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以作者查詢圖書館館藏 、以作者查詢臺灣博碩士 、以作者查詢全國書目 、勘誤回報 、線上人數：57 、訪客IP：3.145.47.193
姓名 吳佩琪(Pei-chi Wu) 查詢紙本館藏 畢業系所 化學學系 論文名稱 腺苷與香豆素共軛連結化合物之合成與其構形之探討
(Conjugation of Adenosine with Coumarins:Synthesis and Study on their Conformation)相關論文 檔案 [Endnote RIS 格式]
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摘要(中) 根據世界衛生組織(WHO)統計，全球大約有1億7千萬人口感染C型肝炎病毒(Hepatitis C Virus, HCV)，台灣亦有92萬人口為C型肝炎病患。然而感染初期病徵是隱伏的，因此病患往往不自覺已罹患C型肝炎，錯失提早治療機會造成日益越發嚴重之肝臟病變。
我們希望合成出具有抗C型肝炎病毒效果的化合物，並進一步討論其合成與立體結構。在DMF中，使用pyridine當鹼的條件，於低溫下以adenosine衍生物與6-substituted coumarin carboxylic chlorides進行先加成後消去之偶合反應，可得到目標化合物以adenosine–coumarin連結在一起的共軛化合物。
藉由了解分子之結構構形，可利於抗C型肝炎病毒活性數據之解釋，我們利用核磁共振圖譜、紅外線光譜以及分子模擬計算的技術，發現共軛物醯胺鍵上NH的氫原子與coumarin結構中C=O的氧原子之間，其構形在最穩定能量態下，可觀察到分子內氫鍵的形成；不同取代基之共軛化合物，其purine環及coumarin此兩平面基團，其dihedral angle為0.37°–38.25°，有關此分子構形之觀察數據，可提供我們研究此類化合物於抑制C型肝炎病毒作用機制，提供參考依據。
摘要(英) According to the World Health Organization (WHO) statistics, about 170 million people infected with hepatitis C virus (HCV) worldwide, and in Taiwan is also a population of 920,000 patients with hepatitis C virus. However, the symptoms are latent early, so patients often do not know they have risk of hepatitis C, resulting in more serious liver disease.
Our aim is to synthesis the novel compounds which can inhibit the hepatitis C virus. We successfully synthesized the compounds in which adenosine bound together with coumarin moiety, and these compounds can be easily synthesized by using addition-elimination reaction. We used different techniques like 1H NMR, mass spectroscopy, IR spectroscopy and molecular modeling to study the structure and conformation of the compounds. By comparing all the we conclude that the conformation with the thermodynamically most stable form contain intramolecular hydrogen bondings between the NH proton in amide bond and the carbonyl group in coumarin. The angle between puriune and coumarin planes were 0.37°–38.25°. In the future, we will discuss the structure–activity relationship of anti-HCV, the results of these compounds shall help us to understand the mechanism for the inhibition of hepatitis C virus.
