合成醯胺鍵及胺鍵連結之鳥?與香豆素共軛化合物並探討其構形; Syntheses of Guanosine–Coumarin Conjugates with Amide and Amine Linkers and Study on Their Conformation

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题名:	合成醯胺鍵及胺鍵連結之鳥?與香豆素共軛化合物並探討其構形;Syntheses of Guanosine–Coumarin Conjugates with Amide and Amine Linkers and Study on Their Conformation
作者:	鍾國政;Kuo-Cheng Chung
贡献者:	化學研究所
关键词:	鳥苷;coumarin;Guanosine
日期:	2011-08-29
上传时间:	2012-01-05 14:29:40 (UTC+8)
摘要:	全球約有1億7千萬人口感染C型肝炎病毒（Hepatitis C Virus, HCV），HCV亦造成國內日益嚴重的肝臟疾病和死亡原因。近年來以核苷為主的抗癌藥物日益增加，且在抑制病毒上也有良好的活性。綜合以上原因，我們希望合成出具有抗C型肝炎病毒潛力的核苷化合物。利用鳥苷衍生物與三乙胺於二氯甲烷溶劑中，在0 ?C下加入coumarin-3-carboxylic chlorides進行先加成後消去之偶合反應，再進行去保護反應，可以得到以醯胺鍵連結的N2-(coumarin-3'-carbonyl)guanosine。利用鳥苷衍生物與三乙胺於氯仿溶劑中，在50 ?C下加入3-(chloromethyl)- coumarins進行SN2反應，再進行去保護反應，可以得到以胺鍵連結的N2-[(coumarin-3'-yl)methyl]guanosine。藉由了解分子的結構，可利於抗C型肝炎病毒活性數據之解釋，我們利用核磁共振之氫譜（1H NMR）、質譜儀（FAB Mass）與紅外線光譜（FT-IR）判定合成出化合物的結構。以醯胺鍵為連接的化合物，其構形在最穩定的狀態下可觀察到分子內氫鍵的形成。在胺鍵的鍵結上，利用核磁共振之氫譜得知在N-1位置反應，其NCH2C=C的氫在5.15 ppm，與Haeberli教授團隊所合成的化合物相近；N-2位置反應，其NHCH2C=C的氫在4.36與5.05 ppm，與Guengerich教授團隊所合成的化合物相近。在水溶性的比較上，發現具有五圓醣基團的化合物其水溶性有具有開發成口服藥物的特性。有關所合成化合物之構形與觀察數據可幫助討論結構與活性關係（SAR）時的參考依據，在未來可以用其結果開發出更具有抑制作用的抗C型肝炎藥物。 Hepatitis C virus (HCV) constitutes a global health problem with 170 million people infected worldwide. In Taiwan HCV is a contagious viral disease that leads to serious, permanent liver damage and in many cases death. In recent years, using nucleoside to be anti-virus and anti-cancer drugs case is increased and the suppression of the virus had good inhibitory activity, we using guanosine as the main antiviral research. We hope that the guanosine derivatives which synthesized in our laboratory has the anti-HCV activity. We carried out the reaction between triethylamine and guanosine in dichloromethane, and added coumarin-3-carboxylic chlorides at 0?C, then we used tetrabutylammonium fluoride solution to get N2-(coumarin-3'-carbonyl)guanosine. We carried out the reaction between triethylamine and guanosine in chloroform, and added 3-(chloromethyl)coumarins at 50?C, then we used tetrabutylammonium fluoride solution to get N2-[(coumarin-3'-yl)methyl]guanosine. We used nuclear magnetic resonance spectra of hydrogen (1H NMR) to comfirm characteristic peak’s chemistry shift. We used mass spectrometry (FAB Mass) to comfirm the m/z ratio of the compoumd, and infrared spectroscopy (FT-IR) to confirm the -NH and –OH group. The stable amide linker compounds shows intramolecular hydrogen bonding. By using the NMR we can observe characteristic peak for N-1 binding site at 5.15 ppm and for N-2 binding site at 4.36 and 5.05 ppm. When we compared the water solubility between 1a and 2, the compound 1a which contain furanose group has the water solubility 71.0 ?g/mL. Therefore compound 1a result in increase in oral absorption and good permeation rate across the intestinal mucosa into the circulation. Then we used 1H NMR and molecular simulation to discuss the stereo structure and conformation. The results can help us to discuss the structure and activity relationship (SAR). In future we can use the above results to develop more resistance drugs to inhibit hepatitis C virus (HCV).
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