當今醫療科技最發達的美國，每年統計有超過十萬人死於感染 C 型肝炎（Hepatitis C Virus, HCV），直到今天，對於 C 型肝炎的治療並無疫苗和標靶藥物，唯一的治療方式為單獨使用長效型干擾素-α 或合併廣效性抗病毒藥物雷巴威林（ribavirin）的合併療法，但是此治療方式具有嚴重的副作用並且成效有限；此外，與C 型肝炎同屬於黃病毒科（Flaviviridae）的登革熱病毒（Dengue virus），同樣造成全球性的疫情，在熱帶與亞熱帶國家尤其嚴重，並且也尚無有效的治療藥物及疫苗，因此發展出強效的抗黃病毒科病毒藥物是目前非常重要的課題。
　　「二核苷多磷酸」（dinucleoside polyphosphates）化合物不僅是存在於人體的天然物結構，目前也有研究將其應用在抗病毒的前驅藥物，是全球最新穎的抗病毒結構之一，相較於以往的核苷類似物（nucleoside analogues）具有更低的毒性以及更好的專一性。在本論文中，本人將具有抗 C 型肝炎病毒活性的「香豆素共軛腺苷」（adenosine–coumarin conjugates）化合物進行耦合，合成出「雙香豆素共軛腺苷焦磷酸」（bis(adenosine–coumarin) pyrophosphates）化合物，並以氫譜、碳譜以及高解析度質譜佐證其結構。接著探討這一類新型化合物是否能夠如預期的在無顯著細胞毒性下，對於抑制C 型肝炎病毒，甚至是登革熱等黃病毒科之病毒，都能呈現出更好的專一性及活性。

In the U.S., a country with supreme advanced pharmaceutical and medical technologies, more than 100,000 patients die annually, which is attributed to hepatitis C. The search for effective vaccine is not yet available and therapeutic options are still limited. Use of pegylated interferon-α alone or its combination with ribavirin is the only treatment option available nowadays. Unfortunately, the treatment is associated with serious adverse effects, and its efficacy is limited. Besides, Dengue virus, categorized in the same family (Flaviviridae) with HCV, has caused severe worldwide epidemic, especially in tropical and subtropical area. So far, there is no effective cure to Flaviviridae-related diseases, thus it is urgent for development of potent anti-Flaviviridae compounds.
　　Dinucleoside polyphosphates derivatives are abundant in life systems, and recently, these polyphosphates are used as prodrugs and the most novel anti-viral structure of the world. Compared with previous nucleoside analogues, dinucleoside polyphosphates have lower toxicity to normal cells and higher specificity to the viruses. In this thesis, a series of bis(adenosine–coumarin) pyrophosphates were synthesized by coupling of adenosine–coumarin conjugates. All the structures were confirmed by analysis of 1H NMR, 13C NMR, and high resolution mass spectroscopy. The cell viability and antiviral activity of synthesized bis(adenosine–coumarin) pyrophosphates will be further evaluated to confirm their low toxicity to normal cells and specific lethal effect to HCV, even other viruses of Flaviviridae.

中 文 摘 要 i
Abstract iii
謝 誌 v
目 錄 vi
圖 目 錄 xiv
表 目 錄 xvi
縮 寫 對 照 表 xvii
一、緒 論（Introduction） 1
二、結 果（Results） 22
2-1 合成香豆素共軛腺苷酸化合物（7a–d） 22
2-2 鑑定香豆素共軛腺苷酸化合物（7a–d） 23
2-3 製備耦合試劑（11） 25
2-4 合成雙香豆素共軛腺苷焦磷酸化合物（12c–d） 26
2-5 鑑定雙香豆素共軛腺苷焦磷酸化合物（12c–d） 27
2-6 磷酸化反應中加入水量影響產率之最佳化條件 30
2-7 嘗試不同條件將香豆素共軛鳥苷化合物（20）進行磷酸化反應 31
2-8 使用不同耦合試劑與產率之關係 34
2-9 利用UV-Vis 測定化合物 7a–d 與化合物 12d 之水脂溶性 35
三、討 論（Discussion） 39
3-1 磷酸化反應中加入水量影響產率之探討 39
3-2 香豆素共軛腺苷酸化合物（7a–d）質譜分析探討 41
3-3 香豆素位置與磷酸化反應性之探討 42
3-4 耦合試劑之反應性探討 44
3-5 雙香豆素共軛腺苷焦磷酸化合物（12c–d）質譜分析探討 47
3-6 雙香豆素共軛腺苷焦磷酸化合物（12a–d）未來的應用性探討 48
3-7 利用分子模擬預測化合物 5、6d、7d及12d 之構形 50
3-8 雙香豆素共軛腺苷焦磷酸化合物純化問題之探討 53
四、結 論 （Conclusions） 54
五、實 驗 部 分（Experimental Section） 56
Disodium 6-(6'-Chlorocoumarin-3'-yl)methylthio-9-
(β-D-ribofuranos-1''- yl)purine-5''-monophosphate (7a). 58
Disodium 6-(6'-Bromocoumarin-3'-yl)methylthio-9-
(β-D-ribofuranos-1''- yl)purine-5''-monophosphate (7b). 59
Disodium 6-(6'-Methylcoumarin-3'-yl)methylthio-9-
(β-D-ribofuranos-1''- yl)purine-5''-monophosphate (7c). 60
Disodium 6-(6'-Methoxycoumarin-3'-yl)methylthio-9-
(β-D-ribofuranos-1''- yl)purine-5''-monophosphate (7d). 61
P1,P2-Bis-6-(6'-methylcoumarin-3'-yl)methylthio-9-
(β-D-ribofuranos-1''- yl)purine-5''-diphosphate (12c). 62
P1,P2-Bis-6-(6'-methoxycoumarin-3'-yl)methylthio-9-
(β-D-ribofuranos-1''- yl)purine-5''-diphosphate (12d). 63
Water Solubility. 63
Partition Coefficient. 64
六、參 考 文 獻（Reference） 65
七、光 譜 74
1H NMR spectrum of disodium 6-(6'-chlorocoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7a) 76
