合成具有抗腸病毒活性「二苯」及 「亞甲基二苯」與「阿昔洛韋」之共軛化合物

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羅世偉(Shih-Wei Lo) 查詢紙本館藏

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化學學系

論文名稱

合成具有抗腸病毒活性「二苯」及「亞甲基二苯」與「阿昔洛韋」之共軛化合物
(Synthesis of Benzhydryl– and Benzhydrylidene–Acyclovir Conjugates with Anti-enterovirus Activity)

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摘要(中)

病毒造成的疾病與死亡是人類必須面對的問題，其中以高變異性RNA病毒所造成的傷害最為嚴重，至今仍缺乏合適抗該等病毒藥物與疫苗。因此「歐盟第七架構計畫」中將「黃病毒科」、「微小核醣核酸」病毒科等RNA病毒列為優先研究目標，欲開發抑制此類RNA病毒的化合物。本實驗室參與「歐盟第七架構計畫」中名為SILVER之計畫，致力於先導藥物開發。
胡紀如教授實驗室過去將有抗病毒活性之藥物以連接鍵在一起，發現藥物「去甲替林」與「阿昔洛韋」鍵結之化合物對腸病毒具有良好的抑制活性，因此本人採用類似的架構設計分子，使用結構類似於「去甲替林」的「二苯胺類」或「亞甲基二苯胺類」化合物與「阿昔洛韋」鍵結。合成的方法為將「二苯胺類」或「亞甲基二苯胺類」藉由「三光氣」從胺基反應成「異氰酸酯」，再與「阿昔洛韋」衍生物進行加成反應。
本人利用「核磁共振光譜儀」、「高解析質譜儀」和「紅外線光譜儀」鑑定合成之共軛化合物結構，最後將保護基去除得到目標分子。其中共軛化合物21具有抑制「腸病毒71型」之活性，其EC50 = 23.7 μM。

摘要(英)

Virus-related diseases pose a serious global treat to human health. In particular, RNA viruses lack effective drugs and vaccines, largely owing to the rapid mutation rate of such viruses. Therefore, the Seventh Framework Programme in the European Union has approved a project that focuses on drugs discovery towards Flaviviridae and Picornaviridae. Our laboratory participating in this program, referred to as SILVER, Our laboratory is devoting its efforts developing lead candidate.
The laboratory of Professor Jih Ru Hwu has combined two antiviral activity-related drugs together. Based on those results, nortriptyline–acyclovir conjugates to inhibit of enterovirus replication activity, Correspondingly, this study use a similar architecture design to molecular structure. Our indicate that benzhydryl or benzhydrylidene is similar to nortriptyline, so we replaces "nortriptyline" with benzhydryl or benzhydrylidene. This study focuses on benzhydryl–acyclovir and benzhydrylidene–acyclovir conjugates as the target product, The synthetic method uses triphosgene react with amines, allowing for functional group from amine to isocyanate, and then reacting with acyclovir derivatives.
The target structures are confirmed by nuclear magnetic resonance, high resolution mass spectrometers, and infrared spectroscopy. Finally, a protecting group is removed to achieve the final target. For the conjugated compound 21 which inhibits "EV71" activity, its EC50 = 23.7 μM.

關鍵字(中)

★ 阿昔洛韋
★ 腸病毒

關鍵字(英)

