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姓名 鍾國政(Kuo-Cheng Chung) 查詢紙本館藏 畢業系所 化學學系 論文名稱 合成醯胺鍵及胺鍵連結之鳥苷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)相關論文 檔案 [Endnote RIS 格式]
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至系統瀏覽論文 ( 永不開放)
摘要(中) 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。
摘要(英) 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).
關鍵字(中) ★ 香豆素
★ 鳥苷關鍵字(英) ★ coumarin
★ Guanosine論文目次 目 錄
中文摘要 …………………………………………………….....…………..….. i
英文摘要 …………………………………………………….....……….....…. iii
謝誌 ………………………………………………………...…..………...…… v
縮寫對照表 ……………..…………………...……………………...…..…..... vi
目錄 …………………………………………………………….…...…......… vii
圖目錄 ……………………………………………………….......…...…...… xiv
表目錄 ............................................................................................................. xvi
一、 緒 論 …………………………………………………...…..…………... 1
二、 結 果 ………………………………………………...…………...…….. 6
2-1 製備已知具有不同官能基之Coumarin-3-carboxylic chlorides
(8a–d) ................................................................................................ 6
2-2 製備已知2',3',5'-Tri-O-(tert-butyldimethylsilyl)guanosine (10) ….. 6
2-3 合成具有不同官能基之N2-(Coumarin-3'-carbonyl)guanosine
新化合物(1a–d) ……...…………..................…………………....... 7
2-4 合成N2-(Coumarin-3'-carbonyl)guanine新化合物 (2) …….....… 14
2-5 製備已知具有不同官能基之3-(Chloromethyl)coumarins 化合
物(14a–c) ……..……………..………………………....……….... 16
2-6 合成N2-[(Coumarin-3'-yl)methyl]guanosine新化合物 (15a–c) …16
2-7 合成2',3',5'-tri-O-(tert-butyldimethylsilyl)-N2-[(coumarin-3'-yl)-
methyl]guanosine新化合物 (16) ………….……………….…..... 19
2-8 合成N1-[(Coumarin-3'-yl)methyl]guanosine新化合物 (3)…........ 22
三、 討 論 …………….……………………………..……….…………..… 24
3-1 利用FT-IR討論產物11a–d之構形 …..………….....…….…..... 24
3-2 利用分子模擬和NMR光譜討論產物1a–d之氫鍵與結構 ….... 26
3-3 化合物15與16最佳化合成條件 …...................…....……..……. 29
3-4 利用NMR光譜判斷化合物15與16合成位置 .......................... 30
3-5 利用UV-Vis判斷產物1a與2之水溶解度 …………..……...….. 32
3-6 討論化合物1a–d純化時四級胺鹽的殘留與解決的方法 .....….. 33
四、 結 論 ………………...…………..…………………………….…….... 35
五、 實 驗 部 分 …………………………………………..…….…...…… 37
合成N2-(Coumarin-3'-carbonyl)guanosine (1a) ……………….........… 38
合成N2-(6'-Chlorocoumarin-3'-carbonyl)guanosine (1b) ……….......… 39
合成N2-(6'-Bromocoumarin-3'-carbonyl)guanosine (1c) ………...….... 40
合成N2-(6'-Flurocoumarin-3'-carbonyl)guanosine (1d) ………….…… 40
合成N2-(Coumarin-3'-carbonyl)guanine (2) …………......................…. 41
合成N1-[(Coumarin-3'-yl)methyl]guanosine (3a) …………...……...… 42
合成N1-[(6'-Bromocoumarin-3'-yl)methyl]guanosine (3c) ……..…….. 43
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(coumarin-3'-
carbonyl)guanosine (11a) ……………..................…..………….... 44
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-chlorocoumarin-
3'-carbonyl)-guanosine (11b) ………..………....…………..…….. 44
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-bromocoumarin-
3'-carbonyl)guanosine (11c) …………………………………...…. 45
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-flurocoumarin-3'-
carbonyl)guanosine (11d) ……………...……….………....…...…. 46
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(coumarin-3'-yl)-
methyl]guanosine (15a) ………………………………...….…...… 47
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-chlorocoumarin-
3'-yl)-methyl]guanosine (15b) ………...........................…..…....… 47
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-bromocoumarin-
3'-yl)-methyl]guanosine (15c) ……………………....……...…….. 48
合成2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N1-[(coumarin-3'-yl)-
methyl]-guanosine (16) ................................................................... 49
六、 參 考 文 獻 …………………………………………...……………... 51
