合成腺?與含氮雜環之硫烷鍵共軛化合物作為抗病毒試劑; Syntheses of Adenosine Conjugated Nitrogen–Containing Heterocycles with a Thioalkyl Linker as Antiviral Agents

Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/48097

Title:	合成腺?與含氮雜環之硫烷鍵共軛化合物作為抗病毒試劑;Syntheses of Adenosine Conjugated Nitrogen–Containing Heterocycles with a Thioalkyl Linker as Antiviral Agents
Authors:	謝秉勳;Bing-shiun Hsieh
Contributors:	化學研究所
Keywords:	病毒;腺苷;Thioalkyl;Antiviral;Adenosine
Date:	2011-08-31
Issue Date:	2012-01-05 14:29:51 (UTC+8)
Abstract:	目前病毒所造成的疾病和死亡是人類所面臨的重大問題之一，但由於病毒基因的快速變異，至今仍缺乏合適的藥物和疫苗。歐盟第七架構計畫中更將登革熱病毒、腸病毒和副黏液病毒列為優先針對目標，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。由於含氮的雜環分子因為具有多種生物活性，已被廣泛應用於藥物開發上，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，因此為了拓展更多活性分子骨架，我們以合成硫烷鍵結腺苷與具抗病毒活性的含氮雜環分子為目標，分別為adenosine–TBBT 23、24與adenosine–HBB 28以及adenine–TBBT 25、26等共軛化合物。其合成方法為利用具有硫醇結構的腺苷與帶有離去基的含氮雜環分子在pH值為11.6的條件之下，進行親核性取代反應，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。此外本人對於benzotraiazole與醛類反應時所造成的一號與二號氮互變異構，以及化合物8-[(4',5',6',7'-tetrabromobenzotriazol-1'-yl)methylthio]- adenosine與8-[(benzimidazol-2-yl)(phenyl)methylthio]adenosine在核磁共振光譜中造成的化學偏移進行探討。最後，本人也針對在不同的pH值環境下，親核性取代反應的反應性進行討論。 Many disease and death around the world caused by viruses are major problems of human being. However, because of fast mutation rate of the RNA viruses, 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. We are participating in this program, so called SILVER, and devoting our efforts on drugs development in our laboratory. In the research of drugs designing, scientists currently focus on the nitrogen–containing heterocycles, which contain various bioactivities. Moreover, our laboratory synthesized a series of nucleoside–coumarin conjugates, which exhibited potent activity on HCV. Therefore, I synthesized adenosine conjugated nitrogen–containing heterocycles, adenosine–TBBT 23, adenosine–TBBT 24, adenosine–HBB 28, adenine–TBBT 25 and adenine–TBBT 26, with thioalkyl linker as antiviral agent candidates. The synthetic method was a nucleophilic substitution in basic condition with 8-mercaptoadenosine as a nucleophile and heterocycles containing a leaving group as a electrophile. The target structures was checked by nuclear magnetic resonance and high resolution mass spectrometers. On the other hand, I discussed the N-1 and N-2 tautomerization of benzotriazole when reacted with formaldehyde. I also discussed phenomena of the chemical shift of 8-[(4',5',6',7'-tetrabromobenzotriazol-1'-yl)methylthio]adenosine (23) and 8-[(benzimidazol- 2'-yl)(phenyl)methylthio]adenosine (28) in nuclear magnetic resonance spectroscopy. Finally, the reactivity of nucleophilic substitution with 8-mercaptoadenosine (22) in different pH values is also discussed.
Appears in Collections:	[Graduate Institute of Chemistry] Electronic Thesis & Dissertation

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