博碩士論文 100223039 詳細資訊




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姓名 劉信宏(Shin-Hong Liu)  查詢紙本館藏   畢業系所 化學學系
論文名稱 合成「核苷」與「金剛胺」連結之脲鍵化合物作為抗病毒藥劑
(Synthesis of Nucleoside–Amantadine Carbamides as Antiviral Agents)
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★ 設計及合成含藥物之新穎鉑錯合物
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摘要(中) 病毒所造成的危害是人類面臨的重大問題,其中又以RNA病毒具有較高的變異性,至今仍缺乏合適的藥物和疫苗。「歐盟第七架構計畫」中更將「黃病毒科」、「微小核醣核酸病毒科」和「副黏液病毒科」列為優先針對目標,並對其對應藥物進行合成和優化。本實驗室參與了這項定名為SILVER之計畫,致力於新藥的開發。
由於「金剛胺」是最早用於抑制流感病毒的抗病毒藥,該藥對成年患者的療效及安全性已得到廣泛認同,且本實驗室以「核苷」鍵結「香豆素」,發現其對於「C型肝炎病毒」具有良好的抑制活性,所以我們採用類似的架構設計新分子,將「金剛胺」與各種核苷衍生物以脲鍵結合為目標。其合成方法先將「金剛胺」藉由「三光氣」從胺基反應成「異氰酸酯」,再與矽保護的核苷衍生物進行加成反應,並利用核磁共振光譜儀和高解析質譜儀鑑定結構,證實我們成功地合成目標分子。
此外我們將「腺苷」與「阿糖胞苷」對於「金剛烷異氰酸酯」反應時的反應性不同,以及使用FT–IR圖譜判定目標產物的反應位置進行探討。最後我們也對目標產物進行水溶、脂溶與活性的測定,探討是否具有開發成抗病毒藥物的潛力。
摘要(英) Many human diseases and deaths are caused by viruses. RNA viruses generally have very high mutation rates, there are lack of suitable drugs and vaccines to control them. To solve these problems, Seventh Framework Programme in European Union has proved a project that focus on drugs discovery towards dengue-, entero- and paramyxoviruses. Our laboratory participating in this program, referred to as SILVER. Our laboratory is devoting its efforts developing relates drug.
Since amantadine is the first antiviral drug for inhibits the influenza virus. Its efficacy and safety for adult patients has been extensively recognized. A series of nucleoside–coumarin conjugates with potent activity toward HCV were synthesized at our laboratory. The developed molecules herein were designed with a similar architecture. The goal of study was to use amantadine and a variety of nucleoside derivatives with carbamide. The synthesis involved reacting amantadine with triphosgene, allowing the functional group transfer from amine to isocyanate, then reacting with nucleoside analogous by addition reaction. The target structures were examined by nuclear magnetic resonance and high-resolution mass spectrometry.
The reactivities of reactants adenosine and cytarabine with 1-adamantyl isocyanate were discussed. FT–IR spectra were used to determine the reaction position of the target product. Finally, the solubility in water, the solubility in lipid, and the activity are determined.
關鍵字(中) ★ 抗病毒藥劑
★ 核苷
★ 金剛胺
關鍵字(英) ★ antiviral agents
★ nucleoside
★ amantadine
論文目次 中文摘要 ............................................................................................................. i
英文摘要 ............................................................................................................ ii
謝誌 ................................................................................................................... iii
目錄 ................................................................................................................... iv
圖目錄 .............................................................................................................. xv
表目錄 ............................................................................................................. xvi縮寫對照表...................................................................................................... xvii
一、 緒 論(Introduction).............................................................................. 1
二、 結 果(Results)....................................................................................... 8
2-1 製備1-Adamantyl Isocyanate (2)化合物 …….....………..……… 8
2-2 合成含矽保護基Adenosine–Amantadine與
Vidarabine–Amantadine共軛化合物 (9–11) ...…………..……... 8
2-3 合成含矽保護基Guanosine–Amantadine與
Acyclovir–Amantadine共軛化合物 (18–20) ...……....….....….. 13
2-4 合成含矽保護基Cytidine–Amantadine與
Cytarabine–Amantadine共軛化合物 (27–29) ............................ 14
2-5 合成含矽保護基Ribavirin–Amantadine共軛化合物 (32) ….… 16
2-6 合成Nucleoside–Amantadine脲鍵化合物 (33–42) ………….... 16
三、 討 論 (Discussion) ............................................................................... 18
3-1 探討「腺苷」與「阿糖胞苷」在鹼性條件下的反應性差異 ... 18
3-2 探討合成共軛化合物之最佳試劑 .............................................. 19
3-3 探討目標產物抑制「腸病毒71型」的活性表現 .................... 20
3-4 探討合成目標化合物時去保護的合成步驟 .............................. 23
3-5 探討Cytarabine–Amantadine Conjugate的反應位置
..與結構確定 ..……………………………………………………. 24
3-6 利用1H NMR光譜鑑定共軛化合物的位向 ............................... 26
3-7 利用UV-VIS測定脲鍵化合物33、34與41之水溶性 ................ 26
3-8 利用UV-VIS測定脲鍵化合物33、34與41之脂溶性 ................ 28