七、 光 譜 ……………………………………………………………..…… 58
N2-(Coumarin-3'-carbonyl)guanosine (1a) 1H 核磁共振光譜圖 ….… 59
N2-(Coumarin-3'-carbonyl)guanosine (1a) 13C 核磁共振光譜圖 ….... 59
N2-(Coumarin-3'-carbonyl)guanosine (1a) 紅外線光譜圖 ..…….....… 60
N2-(6'-Chlorocoumarin-3'-carbonyl)guanosine (1b) 1H 核磁共振光
譜圖 ................................................................................................ 60
N2-(6'-Chlorocoumarin-3'-carbonyl)guanosine (1b) 13C 核磁共振光
譜圖 …............................................................................................ 61
N2-(6'-Chlorocoumarin-3'-carbonyl)guanosine (1b) 紅外線光譜圖 .... 61
N2-(6'-Bromocoumarin-3'-carbonyl)guanosine (1c) 1H 核磁共振光
譜圖 …………........................................………………………… 62
N2-(6'-Bromocoumarin-3'-carbonyl)guanosine (1c) 13C 核磁共振光
譜圖 …............................................................................................ 62
N2-(6'-Bromocoumarin-3'-carbonyl)guanosine (1c) 紅外線光譜圖 ..... 63
N2-(6'-Flurocoumarin-3'-carbonyl)guanosine (1d) 1H 核磁共振光
譜圖 ................................................................................................ 63
N2-(6'-Flurocoumarin-3'-carbonyl)guanosine (1d) 13C 核磁共振光
譜圖 .................................................................................................64
N2-(6'-Flurocoumarin-3'-carbonyl)guanosine (1d) 紅外線光譜圖 ....... 64
N2-(Coumarin-3'-carbonyl)guanine (2) 1H 核磁共振光譜圖 ……...… 65
N2-(Coumarin-3'-carbonyl)guanine (2) 13C 核磁共振光譜圖 .............. 65
N2-(Coumarin-3'-carbonyl)guanine (2) 紅外線光譜圖 ..……..........… 66
N1-[(Coumarin-3'-yl)methyl]guanosine (3a) 1H 核磁共振光譜圖 ....... 66
N1-[(Coumarin-3'-yl)methyl]guanosine (3a) 13C 核磁共振光譜圖 ..... 67
N1-[(Coumarin-3'-yl)methyl]guanosine (3a) 紅外線光譜圖 ................ 67
N1-[(6'-Bromocoumarin-3'-yl)methyl]guanosine (3c) 1H 核磁共振光
譜圖 …..……………........................................………….…....…. 68
N1-[(6'-Bromocoumarin-3'-yl)methyl]guanosine (3c) 13C 核磁共振光
譜圖 …............................................................................................ 68
N1-[(6'-Bromocoumarin-3'-yl)methyl]guanosine (3c) 紅外線光譜圖 .. 69
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(coumarin-3'-carbonyl)-
guanosine (11a) 1H 核磁共振光譜圖 ………...........................… 69
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(coumarin-3'-carbonyl)-
guanosine (11a) 13C 核磁共振光譜圖 ……….....................……. 70
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(coumarin-3'-carbonyl)-
guanosine (11a) 紅外線光譜圖 ..………..................................… 70
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-chlorocoumarin-
3'-carbonyl)-guanosine (11b) 1H 核磁共振光譜圖 ……....…..… 71
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-chlorocoumarin-
3'-carbonyl)-guanosine (11b) 13C 核磁共振光譜圖 …......…..…. 71
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-chlorocoumarin-
3'-carbonyl)-guanosine (11b) 紅外線光譜圖 ..…….................… 72
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-bromocoumarin-
3'-carbonyl)guanosine (11c) 1H 核磁共振光譜圖 …..........…..… 72
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-bromocoumarin-
3'-carbonyl)guanosine (11c) 13C 核磁共振光譜圖 …………..…. 73
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-bromocoumarin-
3'-carbonyl)guanosine (11c) 紅外線光譜圖 ..………..….........… 73
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-flurocoumarin-3'-
carbonyl)guanosine (11d) 1H 核磁共振光譜圖 ……….……….. 74
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-flurocoumarin-3'-
carbonyl)guanosine (11d) 13C 核磁共振光譜圖 ………...…..…. 74
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-flurocoumarin-3'-
carbonyl)guanosine (11d) 紅外線光譜圖 ..……….…..............… 75