13C NMR spectrum of disodium 6-(6'-chlorocoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7a) 76
Mass spectrum of disodium 6-(6'-chlorocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7a) 77
IR spectrum of disodium 6-(6'-chlorocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7a) 77
HPLC spectrum of disodium 6-(6'-chlorocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7a) 78
UV spectrum of disodium 6-(6'-chlorocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7a) 78
1H NMR spectrum of disodium 6-(6'-bromocoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7b) 79
13C NMR spectrum of disodium 6-(6'-bromocoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7b) 79
Mass spectrum of disodium 6-(6'-bromocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7b) 80
IR spectrum of disodium 6-(6'-bromocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7b) 80
HPLC spectrum of disodium 6-(6'-bromocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7b) 81
UV spectrum of disodium 6-(6'-bromocoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7b) 81
1H NMR spectrum of disodium 6-(6'-methylcoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7c) 82
13C NMR spectrum of disodium 6-(6'-methylcoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7c) 82
Mass spectrum of disodium 6-(6'-methylcoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7c) 83
IR spectrum of disodium 6-(6'-methylcoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7c) 83
HPLC spectrum of disodium 6-(6'-methylcoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7c) 84
UV spectrum of disodium 6-(6'-methylcoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7c) 84
1H NMR spectrum of disodium 6-(6'-methoxycoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7d) 85
13C NMR spectrum of disodium 6-(6'-methoxycoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7d) 85
Mass spectrum of disodium 6-(6'-methoxycoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7d) 86
IR spectrum of disodium 6-(6'-methoxycoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7d) 86
HPLC spectrum of disodium 6-(6'-methoxycoumarin-3'-
yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-
monophosphate (7d) 87
UV spectrum of disodium 6-(6'-methoxycoumarin-3'-yl)methylthio- 9-(β-D-ribofuranos-1''-yl)purine-5''-monophosphate (7d) 87
1H NMR spectrum of P1,P2-bis-6-(6'-methylcoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12c) 88
Mass spectrum of P1,P2-bis-6-(6'-methylcoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12c) 88
IR spectrum of P1,P2-bis-6-(6'-methylcoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12c) 89
HPLC spectrum of P1,P2-bis-6-(6'-methylcoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12c) 89
UV spectrum of P1,P2-bis-6-(6'-methylcoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12c) 90
1H NMR spectrum of P1,P2-bis-6-(6'-methoxycoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12d) 90
13C NMR spectrum of P1,P2-bis-6-(6'-methoxycoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12d) 91
Mass spectrum of P1,P2-bis-6-(6'-methoxycoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12d) 91
IR spectrum of P1,P2-bis-6-(6'-methoxycoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12d) 92
HPLC spectrum of P1,P2-bis-6-(6'-methoxycoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12d) 92
UV spectrum of P1,P2-bis-6-(6'-methoxycoumarin-3'- yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine-5''-
diphosphate (12d) 93

1. (a) Lauer, G. M.; Walker, B. D. Hepatitis C virus infection. N. Engl. J. Med. 2001, 345, 41–52. (b) Huang, Z.; Murray, M. G.; Secrist, J. A. III. Recent development of therapeutics for chronic HCV infection. Antiviral Res. 2006, 71, 351–362.