四、 結 論(Conclusion)….......................................................................... 31
五、 實 驗 部 分(Experimental Section)…............................................. 32
1-Adamantyl isocyanate (2) ...……..……………………………..……. 33
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
deoxyadenosine (9) ...………….………………………….……...... 34
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
adenosine (10) ...………………………………...………………… 35
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-9-β-D-
arabinofuranosyladenine (11) ...………………………….………... 36
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-adamantylcarbamoyl-1-
(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (32) ....….… 37
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
deoxyguanosine (18) ...…………………..…………….………….. 38
N2-Adamantylcarbamoyl-9-[2’-(tert-butyldimethylsilyloxy)-
ethoxymethyl]guanine (20) ...……………….......………....……… 39
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
guanosine (19) ...…………………..……………….……………… 40
3’,5’-Di-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
deoxycytidine (27) ...…………………..………………………….. 41
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
cytidine (28) ...…………………..……………….……...………… 42
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-1-β-D-
arabinofuranosylcytosine (29) ...……………………..……………. 43
N6-Adamantylcarbamoyldeoxyadenosine (33) ...…..….......................... 44
N6-Adamantylcarbamoyladenosine (34) ..…….....…………...………... 45
N6-Adamantylcarbamoyl-9-β-D-arabinofuranosyladenine (35) ..…........ 46
N2-Adamantylcarbamoyldeoxyguanosine (36) ...…..…..…..……….…. 46
N2-Adamantylcarbamoylguanosine (37) ..…..…...…………...………... 47
N2-Adamantylcarbamoyl-9-[(2-hydroxyethoxy)methyl]guanine (38) .... 48
N4-Adamantylcarbamoyldeoxycytidine (39) .......…............................... 49
N4-Adamantylcarbamoylcytidine (40) ...…..…....................................... 50
N4-Adamantylcarbamoyl-1-β-D-arabinofuranosylcytosine (41) ............. 51
N3-Adamantylcarbamoyl-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (42) ....…………………………………….....……… 51
六、 參 考 文 獻(References)……............................................................ 53
七、 光 譜 ...................................................................................................... 60
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
deoxyadenosine (9) 1H NMR spectrum ...………………..……..…. 62
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
deoxyadenosine (9) 13C NMR spectrum ...……..…….....…………. 62
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
deoxyadenosine (9) IR spectrum ...………………...….………..…. 63
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
deoxyadenosine (9) HPLC chromatogram ….…………...……..…. 63
3’,5’-Di-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
deoxyadenosine (9) UV spectrum ….……………...….………..…. 64
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
adenosine (10) 1H NMR spectrum ...………….…………......……. 64
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
adenosine (10) 13C NMR spectrum ...………………..……………. 65
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
adenosine (10) IR spectrum ...………...……….……………….…. 65
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
adenosine (10) HPLC chromatogram ...………...…….……..……. 66
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-
adenosine (10) UV spectrum ...………...……..……………..……. 66
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-9-β-D-
arabinofuranosyladenine (11) 1H NMR spectrum ...………..…..…. 67
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-9-β-D-
arabinofuranosyladenine (11) 13C NMR spectrum ...………...……. 67
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-9-β-D-
arabinofuranosyladenine (11) IR spectrum ...………….….………. 68
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-9-β-D-
arabinofuranosyladenine (11) HPLC chromatogram ...…...………. 68
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N6-adamantylcarbamoyl-9-β-D-
arabinofuranosyladenine (11) UV spectrum ...………....….………. 69
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyldeoxy-
guanosine (18) 1H NMR spectrum ....…….………..…...…………. 69
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyldeoxy-
guanosine (18) 13C NMR spectrum ...…………….….....…………. 70
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyldeoxy-
guanosine (18) IR spectrum ...………….………….……...………. 70
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyldeoxy-