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(coumarin-3'-yl)-
methyl]guanosine (15a) 1H 核磁共振光譜圖 ……………......… 75
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(coumarin-3'-yl)-
methyl]guanosine (15a) 13C 核磁共振光譜圖 …………........…. 76
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(coumarin-3'-yl)-
methyl]guanosine (15a) 紅外線光譜圖 ..…………..................… 76
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-chlorocoumarin-
3'-yl)-methyl]guanosine (15b) 1H 核磁共振光譜圖 ……....…… 77
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-chlorocoumarin-
3'-yl)-methyl]guanosine (15b) 13C 核磁共振光譜圖 …..........…. 77
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-chlorocoumarin-
3'-yl)-methyl]guanosine (15b) 紅外線光譜圖 ..…....................… 78
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-bromocoumarin-
3'-yl)-methyl]guanosine (15c) 1H 核磁共振光譜圖 ….........…… 78
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-bromocoumarin-
3'-yl)-methyl]guanosine (15c) 13C 核磁共振光譜圖 …...........…. 79
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-[(6'-bromocoumarin-
3'-yl)-methyl]guanosine (15c) 紅外線光譜圖 ..……………....… 79
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N1-[(coumarin-3'-yl)
methyl]-guanosine (16) 1H 核磁共振光譜圖 ....……...............… 80
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N1-[(coumarin-3'-yl)
methyl]-guanosine (16) 13C 核磁共振光譜圖 ….....................…. 80
2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N1-[(coumarin-3'-yl)
methyl]-guanosine (16) 紅外線光譜圖 ..……………..............… 81
圖目錄
Figure 1. 核苷之RNA複製酶抑制劑 ………………................................... 2
Figure 2. 實驗室合成對於HCV有抑制活性的藥物 ………………........... 3
Figure 3. 醯胺鍵及胺鍵連結之鳥苷與香豆素共軛化合物 …..……........ 4
Figure 4. 化合物與病毒的預測機制圖 ......................................................... 5
Figure 5. 由核磁共振氫譜(1H NMR)判斷產物11a結構 …....….…..…...... 9
Figure 6. 由核磁共振氫譜(1H NMR)判斷產物1a結構 .…....……..…….. 11
Figure 7. 化合物1c分子共振示意圖 .........……………...…...….......…… 12
Figure 8. 分子模擬化合物1c可能構形圖I–IV ........................................... 14
Figure 9. 由核磁共振氫譜(1H NMR)判斷產物2結構 …..………….....… 15
Figure 10. 由核磁共振氫譜(1H NMR)判斷產物15a結構 ……......…….… 18
Figure 11. 由核磁共振氫譜（1H NMR）判斷產物16結構 ............................ 21
Figure 12. 由核磁共振氫譜(1H NMR)判斷產物3a結構 …...…...…...…… 23
Figure 13. N2-(Coumarin-3'-carbonyl)guanine (1)可能形成氫鍵的位置 ….. 24
Figure 14. 產物2',3',5'-Tri-O-(tert-butyldimethylsilyl)-N2-(6'-bromo-
coumarin-3'-carbonyl)guanosine (11c) FT–IR圖 ……........… 25
Figure 15. 化合物1c分子位能圖 .................................................................. 27
Figure 16. 化合物1c分子模擬示意圖(平面夾角) ………………………… 27
Figure 17. 化合物1c分子模擬示意圖(氫鍵距離) ……..……….........……. 28
Figure 18. 不同濃度的化合物11c NMR光譜 …..………............................ 29
Figure 19. 2',3',5'-Tri-O-(tert-butyldimethylsilyl)guanosine (10)可能與
3-(chloro-methyl)coumarins (15)進行SN2反應的位置 ……… 30
Figure 20. 化合物15與16核磁共振氫譜(1H NMR) ..................................... 31
Figure 21. 產物1a與2溶解度與吸收度示意圖 ……………………..….… 32
Figure 22. 由核磁共振氫譜(1H NMR)判斷產物11a …………………....… 34
表目錄
Table 1. 利用分子模擬，計算1c後的位能與氫鍵距離 ................................ 12
Table 2. 在鹼性條件下化合物10與14a之反應 ........................................... 20
Table 3. 化合物1a與2之水溶性比較 ........................................................... 32
參考文獻 1. Chang, W.; Bao, D.; Chun, B. K.; Naduthambi, D.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Zhang, H. R.; Bansal, S.; Espirtu, C. L.; Keilman, M.; Niu, L. C.; Steuer, H. M.; Furman, P. A.; Otto, M. J.; Sofia, M. J. Discovery of PSI-353661, a novel purine nucleotide prodrug for the treatment of HCV infection. ACS Med. Chem. Lett. 2011, 2, 130–135.
