臺灣博碩士論文加值系統

由於感染C型肝炎、或是C型肝炎和B型肝炎及愛滋病毒之雙重感染，與酒精的濫用，單在美國每年統計就有超過十萬的死亡人數。直至現今，唯一治療方式為僅單獨使用長效型干擾素-α或其合併廣效性抗病毒藥物ribavirin 的合併療法，但此治療方式有嚴重的副作用並且成效有限，因此發展強效的抗C型肝炎病毒藥物仍為當務之急。
在本論文中，本人報導薰香素耦合多種不同系列異環分子的目標化合物之合成策略，其中系列包含：鳥苷、肌苷、腺苷、尿苷、胸苷、嘌呤、尿嘧啶，與胞嘧啶。經由多種不同之核苷硫脲類與多樣取代基之薰香素耦合後，可成功地得到一百一十二個新型耦合化合物，於此新型化合物資料庫中，我們呈現其抗C型肝炎病毒與細胞毒性之生物活性數據，並從中建立化合物之結構–活性關係。這些新型化合物中，數個新型化合物可於無顯著細胞毒性下，展現抑制病毒之優良活性，其50%有效抑制濃度低於10μM。除此，本論文亦揭露此系列藥物分子結構之必要活性基團，並探討其結構基團與水溶性之影響。

Contents
English Abstract …………………… i
Chinese Abstract …………………… ii
Acknowledgement …………………… iii
Contents …………………………… iv
Introduction ……………………… 1
Results …………………………… 10
Synthesis of Guanosine–Coumarin Conjugates 6 …… 10
Synthesis of 2'-Deoxyguanosine–Coumarin Conjugates 10 ……………… 11
Synthesis of Acyclovir–Coumarin Conjugates 14 ……………… 12
Synthesis of Inosine–Coumarin Conjugates 19 .……………… 14
Synthesis of Adenosine–Coumarin Conjugates 21 ………………… 15
Synthesis of 2'-Deoxyadenosine–Coumarin Conjugates 24 …………… 16
Synthesis of 2',3'-Didehydro-2',3'-dideoxyadenosine–Coumarin Conjugates 31 …………………………… 17
Synthesis of Adenine–Coumarin Conjugates 33 ………… 20
Synthesis of Purine-8-thione-Ribofuranose Conjugates and the Corresponding Purine Ribofuranoside–Coumarin Analog ………………………… 21
Synthesis of 2',3',5'-Tri-O-Acetyl Purine Ribofuranoside–Coumarin Conjugates 38 ………………………… 23
Synthesis of 5'-O-Acetyl Purine Ribofuranoside–Coumarin
Conjugates 39 ……………………………………… 23
Synthesis of Purine Ribofuranoside–Coumarin Conjugates 40 …………… 24
Synthesis of 2',3'-O-Isopropylidene Purine Ribofuranoside–Coumarin Conjugates 43 ………………………… 25
Synthesis of Purine–Coumarin Conjugates 44 ………… 27
Water Solubility …………………………………………… 27
Synthesis of 6-Thioinosine–Coumarin Conjugates 46 …………………… 28
Synthesis of 2'-Deoxy-6-thioinosine–Coumarin Conjugates 52 ……………… 29
Synthesis of 6-Thioguanosine–Coumarin Conjugates 56 …………………… 31
Synthesis of 6-Thiopurine–Coumarin Conjugates 59 and 60 ………………… 32
Synthesis of 4-Thiopyrimidine Ribofuranoside–Coumarin
Conjugates 69 and 70 ……………………………………… 33
Synthesis of 4-Thiopyrimidine–Coumarin Conjugates 73 and 74 ……………… 34
Synthesis of 2-Thiopyrimidine–Coumarin Conjugates 76 …………………… 35
Synthesis of Cytosine–Coumarin Conjugates 78 ………… 36
Antiviral Evaluation in the HCV Genotype 1b Subgenomic Replicon …………… 37
Other Antiviral Activity Tests ………………………… 44
Molecular Modelling ……………………………………… 47
Discussion ………………………………………………… 48
Essential Moieties and Functional Groups:
Structure–Activity Relationship (SAR) ……………… 48
Conclusion …………………………………………………… 65
Experimental Section ……………………………………… 66
General Experimental ……………………………………… 66
Standard Procedure 1 for the Preparation of Conjugated Compounds 6, 10, 19, 21, 24, 31, 33, 40, 46, 52, 56, 59, 60, 69, 70, 73, 74, 76, 78 ………………………… 68
Standard Procedure 2 for the Preparation of 8-[(Coumarin-3'-yl)methylthio] acyclovirs 14 ……………………………… 76
Standard Procedure 3 for the Preparation of Conjugated Compounds 38 and 43 ………………………… 102
Standard Procedure 4 for the Preparation of the 9-(5''-O-Acetyl-??D-ribofuranos-1''-yl)-8-[(coumarin-3'-yl)methylthio]purines 39 ………………………… 107
References …………………………………………… 149
Spectra …………………………………………… 157

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