guanosine (18) HPLC chromatogram ...…..….…….……...………. 71
3’,5’-Di-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyldeoxy-
guanosine (18) UV spectrum ...…..……..………….……...………. 71
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
guanosine (19) 1H NMR spectrum ...………….…..………………. 72
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
guanosine (19) 13C NMR spectrum ...……………...…...…………. 72
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
guanosine (19) IR spectrum ...………….……..……..……………. 73
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
guanosine (19) HPLC chromatogram ...……...……....……………. 73
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N2-adamantylcarbamoyl-
guanosine (19) UV spectrum ...……...………...……..……………. 74
N2-Adamantylcarbamoyl-9-[2’-(tert-butyldimethylsilyloxy)ethoxy-
methyl]guanine (20) 1H NMR spectrum ...……...................…...…. 74
N2-Adamantylcarbamoyl-9-[2’-(tert-butyldimethylsilyloxy)ethoxy-
methyl]guanine (20) 13C NMR spectrum ...….……………………. 75
N2-Adamantylcarbamoyl-9-[2’-(tert-butyldimethylsilyloxy)ethoxy-
methyl]guanine (20) IR spectrum ...…………...….………………. 75
N2-Adamantylcarbamoyl-9-[2’-(tert-butyldimethylsilyloxy)ethoxy-
methyl]guanine (20) HPLC chromatogram ...…….....….…………. 76
N2-Adamantylcarbamoyl-9-[2’-(tert-butyldimethylsilyloxy)ethoxy-
methyl]guanine (20) UV spectrum ...…….....……..………………. 76
3’,5’-Di-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyldeoxy-
cytidine (27) 1H NMR spectrum ....…….………..…...…...………. 77
3’,5’-Di-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyldeoxy-
cytidine (27) 13C NMR spectrum ...…………….….....….…..……. 77
3’,5’-Di-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyldeoxy-
cytidine (27) IR spectrum ...………….………….……...…………. 78
3’,5’-Di-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyldeoxy-
cytidine (27) HPLC chromatogram ...………...………...…………. 78
3’,5’-Di-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyldeoxy-
cytidine (27) UV spectrum ...…………...……….……...…………. 79
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
cytidine (28) 1H NMR spectrum ...………….…..…………...……. 79
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
cytidine (28) 13C NMR spectrum ...……………...…...…...………. 80
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
cytidine (28) IR spectrum ...………….……..……..………………. 80
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
cytidine (28) HPLC chromatogram ...…..….……...………………. 81
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-
cytidine (28) UV spectrum …...…..….……..……..………………. 81
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-1-β-D-
arabinofuranosylcytosine (29) 1H NMR spectrum ...…….……..…. 82
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-1-β-D-
arabinofuranosylcytosine (29) 13C NMR spectrum ...……..………. 82
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-1-β-D-
arabinofuranosylcytosine (29) IR spectrum ...……………….……. 83
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-1-β-D-
arabinofuranosylcytosine (29) HPLC chromatogram ...……......…. 83
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N4-adamantylcarbamoyl-1-β-D-
arabinofuranosylcytosine (29) UV spectrum ...………………...…. 84
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-adamantyl-carbamoyl-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (32)
1H NMR spectrum ...………………………….…....…….……..…. 84
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-adamantyl-carbamoyl-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (32)
13C NMR spectrum ...…………………….………..………………. 85
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-adamantyl-carbamoyl-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (32)
IR spectrum ...…………...………….……………………..………. 85
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-adamantyl-carbamoyl-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (32)
HPLC chromatogram ...…...….…….……………………..………. 86
2’,3’,5’-Tri-O-(tert-butyldimethylsilyl)-N3-adamantyl-carbamoyl-1-(β-D-
ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide (32)
UV spectrum ...…………….…….….……………………..………. 86
N6-Adamantylcarbamoyldeoxyadenosine (33)
1H NMR spectrum ...…………….………………………………… 87
N6-Adamantylcarbamoyldeoxyadenosine (33)
13C NMR spectrum ...…………………………….………….…….. 87
N6-Adamantylcarbamoyldeoxyadenosine (33)
IR spectrum ...……………………….…………………………….. 88
N6-Adamantylcarbamoyldeoxyadenosine (33)
HPLC chromatogram ...….………….…………………………….. 88
N6-Adamantylcarbamoyldeoxyadenosine (33)