2. (a) Roingeard, P.; Hourioux, C. Hepatitis C virus core protein, lipid droplets and steatosis. J. Viral Hepat. 2008, 15, 157–164. (b) Deutsch, M.; Hadziyannis, S. J. Old and emerging therapies in chronic hepatitis C: an update. J. Viral Hepat. 2008, 15, 2–11.
3. (a) De Francesco, R.; Tomei, L.; Altamura, S.; Summa, V.; Migliaccio, G. Approaching a new era for hepatitis C virus therapy: inhibitors of the NS3-4A serine protease and the NS5B RNA-dependent RNA polymerase. Antiviral Res. 2003, 58, 1–16. (b) Sklan, E. H.; Charuworn, P.; Pang, P. S.; Glenn, J. S. Mechanisms of HCV survival in the host. Nat. Rev. Gastroenterol. Hepatol. 2009, 6, 217–277.
4. Pawlotsky, J. M.; Gish, R. G. Future therapies for hepatitis C. Antivir. Ther. 2006, 11, 397–408.
5. 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.
6. Driesel, G.; Wirth, D.; Stark, K.; Baumgarten, R.; Sucker, U.; Schreier, E. Hepatitis C virus (HCV) genotype distribution in German isolates: studies on the sequence variability in the E2 and NS5 region. Arch. Virol. 1994, 139, 379–388.
7. Thomas, B.; Uwe, H.; Klaus, S.; Renate, B.; Hartmut, L.; Eckart, S. Distribution of hepatitis C virus genotypes in German patients with chronic hepatitis C: correlation with clinical and virological parameters. J. Hepatol. 1997, 26, 484–491.
8. Hoofnagle, J. H. Course and outcome of hepatitis C. J. Hepatol. 2002, 36, 21–29.
9. Simmonds, P. Genetic diversity and evolution of hepatitis C virus – 15 years on. J. Gen. Virol. 2004, 85, 3173–3188.
10. 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. J. Hepatol. 2005, 42, 962–973.
11. 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.
12. Di Bisceglie, A. M.; Hoofnagle, J. H. Optimal therapy of hepatitis C. J. Hepatol. 2002, 36, S121–S127.
13. Zein, N. N. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J. Hepatol. 2005, 42, 315–322.
14. Bretner, M. Existing and future therapeutic options for hepatitis C virus infection. Acta Biochim. Pol. 2005, 52, 57–70.
15. Manns, M. P.; Foster, G. R.; Rockstroh, J. K.; Zeuzem, S.; Zoulim, F.; Houghton, M. The way forward in HCV treatment – finding the right path. Nat. Rev. Drug Disc. 2007, 6, 991–1000.
16. Moradpour, D.; Penin, F.; Rice, C. M. Replication of hepatitis C virus. Nat. Rev. Microb. 2007, 5, 453–463.
17. Sklan, E. H.; Charuworn, P.; Pang, P. S.; Glenn, J. S. Mechanisms of HCV survival in the host. Nat. Rev. Gastroenterol. Hepatol. 2009, 6, 217–277.
18. Bartenschlager, R. Cytokines and hepatitis C virus replication. Nat. Rev. Drug Disc. 2002, 1, 911–916.
19. Bartenschlager, R.; Cosset F. L.; Lohmann, V. Hepatitis C virus replication cycle. J. Hepatol. 2010, 53, 583–585.
20. Hafsa, A.; Abida, R.; Shahnaz, M.; Yasir, W.; Ali, K.; Javaid, I.; Zahoor, S.; Muhammad, A. Molecular epidemiology of hepatitis C virus genotypes in different geographical regions of Punjab Province in Pakistan and a phylogenetic analysis. Int. J. Infect. Dis. 2013, 17, 247–253.
21. Hiroshi, K.; Kazuhito, Y.; Shin, O.; Kazuhiko, K.; Tatsuhiko, K. RNA-dependent RNA polymerase of hepatitis C virus binds to its coding region RNA stem–loop structure, 5BSL3.2, and its negative strand. J. Gen. Virol. 2010, 91, 1207–1212.