★ Acyclovir
★ enterovirus

論文目次

中文摘要 ............................................................................................................. i
英文摘要 ............................................................................................................ ii
謝誌 ................................................................................................................... iii
目錄 ................................................................................................................... iv
圖目錄 ............................................................................................................... xi
表目錄 ............................................................................................................... xii縮寫對照表........................................................................................................ xiii
一、緒論（Introduction）.............................................................................. 1
二、結果（Results）....................................................................................... 7
2-1 合成含矽保護基的benzhydryl–acyclovir新化合物 (21–23)..….. 7
2-2 合成benzhydryl–acyclovir新化合物 (12–14)..………….…….. 12
2-3 合成含矽保護基的benzhydrylidene–acyclovir新化合物
(31及32)…………………………………………………….…... 13
2-4 合成Benzhydrylidene–Acyclovir新化合物 (15及16)..………... 15
三、討論 (Discussion) ................................................................................. 16
3-1 探討不同「異氰酸酯」與「阿昔洛韋」衍生物反應
的最佳化反應條件 …..………………………………………….. 16
3-2 探討Benzhydryl––Acyclovir Conjugate的反應位置
與結構確定 …………………………...…...……........................ 18
3-3 探討目標產物抑制「腸病毒71型」的活性表現…..………..…... 21
3-4 利用UV-VIS測定新穎化合物之水溶性 ….....................…….... 24
3-5 利用UV-VIS光譜法測定具有抗「腸病毒71型」
之化合物 21的脂溶性 .…..……...……….…..…….….………. 26
四、結論（Conclusion）…............................................................................. 28
五、實驗部分（Experimental Section）…................................................. 29
N2-Benzhydrylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]guanine (12) .. 30
N2-2’’,2’’-Diphenylethylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (13) ...................................................................................... 31
N2-3’’,3’’-Diphenylpropylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (14) .……………..……………………………..…………. 32
N2-3’’,3’’-Diphenylallylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (15) .…………..………………………...………………… 33
N2-4’’,4’’-Diphenylbut-3-en-carbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (16) .……………..………………………………………... 34
N2-Benzhydrylcarbamoyl-9-[2’-O-(tert-butyldimethylsilyl)methyl]
guanine (21) …….……………………………………………....…. 35
N2-(2’’,2’’-Diphenylethylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (22) ……………………………………………….. 36
N2-(3’’,3’’-Diphenylpropylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (23) ……………...………………..………………. 37
N2-(3’’,3’’-Diphenylallylcarbamoyl)-9-[(2’-O-tert-butyldimethylsilyl)
methyl]guanine (31) ………..……………………………………… 38
N2-(4’’,4’’-Diphenylbut-3-en-carbamoyl)-9-[(2’-O-(tert-butyldimethyl
silyl)methyl]guanine (32)….....…….……………………………… 39
六、參考文獻（References）……............................................................ 41
七、光譜 ...................................................................................................... 47
N2-Benzhydrylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]guanine (12)
之1H NMR spectrum ………….………………………………… 48
N2-Benzhydrylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]guanine (12)
之13C NMR spectrum …..……………………….………….…….. 48
N2-Benzhydrylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]guanine (12)
之IR spectrum …………..………….…………………………….. 49
N2-Benzhydrylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]guanine (12)
之 HPLC chromatogram …………..………….……………………49
N2-Benzhydrylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]guanine (12)
之UV spectrum ………….……….…………………………….. 50
N2-2’’,2’’-Diphenylethylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (13)之1H NMR spectrum ……….….…………....……… 50
N2-2’’,2’’-Diphenylethylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (13)之13C NMR spectrum …..….………...………….….. 51
N2-2’’,2’’-Diphenylethylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (13)之IR spectrum ..…….………………...…………….. 51
N2-2’’,2’’-Diphenylethylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (13)之HPLC chromatogram.……………...…………….. 52
N2-2’’,2’’-Diphenylethylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (13)之UV spectrum ..…….………………...…………….. 52
N2-3’’,3’’-Diphenylpropylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (14)之1H NMR spectrum ….……………….…………… 53
N2-3’’,3’’-Diphenylpropylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (14)之13C NMR spectrum ….….………….……….…….. 53