關鍵字(中) ★ 香豆素
★ 腺苷關鍵字(英) ★ Adenosine
★ Coumarins論文目次 中文摘要 ............................................................................................................. i
英文摘要 ............................................................................................................ ii
謝誌 ................................................................................................................... iii
目錄 ................................................................................................................... iv
圖目錄 .................................................................................................................x
表目錄 ...............................................................................................................xii
縮寫對照表........................................................................................................xiii
一、 緒 論 ........................................................................................................ 1
二、 結 果 ........................................................................................................ 7
2-1製備具有不同官能基之coumarin-3-carboxylic chlorides (12a–d)..... 7
2-2製備2',3',5'-Tri-O-(tert-butyldimethylsilyl)adenosine (13)與3',5'-di-
O-(tert-butyldimethylsilyl)adenosine (14)………................................. 8
2-3合成3',5'-di-O-(tert-butyldimethylsilyl)-N6-(6'-coumarin-3'-carbonyl)
adenosine(15a–d) and 2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-
(6'-coumarin-3'-carbonyl)adenosine (15e–h) .......................................... 9
2-4合成2'-Deoxy-6-carbonyladenosine–coumarin conjugate (16a–b)
and 6-carbonyladenosine–coumarin conjugates (16c–d) .................... 12
2-5將產物15a–h 與17a–d進行分子模擬計算…….............................. 15
三、 討 論 ...................................................................................................... 18
3-1 分析6-Carbonyladenosine–coumarin conjugates and 2'-Deoxy-6-
carbonyladenosine–coumarin conjugate 化合物 (15a–h與17a–d).. 19
3-2 利用FT-IR研究產物15a–h之結構................................................. 20
3-3 利用利用UV-Vis測定產物16c與17c水溶性................................ 21
3-4 利用UV-Vis測定產物16c與17脂溶性........................................23
3-5 利用分子模擬計算討論產物16c能量與結構關係....................... 26
四、 結 論 ...................................................................................................... 28
五、 實 驗 部 分 .......................................................................................... 29
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-coumarin-3'-carbonyl) adenosine (15a)之合成............................................................................ 30
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-carbonyl) adenosine (15b)之合成............................................................................ 31
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-carbonyl) adenosine (15c)之合成............................................................................. 32
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-carbonyl) adenosine (15d)之合成............................................................................ 32
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(coumarin-3'-carbonyl) adenosine (15e)之合成............................................................................. 33
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-carbonyl) adenosine (15f)之合成.............................................................................34
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-carbonyl)adenosine (15g)之合成.......................................................................... 34
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-carbonyl)adenosine (15h)之合成.......................................................................... 35
N6-(6'-Bromocoumarin-3'-carbonyl)deoxyadenosine (17a)之合成..........37
N6-(6'-Cholocoumarin-3'-carbonyl)deoxyadenosine (17b)之合成...........38
N6-(6'-Bromocoumarin-3'-carbonyl)adenosine (17c)之合成................... 38
N6-(6'-Clorocoumarin-3'-carbonyl)adenosine (17d)之合成…….……... 39
六、 參 考 文 獻 .......................................................................................... 40
七、 光 譜 ...................................................................................................... 46
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-coumarin-3'-carbonyl) adenosine (15a) 1H NMR光譜................................................................ 47
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-coumarin-3'-carbonyl) adenosine (15a) 13C NMR光譜............................................................... 47
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-coumarin-3'-carbonyl) adenosine (15a) 紅外線光譜.................................................................. 48
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-carbonyl) adenosine (15b) 1H NMR光譜................................................................ 48
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-carbonyl) adenosine (15b) 13C NMR光譜............................................................... 49
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-
carbonyl)adenosine (15b) 紅外線光譜............................................. 49
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-
carbonyl)adenosine (15c) 1H NMR光譜............................................ 50
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-
carbonyl)adenosine (15c) 13C NMR光譜........................................... 50