22. Jenny, G. L.; Cynthia, S.; Limin, W.; Yuan, W.; Abhay P. S.; Rathore, S. W.; Boon, H. T.; Liying, T.; Lian, T. C.; Yan’an, H.; Angelia, C.; Shiqin, H.; Wing, K. C.; Kah, H. T.; Jasmine, S. C.; Benjamin, P. C.; David, C. L.; Paul, A. Yee, S. L.; Yin, B. C.; Eng, E O.; Subhash, G. V. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infect Dis. 2014, 14, 70730–70733.
23. Xiaowu, P.; Yinhan, G.; Yanfei, Z.; Wenchuan, F.; Xinbin, G. Highly efficient production of a dengue pseudoinfectious virus. Vaccine 2014, 32, 3854–3860.
24. Usa, T.; Chule, T. Latest developments and future directions in dengue vaccines. Ther. Adv. Vaccines 2014, 2(1), 3-9.
25. Kleber, F.; Paula, Machado.; Renato, J.; Ana, A.; Benedito, F. Chloroquine interferes with dengue-2 virus replication in U937 cells. Microbiol Immunol 2014, 58, 318–326
26. Onda, A. Y.; Miyagi, K.; Takahara, H.; Kawai-Yamada, M. Effects of NAD kinase 2 overexpression on primary metabolite profiles in rice leaves under elevated carbon dioxide. Plant Biology 2014, 16, 819–824.
27. Franchetti, P.; Cappellacci, L.; Pasqualini, M.; Grifantini, M.; Lorenzi, T.; Raffaelli, N.; Magni, G. Dinucleoside polyphosphate NAD analogs as potential NMN adenylyltransferase inhibitors. Synthesis and biological evaluation. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 865–868.
28. Hoyle, C. V.; Pintor, J. J. Diadenosine tetraphosphate protects sympathetic terminals from 6-hydroxydopamine-induced degeneration in the eye. Acta Physiol. 2010, 199, 205–210.
29. Vera, R.; Joachim, J.; Hartmut, S. Structure-activity relationships of diadenosine polyphosphates (ApnAs), adenosine polyphospho guanosines (ApnGs) and guanosine polyphospho guanosines (GpnGs) at P2 receptors in the rat mesenteric arterial bed. Br. J. Pharmacol. 2001, 134, 1073–1083.
30. Nicholas A. F.; Brigitte, M.; Stavrou, D. J. The effects of diadenosine polyphosphates on the cardiovascular system. Cardiovasc. Res. 1999, 42, 15–26.
31. Peter, R.; Meyer, A. J.; Smith, S. E.; Walter, A. Chain-Terminating Dinucleoside Tetraphosphates are Substrates for DNA Polymerization by Human Immunodeficiency Virus Type 1 Reverse Transcriptase with Increased Activity against Thymidine Analogue-Resistant Mutants. Antimicrob. Agents Chemother. 2006, 50, 3607–3614.
32. Marjan, A.; Francesca, C.; Christakis, P.; Anna, K.; Nicola, S. The human adenylate kinase 9 is a nucleoside monoand diphosphate kinase. Biochem. Cell Biol. 2013, 45, 925–931.
33. Christopher, M.; Claire, B.; Marco, D.; Nadège, H.; Karen, H.; Sahar, K.; Karolina, M.; Silvia, M.; Fabrizio, P.; Magdalena, S.; Stanley, C.; Alexander, K.; John, V.; Christophe, V.; Andrea, I.; Leonid, M.; Jan, B. Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides. Eur. J. Med. Chem. 2013, 70, 326–340.
34. Steven, J. C.; Ethel, C.; Franck, A.; Maryam, E.; Sheida, A.; Hongwang, Z.; Longhu, Z.; Sebastien, R. L.; Xiao, L.; Lavanya, B.; Jadd, R. S.; Hao, L.; Peng, L.; Chengwei, L.; Jong-Hyun, C, Satish, N. C.; Shaoman, Z.; Judy, M.; Raymond, F. Chutes and ladders in hepatitis C nucleoside drug development. Antiviral Res. 2014, 102, 119–147.
35. De Clercq, E. The design of drugs for HIV and HCV. Nat. Rev. Drug Disc. 2007, 6, 1001–1018.
36. De Francesco, 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 Delivery Rev. 2007, 59, 1242–1262.
37. Galeone, A.; Mayol, L.; Oliviero, G.; Piccialli, G.; Varra, M. Synthesis of a new N1-pentyl analogue of cyclic inosine diphosphate ribose (cIDPR) as a stable potential mimic of cyclic ADP ribose (cADPR). Eur. J. Org. Chem. 2002, 24, 4234–4238.