N2-3’’,3’’-Diphenylpropylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (14)之IR spectrum...…………………………….……….. 54
N2-3’’,3’’-Diphenylpropylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (14)之HPLC chromatogram.……………...…………….. 54
N2-3’’,3’’-Diphenylpropylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (14)之UV spectrum...…………………………….………. 55
N2-3’’,3’’-Diphenylallylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (15)之1H NMR spectrum ….……..……………………… 55
N2-3’’,3’’-Diphenylallylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (15)之13C NMR spectrum ……………………………….. 56
N2-3’’,3’’-Diphenylallylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (15)之IR spectrum …………………………..….…….. 56
N2-3’’,3’’-Diphenylallylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (15)之HPLC chromatogram……….………………………57
N2-3’’,3’’-Diphenylallylcarbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (15)之UV spectrum …………………………..….…….. 57
N2-4’’,4’’-Diphenylbut-3-en-carbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (16)之1H NMR spectrum ………….…………………...…58
N2-4’’,4’’-Diphenylbut-3-en-carbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (16)之13C NMR spectrum ……………………….…...….. 58
N2-4’’,4’’-Diphenylbut-3-en-carbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (16)之IR spectrum …………….………………………...59
N2-4’’,4’’-Diphenylbut-3-en-carbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (16)之HPLC chromatogram……….………………………59 N2-4’’,4’’-Diphenylbut-3-en-carbamoyl-9-[(2’-hydroxyethoxy)methyl]
guanine (16)之UV spectrum …………….………………………...60
N2-Benzhydrylcarbamoyl-9-[2’-O-(tert-butyldimethylsilyl)methyl]
guanine (21)之1H NMR spectrum ..…..……………….…………60
N2-Benzhydrylcarbamoyl-9-[2’-O-(tert-butyldimethylsilyl)methyl]
guanine (21)之13C NMR spectrum …………..……………..…….. 61
N2-Benzhydrylcarbamoyl-9-[2’-O-(tert-butyldimethylsilyl)methyl]
guanine (21)之IR spectrum ………..………………………….….. 61
N2-Benzhydrylcarbamoyl-9-[2’-O-(tert-butyldimethylsilyl)methyl]
guanine (21)之HPLC chromatogram……….………………………62
N2-Benzhydrylcarbamoyl-9-[2’-O-(tert-butyldimethylsilyl)methyl]
guanine (21)之UV spectrum ………..……………..……….….. 62
N2-(2’’,2’’-Diphenylethylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (22)之1H NMR spectrum ………..……………… 63
N2-(2’’,2’’-Diphenylethylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (22)之13C NMR spectrum ……………….…….. 63
N2-(2’’,2’’-Diphenylethylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (22)之IR spectrum …..…………………….…….. 64
N2-(2’’,2’’-Diphenylethylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (22)之HPLC chromatogram ….…………………64
N2-(2’’,2’’-Diphenylethylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (22)之UV spectrum …..………………….…….. 65
N2-(3’’,3’’-Diphenylpropylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (23)之1H NMR spectrum ………….……..……. 65
N2-(3’’,3’’-Diphenylpropylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (23)之13C NMR spectrum …………………….…. 66
N2-(3’’,3’’-Diphenylpropylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (23)之IR spectrum ……..….……...…….………66
N2-(3’’,3’’-Diphenylpropylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (23)之HPLC chromatogram ….…………………67
N2-(3’’,3’’-Diphenylpropylcarbamoyl)-9-[2’-O-(tert-butyldimethylsilyl)
methyl]guanine (23)之UV spectrum ……..….……...…….………67
N2-(3’’,3’’-Diphenylallylcarbamoyl)-9-[(2’-O-tert-butyldimethylsilyl)
methyl]guanine (31)之1H NMR spectrum .…..…….……………. 68
N2-(3’’,3’’-Diphenylallylcarbamoyl)-9-[(2’-O-tert-butyldimethylsilyl)
methyl]guanine (31)之13C NMR spectrum ….……………………. 68
N2-(3’’,3’’-Diphenylallylcarbamoyl)-9-[(2’-O-tert-butyldimethylsilyl)
methyl]guanine (31)之IR spectrum ………..……….……….……. 69
N2-(3’’,3’’-Diphenylallylcarbamoyl)-9-[(2’-O-tert-butyldimethylsilyl)
methyl]guanine (31)之HPLC chromatogram ….…..………………69
N2-(3’’,3’’-Diphenylallylcarbamoyl)-9-[(2’-O-tert-butyldimethylsilyl)
methyl]guanine (31)之UV spectrum ………..……….…….……. 70
N2-(4’’,4’’-Diphenylbut-3-en-carbamoyl)-9-[(2’-O-(tert-butyldimethylsilyl)methyl]guanine (32)之1H NMR spectrum …..………..………...…. 70
N2-(4’’,4’’-Diphenylbut-3-en-carbamoyl)-9-[(2’-O-(tert-butyldimethylsilyl)
methyl]guanine (32)之13C NMR spectrum ………..………………. 71
N2-(4’’,4’’-Diphenylbut-3-en-carbamoyl)-9-[(2’-O-(tert-butyldimethylsilyl)
methyl]guanine (32)之IR spectrum ………..………….….………. 71
N2-(4’’,4’’-Diphenylbut-3-en-carbamoyl)-9-[(2’-O-(tert-butyldimethylsilyl)
methyl]guanine (32)之HPLC chromatogram………...….………. 72
N2-(4’’,4’’-Diphenylbut-3-en-carbamoyl)-9-[(2’-O-(tert-butyldimethylsilyl)
methyl]guanine (32)之IR spectrum ………..………….….………. 72

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指導教授

胡紀如(Jih-Ru Hwu)

審核日期

2013-8-12

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