合成?鍵連結之「去甲替林」與「核?」 共軛化合物用作抗腸病毒藥劑; Synthesis of Nortriptyline–Nucleoside Conjugates with a Urea Joint as Anti-enteroviral Agents

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題名:	合成?鍵連結之「去甲替林」與「核?」共軛化合物用作抗腸病毒藥劑;Synthesis of Nortriptyline–Nucleoside Conjugates with a Urea Joint as Anti-enteroviral Agents
作者:	高銘洋;Gao,Ming-Yang
貢獻者:	化學學系
關鍵詞:	去甲替林;核?;Nortriptyline;Nucleoside
日期:	2013-07-25
上傳時間:	2013-08-22 11:39:42 (UTC+8)
出版者:	國立中央大學
摘要:	病毒所造成的疾病和死亡，是人類一直以來面對的重大問題之一，因此如何克服病毒影響人類發展的問題成為了重要課題。每年有數百萬感染者因缺乏合適的藥物導致死亡，其中又以變異性高的「核糖核酸病毒」(RNA virus)最為嚴重。本實驗室參與歐盟「第七架構計畫」(Seventh Framework Programme)下核准之Small-molecule Inhibitor Leads versus Emerging and Neglected RNA viruses (SILVER)大型跨國計畫，目的在針對「黃病毒科」、「微小核糖核酸病毒科」、「副黏液病毒科」、「冠狀病毒科」、「布尼亞病毒科」、「沙狀病毒科」、「杯狀病毒科」的藥物開發。市面所售「去甲替林」被發現具有抑制「拉薩病毒」之活性，且本身為抗憂鬱藥物，所以本篇將利用去甲替林當作抗病毒藥物的主體之一。在過去本實驗室以「核?」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，所以我們利用類似的設計架構，將「去甲替林」以「?鍵」結合各種「核?」與開發為藥物的核?衍生物做為研究目標。其合成方法先將「去甲替林」與「N,N'-羰基二咪唑」進行取代反應，接著加入「碘化甲烷」對「咪唑」進行甲基化得到「咪唑碘鹽」。將「咪唑碘鹽」做為親電體與「核?衍生物」進行偶合反應，再進行去保護反應得到目標物。本人利用核磁共振光譜儀、高解析質譜儀和紅外線光譜（FT–IR）鑑定結構，證實本人成功地合成出目標化合物，並分析具有抑制病毒活性之化合物其活性與結構關係，以及對具有抗病毒活性化合物進行水溶性、脂溶性測試。 Viruses are responsible for many human diseases and deaths around the world. The fast mutation of RNA viruses is responsible for the lack of effective drugs to treat millions of infections. Such drugs would prevent many deaths annually. Our laboratory are participating in the Seventh Framework Programme of the European Union. Out project is called, “Small-molecule Inhibitor Leads versus Emerging and Neglected RNA viruses’’ , and focuses on the discovery of drugs for treating Flavi-, Picorna-, Paramyxo-, Corona-, Bunya-, Arena- and Caliciviridae. Scientists in the field of drug design, have recently discovered that nortriptyline exhibits anti-lassa virus activity, and can therefore be used as a tricyclic antidepressant. A series of nucleoside–coumarin conjugates with potent activity toward hepatitis C virus were synthesized at our laboratory. The developed molecules herein were designed with a similar architecture. A variety of nortriptyline-conjugated nucleoside derivatives with a urea joint was developed as anti-RNA virus agents. Nortriptyline–nucleoside was produced from carbamoyl imidazolium salts with nucleoside. Carbamoyl imidazolium salts are prepared by a reaction of N,N'-carbonyldiimidazole with nortriptyline, followed by alkylation with iodomethane. Nuclear magnetic resonance spectra were obtained to verify the shift of the characteristic peak mass spectrometry (FAB Mass) was utilized to determine the m/z ratio of compounds, and infrared spectroscopy (FT-IR) was used to verify the carbonyl group. The structure-activity relationship, the solubility of water and the solubility of lipid was discussed. Compound 18 has an anti-enterovirus 71 activity of EC50 = 3.07, a solubility of water in 125 g/mL and Log p = 2.31. In the future we will use the above results to develop drugs that are more resistant to enterovirus 71.
顯示於類別:	[化學研究所] 博碩士論文

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