........................................................................... 79 第三節 Synthestic Procedures and Characterization of Compounds .................. 82 第四章 參考文獻 ...................................................................................................... 107 附錄 化合物之核磁共振光譜 ................................................................................ 129 | |
| dc.language.iso | zh-TW | |
| dc.subject | 瑞樂沙 | zh_TW |
| dc.subject | 流感病毒 | zh_TW |
| dc.subject | influenza virus | en |
| dc.subject | zanamivir | en |
| dc.title | 合成瑞樂沙磷衍生物來對抗流感病毒 | zh_TW |
| dc.title | Design and synthesis of phosphono-zanamivir derivatives against influenza virus | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 羅禮強,李文山,簡敦誠 | |
| dc.subject.keyword | 流感病毒,瑞樂沙, | zh_TW |
| dc.subject.keyword | influenza virus,zanamivir, | en |
| dc.relation.page | 179 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-08-20 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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