2. Hwu, J. R.; Lin, S. Y.; Tsay, S. C.; Clercq, E. D.; Leyssen, P.; Neyts, J. Coumarin-Purine Ribofuranoside Conjugates as new agents against hepatitis C virus. J. Med. Chem. 2011, 54, 2114–2126.
3. Department of Health, Executive Yuan, R.O.C.(TAIWAN), http://www.doh.gov.tw/cht2006/index_populace.aspx
4. Simmonds, P. Genetic diversity and evolution of hepatitis C virus ? 15 years on. J. Gen. Virol. 2004, 85 , 3173–3188.
5. Hoofnagle, J. H. The course and outcome of hepatitis C. Hepatology 2002, 36, S21–S29.
6. Choo, Q.-L.; Kuo, G.; Weiner, A. J.; Overby, L. R.; Bradley, D. W.; Houghton, M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989, 244, 359–362.
7. Simmonds, P.; Bukh, J.; Combet, C.; Deléage, G.; Enomoto, N.; Feinstone, S.; Halfon, P.; Inchauspé, G.; Kuiken, C.; Maertens, G.; Mizokami, M.; Murphy, D. G.; Okamoto, H.; Pawlotsky, J.-M.; Penin, F.; Sablon, E.; Shin, -I. T.; Stuyver, L. J.; Thiel, H.-J.; Viazov, S.; Weiner, A. J.; Widell, A. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005, 42, 962–973.
8. Younossi, Z. M.; Limongi, D.; Stepanova, M.; Pierobon, M.; Afendy, A.; Mehta, R.; Baranova, A.; Liotta, L.; Petricoin, E. Protein pathway activation associated with sustained virologic response in patients with chronic hepatitis C treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). J. Proteome Res. 2011, 10, 774–779.
9. Francesco, R. D.; Tomei, L.; Altamura, S.; Summa, V.; Migliaccio, G. Approaching a new era for hepatitis C virus therapy inhibitors of NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antiver. Res. 2003, 58, 1–16.
10. Alvarez, D.; Dieterich, D. T.; Brau, N.; Moorehead, L.; Ball, L.; Sulkowski, M. S. Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment in HIV-infected persons. J. Viral. Hepat. 2006, 13, 683–689.
11. Gish, R. G. Treating HCV with ribavirin analogues and ribavirin-like molecules. J. Antimicrob. Chemother. 2006, 57, 8–13.
12. Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.; Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. Benzimidazole derivatives bearing substituted biphenyls as hepatitis C virus NS5B RNA-dependent RNA polymerase inhibitors: structure?activity relationship studies and identification of a potent and highly selective inhibitor JTK-109. J. Med. Chem. 2006, 49, 4721–4736.
13. Sofia, M. J.; Bao, D.; Chang, W.; Du, J. Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S.; Wang, P.; Zhang, H. R.; Bansal, S.; Espiritu, C.; Keilman, M.; Lam, A. M.; Steuer, H. M. M.; Niu, C.; Otto, M. J.; Furman, P. A. Discovery of a β-D-2'-Deoxy-2'-r-fluoro-2'-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. J. Med. Chem. 2010, 53, 7202–7218.