38. Kalyan, D.; Eddy, A. HIV-1 reverse transcriptase and antiviral drug resistance. Part 1. Curr Opin Virol. 2013, 3, 111–118.
39. Steven, J. C.; Ethel, C.; Franck, A.; Maryam, E.; Sheida, A.; Hongwang, Z.; Longhu, Z.; Sebastien, R. L.; Xiao, L.; Lavanya, B.; Jadd, R. S.; Hao, L.; Peng, L.; Chengwei, L.; Jong-Hyun, C, Satish, N. C.; Shaoman, Z.; Judy, M.; Raymond, F. Chutes and ladders in hepatitis C nucleoside drug development. Antiviral Res. 2014, 102, 119–147.
40. Christal D.; Sohl, R.; Kasiviswanathan, J.; Ugo, P.; Raymond, F.; Schinazi, C.; Copeland, M.; Masanori, B.; Karen, S. Balancing Antiviral Potency and Host Toxicity: Identifying a Nucleotide Inhibitor with an Optimal Kinetic Phenotype for HIV-1 Reverse Transcriptase. Mol. Pharmacol. 2012, 82, 125–133.
41. Rossi, L.; Serafini1, S.; Franchetti, P.; Cappellacci, L.; Fraternale1, A.; Casabianca1, A.; Brandi, G.; Pierigé, F.; Perno, E.; Balestra, U.; Benatti, E.; Millo, M.; Grifantini M. Targeting Nucleotide Dimers Containing Antiviral Nucleosides. Curr. Med. Chem.: Anti-Infect. Agents 2005, 4, 37–54.
42. Pingzu, J.; Weiwei, X.; Yulin, S.; Nengzhi, J.; Huanxiang, L. Understanding the drug resistance mechanism of hepatitis C virus NS5B to PF-00868554 due to mutations of the 423 site: a computational study. Mol. BioSyst. 2014, 10, 767–777.
43. Isabel, N. Resistance to HCV nucleoside analogue inhibitors of hepatitis C virus RNA-dependent RNA polymerase. ScienceDirect 2013, 3, 508–513.
44. Jeremie, G.; Harel, D.; Emi, S.; Patrick, S.; Alan, S. Hepatitis C Viral Kinetics with the Nucleoside Polymerase Inhibitor Mericitabine (RG7128). J. Hepatol. 2012, 55, 1030–0137.
45. Peter, R.; Suaznne, E.; Matsuura, A. G.; Walter, A. S. Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Biochemistry 1998, 95, 13471–13476.
46. Zhinan, J.; Vincent, L.; Han, M.; Kenneth, A.; Klaus, K. NTP-mediated nucleotide excision activity of hepatitis C virus RNA-dependent RNA polymerase. Pans. Org. 2012, 110, 348–357.
47. Rossi, L.; Serafini1, S.; Franchetti, P.; Cappellacci, L.; Fraternale1, A.; Casabianca1, A.; Brandi, G.; Pierigé, F.; Perno, E.; Balestra, U.; Benatti, E.; Millo, M.; Grifantini M. Targeting Nucleotide Dimers Containing Antiviral Nucleosides. Curr. Med. Chem.: Anti-Infect. Agents 2005, 4, 37–54.
48. Peter, R.; Walter, A. Dinucleoside Polyphosphate Inhibitors of Reverse Transcriptase. World Intellectual Property Organization 2006, 133375 A2.
49. Shirokova, A.; Khandazhinskaya, L.; Skoblov, S.; Goryunova, Y.; Beabealashvilli, S.; Krayevsky, A. Modified Dinucleoside Tetraphosphonates, New Potential Inhibitors of HIV Reverse Transcriptase. Nucleosides, Nucleotides Nucleic Acids 2001 , 20, 1033–1036.
50. Benjamin, A.; Jingyang, W. Dinucletide Compound for HCV Infection. World Intellectual Property Organization 2013, 063019 A1.
51. Congrong, N.; Tatiana, T.; Haiying, B.; Yeojin, P.; Darius, B.; Angela, M. L.; Shalini, B.; Jinfa, D.; Wonsuk, C.; Ganapati, R.; Hai-Ren, Z.; Joseph, W.; Li-Quan, W.; Piyun, C.; Adrian, S. R.; Michael, J.; Phillip, A.; Eisuke, M. Metabolic Activation of the Anti-Hepatitis C Virus Nucleotide Prodrug PSI-352938. Antimicrob. Agents Chemother. 2012, 56(7), 3767–3775.