UV spectrum ...………...…………….…………………………….. 89
N6-Adamantylcarbamoyladenosine (34)
1H NMR spectrum ...……………………………………….……… 89
N6-Adamantylcarbamoyladenosine (34)
13C NMR spectrum ...……………………………….……….…….. 90
N6-Adamantylcarbamoyladenosine (34)
IR spectrum ...……….…………………………………………….. 90
N6-Adamantylcarbamoyladenosine (34)
HPLC chromatogram ...……….……….………………………….. 91
N6-Adamantylcarbamoyladenosine (34)
UV spectrum ...……….…….……..……………………………….. 91
N6-Adamantylcarbamoyl-9-β-D-arabinofuranosyladenine (35)
1H NMR spectrum ...……………………….……………………… 92
N6-Adamantylcarbamoyl-9-β-D-arabinofuranosyladenine (35)
13C NMR spectrum ...……………………………….……….…….. 92
N6-Adamantylcarbamoyl-9-β-D-arabinofuranosyladenine (35)
IR spectrum ...………………………….………………………….. 93
N6-Adamantylcarbamoyl-9-β-D-arabinofuranosyladenine (35)
HPLC chromatogram ...………………..………………………….. 93
N6-Adamantylcarbamoyl-9-β-D-arabinofuranosyladenine (35)
UV spectrum ...…………….……..…….………………………….. 94
N2-Adamantylcarbamoyldeoxyguanosine (36)
1H NMR spectrum ...………………….…………………………… 94
N2-Adamantylcarbamoyldeoxyguanosine (36)
13C NMR spectrum ...……………………….……………….…….. 95
N2-Adamantylcarbamoyldeoxyguanosine (36)
IR spectrum ...……………………….…………………………….. 95
N2-Adamantylcarbamoyldeoxyguanosine (36)
HPLC chromatogram ...………………..………………………….. 96
N2-Adamantylcarbamoyldeoxyguanosine (36)
UV spectrum ...………………..……..…………………………….. 96
N2-Adamantylcarbamoylguanosine (37)
1H NMR spectrum ...……………………………….……………… 97
N2-Adamantylcarbamoylguanosine (37)
13C NMR spectrum ...………………………………….…….…….. 97
N2-Adamantylcarbamoylguanosine (37)
IR spectrum ...…………………………….……………………….. 98
N2-Adamantylcarbamoylguanosine (37)
HPLC chromatogram ...……………..…………………………….. 98
N2-Adamantylcarbamoylguanosine (37)
UV spectrum ...…….…………..………….……………………….. 99
N2-Adamantylcarbamoyl-9-[(2-hydroxyethoxy)methyl]guanine (38)
1H NMR spectrum ...……………………….……………………… 99
N2-Adamantylcarbamoyl-9-[(2-hydroxyethoxy)methyl]guanine (38)
13C NMR spectrum ...………………………….…………….….... 100
N2-Adamantylcarbamoyl-9-[(2-hydroxyethoxy)methyl]guanine (38)
IR spectrum ...…………………….…………………………….... 100
N2-Adamantylcarbamoyl-9-[(2-hydroxyethoxy)methyl]guanine (38)
HPLC chromatogram ...…………………...…...……………...…. 101
N2-Adamantylcarbamoyl-9-[(2-hydroxyethoxy)methyl]guanine (38)
UV spectrum ...………………….…...…………………………… 101
N4-Adamantylcarbamoyldeoxycytidine (39)
1H NMR spectrum ...………………….………………………...…102
N4-Adamantylcarbamoyldeoxycytidine (39)
13C NMR spectrum ...……………………….………………...….. 102
N4-Adamantylcarbamoyldeoxycytidine (39)
IR spectrum ...……………………….………………………….... 103
N4-Adamantylcarbamoyldeoxycytidine (39)
HPLC chromatogram ...…………..……….…...……………….... 103
N4-Adamantylcarbamoyldeoxycytidine (39)
UV spectrum ...…………..…….…….………………………….... 104
N4-Adamantylcarbamoylcytidine (40)
1H NMR spectrum ...……………………………….………..…… 104
N4-Adamantylcarbamoylcytidine (40)
13C NMR spectrum ...………………………………….…...…….. 105
N4-Adamantylcarbamoylcytidine (40)
IR spectrum ...…………………………….………………..…….. 105
N4-Adamantylcarbamoylcytidine (40)
HPLC chromatogram ...………………..……………………..….. 106
N4-Adamantylcarbamoylcytidine (40)
UV spectrum ...…………………...……….………………..…….. 106
N4-Adamantylcarbamoyl-1-β-D-arabinofuranosylcytosine (41)
1H NMR spectrum ...……………………….……………..……… 107
N4-Adamantylcarbamoyl-1-β-D-arabinofuranosylcytosine (41)
13C NMR spectrum ...………………………………….…...…….. 107
N4-Adamantylcarbamoyl-1-β-D-arabinofuranosylcytosine (41)
IR spectrum ...……………………………….………………..….. 108
N4-Adamantylcarbamoyl-1-β-D-arabinofuranosylcytosine (41)
HPLC chromatogram ...…………..………....…………..……….. 108
N4-Adamantylcarbamoyl-1-β-D-arabinofuranosylcytosine (41)
UV spectrum ...…………..…….…………….………………..….. 109
N3-Adamantylcarbamoyl-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (42) 1H NMR spectrum ...………………..….…..…. 109
N3-Adamantylcarbamoyl-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (42) 13C NMR spectrum ...…………....……………. 110
N3-Adamantylcarbamoyl-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (42) IR spectrum ...…………………..….…………. 110
N3-Adamantylcarbamoyl-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (42) HPLC chromatogram ...………..……..….….... 111
N3-Adamantylcarbamoyl-1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-
carboxamide (42) UV spectrum ...…………..……..….……..…... 111
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指導教授 胡紀如(Jih-Ru Hwu) 審核日期 2013-7-25
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