14. Wauchope, O. R.; Tomney, M. J.; Pepper, J. L.; Korba, B. E.; Seley-Radtke, K. L. Tricyclic 2′-C-modified nucleosides as potential anti-HCV therapeutics. Org. Lett., 2010, 12, 4466–4469.
15. Gardelli, C.; Attenni, B.; Donghi, M.; Meppen, M.; Pacini, B.; Harper, S.; Marco, A. D.; Fiore, F.; Giuliano, C.; Pucci, V.; Laufer, R.; Gennari, N.; Marcucci, I.; Leone, J. F.; Olsen, D. B.; MacCoss, M.; Rowley, M.; Narjes, F. Phosphoramidate prodrugs of 2'-C-methylcytidine for therapy of hepatitis C virus infection. J. Med. Chem. 2009, 52, 5394–5407.
16. Rudd, M. T.; McCauley, J. A.; Butcher, J. W.; Romano, J. J.; McIntyre, C. J.; Nguyen, K. T.; Gilbert, K. F.; Bush, K. J.; Holloway, M. K.; Swestock, J.; Wan, B. L.; Carroll, S. S.; DiMuzio, J. M.; Graham, D. J.; Ludmerer, S. W.; Stahlhut, M. W.; Fandozzi, C. M.; Trainor, N.; Olsen, D. B.; Vacca, J. P.; Liverton, N. J. Discovery of MK-1220: a macrocyclic inhibitor of hepatitis C virus NS3/4A protease with improved preclinical plasma exposure. ACS Med. Chem. Lett. 2011, 2, 207–212.
17. Koch, U.; Attenni, B.; Colarusso, S.; Conte, I.; Filippo, M. D.; Harper, S.; Pacini, B.; Giomini, C.; Thomas, S.; Incitti, I.; Tomei, L.; Francesco, R. D.; Altamura, S.; Matassa, V. G.; Narjes, F. 2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C Virus NS5B polymerase: discovery, SAR, modeling, and mutagenesis. J. Med. Chem. 2006, 49, 1693-1705.
18. Powers, J. P.; Piper, D. E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J. M.; Jaen, J. C.; Lee, G.; Liu, J.; Peterson, M. G.; Tonn, G. R.; Ye, Q.; Walker, N. P. C.; Wang, Z. SAR and mode of action of novel Non-Nucleoside inhibitors of hepatitis C NS5b RNA polymerase. J. Med. Chem. 2006, 49, 1034-1046.
19. Tsantrizos, Y. S. Peptidomimetic Therapeutic Agents Targeting the Protease Enzyme of the Human Immunodeficiency Virus and Hepatitis C Virus. Acc. Chem. Res. 2008, 41, 1252–1263.
20. De Francesco and R.; Carfi, A. Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus. Adv. Drug Deliv. Rev. 2007, 59, 1242–1262.
21. Graci, J. D. and Cameron, C. E. Challengs for the development of ribonucleoside analogues as inducers of error catastrophe. Antiviral Chem. Chemother. 2004, 15, 1–13.
22. Chung, D. H.; Strouse, J. J.; Sun, Y,; Arterburn, J. B.; Parker, W. B.; Jonsson, C.B. Synthesis and anti-Hantaan virus activity of N1-3-fluorophenyl-inosine. Antivir. Res. 2009, 83, 80–85.
23. Wauchope, O. R.; Tomney, M. J.; Pepper, J. L.; Korba, B. E.; Seley-Radtke, K. L. Tricyclic 2′-C-modified nucleosides as potential Anti-HCV therapeutics. Org. Lett. 2010, 12, 4466–4469.
24. McGuigan, C.; Gilles, A.; Madela, K.; Aljarah, M.; Holl, S.; Jones, S.; Vernachio, J.; Hutchins, J.; Ames, B.; Bryant, K. D.; Gorovits, E.; Ganguly, B.; Hunley, D.; Hall, A.; Kolykhalov, A.; Liu, Y.; Muhammad, J.; Raja, N.; Walters, R.; Wang, J.; Chamberlain, S.; Henson, G. Phosphoramidate proTides of 2'-C-methylguanosine as highly potent inhibitors of hepatitis C virus. study of their in vitro and in vivo properties. J. Med. Chem. 2010, 53, 4949–4957.