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-
carbonyl)adenosine (15c) 紅外線光譜.............................................. 51
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-
carbonyl)adenosine (15d) 1H NMR光譜........................................... 51
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-
carbonyl)adenosine (15d) 13C NMR光譜.......................................... 52
3',5'-Di-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-
carbonyl)adenosine (15d) 紅外線光譜............................................. 52
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(coumarin-3'-
carbonyl)adenosine (15e) 1H NMR光譜............................................ 53
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(coumarin-3'-
carbonyl)adenosine (15e) 13C NMR光譜........................................... 53
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(coumarin-3'-
carbonyl)adenosine (15e) 紅外線光譜.............................................. 54
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-
carbonyl)adenosine (15f) 1H NMR光譜............................................ 54
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-
carbonyl)adenosine (15f) 13C NMR光譜........................................... 55
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-fluorocoumarin-3'-
carbonyl)adenosine (15f) 紅外線NMR光譜.................................... 55
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-
carbonyl)adenosine (15g) 1H NMR光譜............................................ 56
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-
carbonyl)adenosine (15g) 13C NMR光譜.......................................... 56
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-chlorocoumarin-3'-
carbonyl)adenosine (15g) 紅外線NMR光譜.................................... 57
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-
carbonyl)adenosine (15h) 1H NMR光譜........................................... 57
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-
carbonyl)adenosine (15h) 13C NMR光譜.......................................... 58
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N6-(6'-bromocoumarin-3'-
carbonyl)adenosine (15h) 紅外線NMR光譜................................... 58
N6-(6'-Bromocoumarin-3'-carbonyl)deoxyadenosine (17a)
1H NMR光譜. ....................................................................................59
N6-(6'-Bromocoumarin-3'-carbonyl)deoxyadenosine (17a)
13C NMR光譜…................................................................................ 59
N6-(6'-Bromocoumarin-3'-carbonyl)deoxyadenosine (17a)
紅外線光譜….....................................................................................60 N6-(6'-Cholocoumarin-3'-carbonyl)deoxyadenosine (17b)
1H NMR光譜…..................................................................................60
N6-(6'-Cholocoumarin-3'-carbonyl)deoxyadenosine (17b)
13C NMR光譜….................................................................................61
N6-(6'-Cholocoumarin-3'-carbonyl)deoxyadenosine (17b)
紅外線光譜…....................................................................................61
N6-(6'-Bromocoumarin-3'-carbonyl)adenosine (17c) 1H NMR光譜….....62
N6-(6'-Bromocoumarin-3'-carbonyl)adenosine (17c) 13C NMR光譜…...62
N6-(6'-Bromocoumarin-3'-carbonyl)adenosine (17c) 紅外線光譜….......63
N6-(6'-Cholocoumarin-3'-carbonyl)adenosine (17d) 1H NMR光譜….....63
N6-(6'-Cholocoumarin-3'-carbonyl)adenosine (17d) 13C NMR光譜…....64
N6-(6'-Cholocoumarin-3'-carbonyl)adenosine (17d) 紅外線光譜…........64
圖 目 錄
Figure 1. C型肝炎病毒基因組………………………..………………..............1
Figure 2. 化合物進入人體之代謝與抑制作用..................................................6
Figure 3. 起始物14與化合物15化學位移部分疊圖..................................... 11
Figure 4. Zhu教授團隊合成結果......................................................................11
Figure 5. 比較(a)四級胺鹽在THF溶液下與(b)產物16的NMR圖譜.......... 13
Figure 6. 產物6-Bromocarbonyladenosine–coumarin 17c NMR光譜...........13
Figure 7. Ciuffreda P. 教授團隊compound 1, 5的NMR光譜資料 .............. 14
Figure 8. 產物6-Bromocarbonyladenosine–coumarin 17c NMR光譜........... 15
Figure 9. 產物6-Bromocarbonyladenosine–coumarin 17c 分子模擬圖.........16
Figure 10. 產物6-Carbonyladenosine–Coumarin 17平面結構及立體結構....18
Figure 11. 比較起始物11d、14b與產物15h、17c的NMR圖譜...................20
Figure 12. 產物2',3',5'-tri-O-(tert-Butyldimethylsilyl)-N6-(6'-bromocoumarin-
3'-carbonyl) adenosine 15h FT–IR光譜.........................................20
Figure 13. 產物2',3',5'-tri-O-(tert-Butyldimethylsilyl)-N6-(6'-bromocoumarin-
3'-carbonyl) adenosine 15h結構.....................................................21
Figure 14. 利用UV-Vis測定具鹽類化合物產物16c與產物17c的水溶性.. 22
Figure 15. 產物16c與產物17c的水溶性log值疊圖......................................23
Figure 16. 產物16c脂溶性檢量線圖...............................................................24
Figure 17. 產物17c的脂溶性檢量線圖...........................................................25
Figure 18. 產物16c與產物17c的脂溶性檢量線圖疊圖................................25
Figure 19. (a)構形a時的分子結構(b)構形c時的分子結構........................... 27
Figure 20. 1H NMR與最穩定狀態分子模擬圖對照圖....................................27
表 目 錄
Table 1. 尋找化合物15最佳反應條件...............................................................7
Table 2. 所有化合物的分子計算數據…………………................................. 15
Table 3. 分子計算時產物17c產生的構形能量.............................................. 21
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指導教授 胡紀如(Jih Ru Hwu) 審核日期 2011-8-30 推文 plurk
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