合成具有抗病毒潛力的香豆素與腺嘌呤、腺苷、
肌苷之胺鍵標靶共軛化合物

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姓名

陳弘政(Hung-Cheng Chen) 查詢紙本館藏

畢業系所

化學學系

論文名稱

合成具有抗病毒潛力的香豆素與腺嘌呤、腺苷、肌苷之胺鍵標靶共軛化合物
(Synthesis of Coumarin Conjugated Adenine, Adenosine, and Inosine with Amine Linkers as Potential Antiviral Hits )

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摘要(中)

全球大約有一億七千萬人口受到C型肝炎病毒(Hepatitis C Virus, HCV)的感染，目前對於C型肝炎的治療並無疫苗和標靶藥物，所以新藥物的開發是當務之急。我們利用修飾腺嘌呤、腺苷、肌苷的結構，期望可以找出有效的抗C型肝炎病毒的化合物。
我們成功地合成將腺嘌呤、腺苷、肌苷與香豆素以胺鍵共軛在一起的化合物，其合成方法為利用腺嘌呤、腺苷與香豆素於二甲基甲醯胺溶劑下加熱至80 °C反應36小時，而肌苷與香豆素於二甲基甲醯胺溶劑下並加入氫化鈉於常溫下反應30分鍾，並且藉由核磁共振光譜圖、高解析質譜儀分析討論獲得的目標產物。將以–NHCH2–鍵結同一系列的化合物8、10、12的1H NMR光譜放在一起，並觀察其–NHCH2–鍵結的化學位移，我們可以發現其化學位移分別出現在5.492 ppm、5.407 ppm、5.429 ppm，此時我們可以更確定合成的化合物8、10、12是以–NHCH2–鍵結的同一系列化合物。
利用分子模擬我們發現胺鍵結上N–H的氫原子與香豆素環上C=O的氧原子之間，其構形在最穩定能量態下沒有觀察到分子內氫鍵形成，且可觀察到腺苷的嘌呤環與香豆素此兩平面分子會藉由以–NHCH2–鍵結旋轉，並且以96.51°的角度扭轉成非共平面結構。此結果可直接與活性數據討論，並有利於我們了解合成的化合物對於抑制C型肝炎病毒結構與活性的關係。

摘要(英)

Approximately one hundred and seventy million people worldwide were affected by hepatitis C virus infection. The search for effective vaccine is not yet available and therapeutic options are still limited, so the development of the drug is a priority. In this project we aim to synthesize some potential anti-hepatitis C virus agents which can be obtained by modifying the structure of adenine, adenosine, and inosine.
We have successfully obtained coumarin conjugated adenine, adenosine, and inosine hybrids with amine linker. To a solution containing of adenine or adenosine in N,N-dimethylformamide was added coumarin. The reaction mixture was heated to 80 °C and stirred for 36 hours. Treatment of inosin in N,N-dimethylformamide was added coumarin in the presence of sodium hydride. Then the reaction mixture was stirred at room temperature for 30 minutes to furnish the desired product. The compounds were further confirmed by using the spectral data of nuclear magnetic resonance and mass spectrometry. We have synthesized a series of compound 8, 10, and 12 which has –NHCH2– bonding. We analyzed compound 8, 10, and 12 by using of 1H NMR spectroscopy to confirm –NHCH2– bonding. We observed chemical shift at 5.492 ppm, 5.407 ppm, and 5.429 ppm for the compound 8, 10, and 12 respectively. So we conclude that compound 8, 10, and 12 are the same series agents.
The molecular modeling studies indicate that the conformation having thermodynamically most stable form did not contain intramolecular hydrogen bonding between the NH proton in purine and the carbonyl group in coumarin. The molecule could be free rotation by –NHCH2– linker. The angle between purine and coumarin plane is 96.51°. The results of this study may help us to understand the structure–activity relationship of the compounds for the inhibition of hepatitis C virus.

關鍵字(中)

★ 肌苷
★ 腺苷
★ 腺嘌呤
★ 香豆素
★ 抗病毒

關鍵字(英)