25. Ito, C.; Itoigawa, M.; Mishina, Y.; Filho, V. C.; Enjo, F.; Tokuda, H.; Nishino, H.; Furukawa, H. Chemical constituents of calophyllum brasiliense. 2. structure of three new coumarins and cancer chemopreventive activity of 4-substituted coumarins. J. Nat. Prod. 2003, 66, 368–371.
26. Chilin, A.; Battistutta, R.; Bortolato, A.; Cozza, G.; Zanatta, S.; Poletto, G.; Mazzorana, M.; Zagotto, G.; Uriarte, E.; Guiotto, A.; Pinna, L. A.; Meggio, F.; Moro, S. Coumarin as attractive casein kinase 2 (CK2) inhibitor scaffold: an integrate approach to elucidate the putative binding motif and explain structure?activity relationships. J. Med. Chem. 2008, 51, 752–759.
27. Robert, S.; Bertolla, C.; Masereel, B.; Dogne, J.-M.; Pochet, L. Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. J. Med. Chem. 2008, 51, 3077–3080.
28. Gupte, A.; Boshoff, H. I.; Wilson, D. J.; Neres, J.; Labello, N. P.; Somu, R. V.; Xing, C.; Barry III, C. E.; Aldrich, C. C. Inhibition of siderophore biosynthesis by 2-triazole substituted analogues of 5'-O-[N-(Salicyl)sulfamoyl]adenosine: antibacterial nucleosides effective against Mycobacterium tuberculosis. J. Med. Chem. 2008, 51, 7495–7507.
29. Derudas, M.; Carta, D.; Brancale, A.; Vanpouille, C.; Lisco, A.; Margolis, L.; Balzarini, J.; McGuigan,C. The application of phosphoramidate protide technology to acyclovir confers Anti-HIV inhibition. J. Med. Chem. 2009, 52, 5520–5530.
30. Banala, A. K.; Levy, B. A.; Khatri, S. S.; Furman, C.A.; Roof, R. A.; Mishra, Y.; Griffin, S. A.; Sibley, D. R.; Luedtke, R. R.; Newman, A. H. N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity. J. Med. Chem. 2011, 54, 3581–3594.
31. Xue, C. B.; Voss, M. E.; Nelson, D. J.; Duan, J. J.-W.; Cherney, R. J.; Jacobson, I. C.; He, X.; Roderick, J.; Chen, L.; Corbett, R. L.; Wang, L.; Meyer, D. T.; Kennedy, M. K.; DeGrado, W. F.; Hardman, K. D.; Teleha, C. A.; Jaffee, B. D.; Liu, R. Q.; Copeland, R. A.; Covington, M. B.; Christ, D. D.; Trzaskos, J. M.; Newton, R. C.; Magolda, R. L.; Wexler, R. R.; Decicoo, C. P. Design, Synthesis, and Structure-Activity Relationships of Macrocyclic Hydroxamic Acids That Inhibit Tumor Necrosis Factor r Release in Vitro and in Vivo. J. Med. Chem. 2001, 44, 2636–2660.
32. Rodenko, B.; Detz, R. J.; Pinas, V. A.; Lambertucci, C.; Brun, R.; Wanner, M. J.; Koomen, G. J. Solid phase synthesis and antiprotozoal evaluation of di- and trisubstituted 5'-carboxamidoadenosine analogues. Bioorg. Med. Chem. 2006, 14, 1618–1629.
33. Golisade, A. G.; Wiesner, J.; Herforth, C.; Jomaa, H.; Link, A. Anti-malarial activity of N6-substituted adenosine derivatives. Part I Bioorg. Med. Chem. 2002, 10, 769–777.
34. Kim, Y. A.; Sharon, A.; Chu, C. K.; Rais, R. H.; Al Safarjalani, O. N.; Naguib, F. N. M.; Kouni, M. H. Synthesis, biological evaluation and molecular modeling studies of N6-benzyladenosine analogues as potential anti-toxoplasma agents. Biochem. Pharmacol. 2007, 73, 1558–1572.
