合成含胺基酸酯之「無環鳥苷」與「去甲替林」共軛化合物作為抗腸病毒藥劑

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姓名

許惠然(Huei-ran Syu) 查詢紙本館藏

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化學學系

論文名稱

合成含胺基酸酯之「無環鳥苷」與「去甲替林」共軛化合物作為抗腸病毒藥劑
(Synthesis of Acyclovir–Nortriptyline Conjugates with Amino Acid Ester as Anti-enteroviral Agents)

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摘要(中)

人類一直以來需要面對病毒造成的種種疾病，由於許多的病毒目前並沒有適當的藥物和疫苗，導致每年都有數百萬人感染致死，其中又以「核糖核酸病毒」(RNA virus)具有較高的變異性，帶來較嚴重的傷亡，因此如何克服病毒影響人類發展的問題成為了重要課題。
本實驗室參與歐盟「第七架構計畫」下核准之大型跨國計畫Small-molecule Inhibitor Leads versus Emerging and Neglected RNA viruses (SILVER)，目的在將「黃病毒科」、「微小核醣核酸病毒科」和「副黏液病毒科」等RNA病毒列為優先研究目標，對其對應藥物進行合成和優化。
過去胡紀如教授實驗室將有抗病毒活性之藥物「無環鳥苷」與「去甲替林」鍵結在一起，所得分子經抗病毒測試後發現對「腸病毒71型」具有良好的抑制活性，因此本人採用此分子架構進行結構修飾，將「無環鳥苷」之羥基與胺基酸鍵結形成酯基作為目標。合成的方法為將含保護之胺基酸藉由耦合試劑「N,N-二環己碳二亞胺」於羧基形成較佳離去基，再和「無環鳥苷」與「去甲替林」共軛化合物進行酯化反應，並將胺基酸上之保護基以「哌啶」去除得到目標產物，並利用「核磁共振光譜儀」及「高解析質譜儀」鑑定其結構。

摘要(英)

Virus-related infections pose a serious global threat to human health, causing many human diseases and deaths. Particularly, treatment of RNA viruses lacks effective drugs and vaccines, largely because such viruses mutate rapidly.
The laboratory of Professor Jih Ru Hwu are participating in the European Union’s Seventh Framework Programme. Out project is called, “Small-molecule Inhibitor Leads versus Emerging and Neglected RNA viruses’’ , and focuses on discovering drugs for treating Flaviviridae, Picronviridae, Paramyxoviridae, Alphaviridae, Arenaviridae, Bunyaviridae, Coronaviridae, Noroviridae,and Rhabdoviridae.
Our laboratory has combined two antiviral activity-related drugs together. Experimental results indicate that acyclovir–nortriptyline conjugates inhibit enterovirus replication activity. Correspondingly, this study uses a similar architecture design to molecular structure. This study focuses on acyclovir–nortriptyline conjugates with amino acid esters as the target products. The synthetic method uses coupling reagent N,N’- dicyclohexylcarbodiimide and catalyst 4-(dimethylamino)pyridine react with amino acids, such that the functional group from the amine to better leaving group, and then react with acyclovir derivatives. Finally, a protecting group is removed by piperidine to achieve the final target. The target structures are confirmed by nuclear magnetic resonance spectrometry and high resolution mass spectrometers.

關鍵字(中)

★ 腸病毒
★ 胺基酸
★ 無環鳥苷
★ 去甲替林
★ 抗病毒藥劑
★ 核醣核酸病毒

關鍵字(英)

論文目次

中文摘要 .................................................. i
英文摘要 ................................................. ii
謝誌 ................................................... iii
目錄 ………………………………………………………………............ iv
圖目錄 …………………………………………...........……........ xiv
表目錄 .................................................. xv
縮寫對照表 .............................................. xvi
一、緒論 ............................................ 1
二、結果 ........................................... 14
2-1　合成含Fmoc保護之Acyclovir–Nortriptyline胺基酸酯共軛化合物(20–23)................................................ 14
2-2　由高解析質譜儀、核磁共振光譜鑑定酯類化合物20之結構..........16
2-3 含Fmoc保護基之Acyclovir–Nortriptyline胺基酸酯共軛化合物20反應的最佳化合成條件...................................... .. 20
2-4 合成Acyclovir–Nortriptyline胺基酸酯共軛化合物 (24–27)… 20
2-5 利用UV-VIS測定胺基酸酯共軛化合物之水溶性................. 21
2-6 利用UV-VIS測定胺基酸酯共軛化合物之脂溶性................. 22
三、討論............................................ 23
3-1　探討含保護基之胺基酸與「無環鳥苷」衍生物反應的最佳化合成條件.. 23
3-2　探討胺基酸保護基的選擇................................. 24
3-3　探討含保護基之胺基酸與「無環鳥苷」衍生物反應的合成步驟....... 26
3-4　由Lipinski’s rule探討化合物之藥物開發能力.............. 27
3-5 探討胺基酸酯共軛化合物之水溶性及其藥物開發能力............. 29
3-6 探討胺基酸酯共軛化合物之脂溶性及其藥物開發能力............. 30
四、結論 ........................................... 31
五、實驗部分（Experimental Section） ............... 32
9-(2-[N-(9-Fluorenylmethoxycarbonyl)-L-valyl]oxyethyloxymethyl)-N2- [N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene) prop-1-carbamoyl]guanine (20).....................................................34
9-(2-[N-(9-Fluorenylmethoxycarbonyl)-L-phenylalanyl]oxyethyloxyme- thyl)-N2-[N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-
ylidene)prop-1-carbamoyl]guanine (21)................... 35
9-(2-[N-(9-Fluorenylmethoxycarbonyl)-L-prolyl]oxyethyloxymethyl)-N2- [N-methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene) prop-1-carbamoyl]guanine (22).................................................... 36
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)
prop-1-carbamoyl]-9-[2-(L-valyl)oxyethyloxymethyl]-
guanine (24)........................................... 38
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)
prop-1-carbamoyl]-9-[2-(L-phenylalanyl)oxyethyloxymethyl]-
guanine (25)........................................... 39
N2-[N-Methyl-3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)
prop-1-carbamoyl]-9-[2-(L-prolyl)oxyethyloxymethyl]-
guanine (26)........................................... 40
六、參考文獻 ..................................... 44
七、光譜 .......................................... 50

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指導教授

胡紀如

審核日期

2014-8-26

推文