★ Adenine
★ Adenosine
★ Inosine
★ Coumarin
★ Antiviral

論文目次

目錄
中文摘要 ............................................................................................................. i
英文摘要 ........................................................................................................... iii
謝誌 .................................................................................................................... v
目錄 ................................................................................................................... vi
圖目錄 ................................................................................................................ x
表目錄 .............................................................................................................. xii
一、緒論 ........................................................................................................ 1
二、結果 ........................................................................................................ 8
2-1製備已知2-benzyloxy-5-bromobenzaldehyde (3) ……...................... 8
2-2製備已知methyl 3-(2-benzyloxy-5-bromophenyl)-3-hydroxy-2-
methylenepropanoate (5) ................................................................... 8
2-3製備已知6-bromo-3-(chloromethyl)-coumarin (6) …....................... 9
2-4合成conjugated adenine –coumarin化合物 (8) ………………...... 10
2-5合成conjugated adenosine–coumarin化合物 (10) …...................... 10
2-6合成conjugated 2'-deoxyadenosine –coumarin化合物 (12) ........... 11
2-7合成conjugated inosine –coumarin化合物 (14) ............................. 12
2-8合成conjugated 2'-deoxyinosine–coumarin化合物 (16) ................ 13
2-9合成conjugated hypoxanthine–coumarin化合物 (17) ……............ 13
2-10利用分子模擬預測化合物8、10、12及14之構形........................ 14
三、討論 ...................................................................................................... 19
3-1　利用1H NMR光譜分析conjugated adenosine–coumarin
化合物 10 ..................................................................................... 19
3-2　利用1H NMR光譜分析化合物8、10及12 ................................... 20
3-3　利用1H NMR光譜分析conjugated inosine–coumari
化合物 14 ..................................................................................... 22
3-4　探討肌苷在鹼性條件下N-alkylation的反應性 ……………..... 25
3-5　藉由1H NMR光譜研究化合物8、10及12是否有分子內
氫鍵 ................................................................................................ 26
3-6　藉由FT-IR研究化合物8、10及12是否有分子內氫鍵 .......... 28
3-7　利用分子模擬討論化合物8、10及12是否具有分子內氫鍵 .... 30
四、結論 ...................................................................................................... 32
五、實驗部分 .......................................................................................... 34
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenine (8) ................................... 35
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenosine (10) .............................. 36
N6-[(6'-Bromocoumarin-3'-yl)methyl]-2'-deoxyadenosine (12) ............... 36
N1-[(6'-Bromocoumarin-3'-yl)methyl]inosine (14) .................................. 37
N1-[(6'-Bromocoumarin-3'-yl)methyl]-2’-deoxyinosine (16) ................. 38
N1-[(6'-Bromocoumarin-3'-yl)methyl]hypoxanthine (17) ....................... 38
六、參考文獻 .......................................................................................... 40
七、光譜 ...................................................................................................... 47
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenine (8) 1H 核磁共振
光譜圖 ............................................................................................ 48
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenine (8) 13C 核磁共振
光譜圖 ............................................................................................ 48
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenine (8) 紅外線光譜圖 ....... 49
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenosine (10) 1H 核磁共振
光譜圖 ……………………………….…………………………... 49
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenosine (10) 13C 核磁共振
光譜圖 …………………………….……………………………... 50
N6-[(6'-Bromocoumarin-3'-yl)methyl]adenosine (10) 紅外線光譜圖 .. 50
N6-[(6'-Bromocoumarin-3'-yl)methyl]-2'-deoxyadenosine (12) 1H 核磁
共振光譜圖 .................................................................................... 51
N6-[(6'-Bromocoumarin-3'-yl)methyl]-2'-deoxyadenosine (12) 13C 核磁
共振光譜圖 .................................................................................... 51
N6-[(6'-Bromocoumarin-3'-yl)methyl]-2'-deoxyadenosine (12) 紅外線
光譜圖 ............................................................................................ 52
N1-[(6'-Bromocoumarin-3'-yl)methyl]inosine (14) 1H 核磁共振
光譜圖 ............................................................................................ 52
N1-[(6'-Bromocoumarin-3'-yl)methyl]inosine (14) 13C 核磁共振
光譜圖 .................................................................................................. 53
N1-[(6'-Bromocoumarin-3'-yl)methyl]inosine (14) 紅外線光譜圖 .... 53
N1-[(6'-Bromocoumarin-3'-yl)methyl]-2’-deoxyinosine (16) 1H 核磁共振光譜圖 …………………………………………………………….. 54
N1-[(6'-Bromocoumarin-3'-yl)methyl]-2’-deoxyinosine (16) 13C 核磁共振光譜圖 …………………………………………………………….. 54
N1-[(6'-Bromocoumarin-3'-yl)methyl]-2’-deoxyinosine (16) 紅外線
光譜圖 ……………………………………………………………….. 55
N1-[(6'-Bromocoumarin-3'-yl)methyl]hypoxanthine (17) 1H 核磁共振
光譜圖 .................................................................................................. 55
N1-[(6'-Bromocoumarin-3'-yl)methyl]hypoxanthine (17) 13C 核磁共振
光譜圖 .................................................................................................. 56
N1-[(6'-Bromocoumarin-3'-yl)methyl]hypoxanthine (17) 紅外線
光譜圖 .................................................................................................. 56

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指導教授

胡紀如(Jih Ru Hwu)

審核日期

2011-8-30

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