35. Chimenti, F.; Secci, D.; Bolasco, A.; Chimenti, P.; Bizzarri, B.; Granese, A.; Carradori, S.; Yáñez, M.; Orallo, F.; Ortuso, F.; Alcaro, S. Synthesis, molecular modeling, and selective inhibitory activity against human monoamine of 3-carboxamido-7-substituted coumarins. J. Med. Chem. 2009, 52, 1935–1942.
36. Fisher, M. G.; Gale, P. A.; Light, M. E. A simple benzimidazole-based receptor for barbiturate and urea neutral guests that functions in polar solvent mixtures. New. J. Chem. 2007, 31. 1583–1584.
37. Lin, C; Kwong, A. D.; Perni, R. B. Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3‧4A serine protease. Infectious Disorders-Drug Targ. 2006, 6, 3-16
38. Folmer, F. Finding NEMO (inhibitors) the search for marine pharmacophores targeting the nuclear factor-κB. chimica oggi-Chemistry Today 2008, 26, 40–46.
39. Lesk, M.lntroduction to Protein Science, 2nd.; Oxford University; U.S.A., 2010; p 213.
40. Zhou, X.; Wang, X. B.; Wang, T.; Kong, L. Y. Design, synthesis, and acetylcholinesterase inhibitory activity of novel coumarin analogues. Bioorg. Med. Chem. 2008, 16, 8011–8021.
41. Kaloudis, P.; Paris, C.; Vrantza, D.; Encinas, S.; Prez-Ruiz, R.; Miranda, M. A.; Gimisis, T. Photolabile N-hydroxypyrid-2(1H)-one derivatives of guanine nucleosides: a new method for independent guanine radical generation. Org. Biomol. Chem. 2009, 7, 4965–4972.
42. Choi, J. -Y. and Guengerich, F. P. Analysis of the effect of bulk at N2-alkylguanine DNA adducts on catalytic efficiency and fidelity of the processive DNA polymerases bacteriophage T7 exonuclease and HIV-1 reverse transcriptase. J. Biol. Chem. 2004, 18, 19217–19229.
43. Bookser, B. C.; Ugarkar, B. G.; Matelich, M. C.; Lemus, R. H.; Allan, M.; Tsuchiya, M.; Nakane, M.; Nakahisa, A.; Wiesner, J. B.; Erion, M. D. Adenosine kinase inhibitors. 6. synthesis, water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-?-D-
ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides and related compounds. J. Med. Chem. 2005, 48, 7808–7820.
44. Kaye, P. T. and Musa, M. A. Efficient and chemoselective access to 3-(chloromethyl)coumarins via direct cyclisation of unprotected Baylis–Hillman adducts. Synthesis, 2002, 4, 2701–2706.
45. Kaye, P. T.; Musa, M. A.; Nocanda, X. W. A convenient and improved Baylis–Hillman synthesis of 3-substututed 2H-1-benzopyran-2-ones. Synthesis 2003, 18, 531–534.
46. Majumdar, K. C.; Ansary, I.; Sinha, B.; Chattopadhyay, B. Palladium(0)-catalyzed intramolecular heck reaction: a resourceful route for the synthesis of naphthoxepine and naphthoxocine derivatives. Synthesis 2009, 21, 3593–3602.
47. Beigelman, L.; Haeberli, P.; Sweedler, D.; Karpeisky, A. Improved synthetic approaches toward 2'-O-Methyl-Adenosine and guanosine and their N-acyl derivatives. Tetrahedron 2000, 56, 1047–1056.
48. Nakanishi, K. and Solomon, P. H. Infrared Absorption Spectroscopy, 2nd ed.; Holden-Day: Oakland, CA, 1977; p 38.
49. Qian, M. and Glaser, R. Demonstration of an alternative mechanism for G-to-G cross-link formation. J. Am. Chem. Soc. 2005, 127, 880–887.
50. Johnson, F. and Huang, Y. Regioselective 1-alkylation of 2'-deoxyguanosine. Nucleos. Nucleot. Nucl. 2002, 21, 435–447.
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