52. Boris, S. E.; Ekaterina, V. E.; Cyrill, S.; Sergey, N.; Balzarini, J.; Erik, D. Nucleic Acids. 111. Antiwiral Activity of Nucleotides and Dinucleoside Phosphates Containing ara-Cytidine. Nucleic Acid Chem. 1967, 10, 777–782.
53. Kaye, P. T.; Musa, M. A. A convenient and improved Baylis–Hillman synthesis of 3-substituted 2H-1-benzopyran-2-ones. Synthesis 2002, 18, 2701–2706.
54. Lee, K. J. A New Synthesis of Methyl 7H-Dibenz[b,g]oxocin-6-carboxylates from Morita-Baylis-Hillman Adducts of 2-Phenoxybenzaldehydes. Synthesis 2011, 3, 377–386.
55. Hwu, Jih Ru; Lin, Shu-Yu; Tsay, Shwu-Chen; Singha, Raghunath; Pal, Benoy Kumar; Leyssen, Pieter; Neyts, Johan. Development of New Sulfur-Containing Conjugated Compounds as Anti-HCV Agents. Phosphorus, Sulfur Silicon Relat. Elem. 2011, 186, 1144–1152.
56. Tomomi, I.; Akira, H.; Hiroyuki, H.; Yoshifumi, K.; Masato, I.; Kiyoshi, N. Phosphorylation of Nucleosides with Phosphorus Oxychloride in Trialkyl Phosphate. Chem. Pharm. Bull. 1995, 43(2), 210–215.
57. Svenja, W.; Chris, M. New and efficient Synthesis of Nucleoside Polyphosphates and Nucleoside Monophosphate Sugars. Nucleic Acids Symp. Ser. 2008, 52, 583–584.
58. Timothy, W.; Abraham, T. I.; Kalman, E. J.; Carston R. W. Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-Fluoro-2'-deoxyuridine and 1-β-Arabinofuranosylcytosine: Evidence of Phosphoramidase Activity. J. Med. Chem. 1996, 39, 4569–4575.
59. Samy, M.; Ahmed, D.; Scott, D. T. Sulfonyl Imidazolium Salts as Reagents for the Rapid and Efficient Synthesis of Nucleoside Polyphosphates and Their Conjugates. Org. Lett. 2012, 14, 402–405.
60. Samy, M.; Ahmed, D.; Scott, D. T. Rapid and efficient synthesis of nucleoside polyphosphates and their conjugates using sulfonyl imidazolium salts. Curr. Protoc. Nucleic Acid Chem. 2012, 13, 1101–1124.
61. Scozzafava, A.; Menabuoni, L.; Mincione, F.; Supuran, C. T. Carbonic anhydrase inhibitors. A general approach for the preparation of water-soluble sulfonamides incorporating polyamino-polycarboxylate tails and of their metal complexes possessing long-lasting, topical intraocular pressure-lowering properties. J. Med. Chem. 2002, 45, 14661476.
62. Kraszni, M.; Banyai, I.; Noszal, B. Determination of conformer-specific partition coefficients in octanol/water systems. J. Med. Chem. 2003, 46, 22412245.
63. Hoyle, V.; Pintor, J. J. Diadenosine tetraphosphate protects sympathetic terminalsfrom 6-hydroxydopamine-induced degeneration in the eye. Acta Physiol. Scand. 2010, 199, 205–210.
64. Cheson, B. D.; Levine, A. M.; Mildvan, D.; Kaplan, L. D.; Wolfe, P.; Rios, A.; Groopman, J. E.; Gill, P.; Volberding, P. A.; Poiesz, B. J.; Gottlieb, M. S.; Holden, H.; Volsky, D. J.; Silver, S. S.; Hawkins, M. J. Suramin Therapy in Aids and Related Disorders - Report of the United-States-Suramin-Working-Group. JAMA, J. Am. Med. Assoc. 1987, 258, 13471351.
65. Nakata, H. Mitogen-activated protein kinase signaling is involved in suramin-induced neurite outgrowth in a neuronal cell line. Biochem. Biophys. Res. Commun. 2007, 355, 842848.
66. Kaur, M.; Reed, E.; Sartor, O.; Dahut, W.; Figg, W. D. Suramin's development: What did we learn? Invest. New Drugs 2002, 20, 209219.