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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民 | |
| dc.contributor.author | Pei-Shan Lee | en |
| dc.contributor.author | 李佩珊 | zh_TW |
| dc.date.accessioned | 2021-06-16T23:42:45Z | - |
| dc.date.available | 2017-07-31 | |
| dc.date.copyright | 2012-07-31 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-07-24 | |
| dc.identifier.citation | 1. Lowen, A. C.; Palese, P. Infect. Disord. Drug Targets 2007, 7, 318–328. Influenza virus transmission: basic science and implications for the use of antiviral drugs during a pandemic.
2. Suzuki, Y. Biol. Pharm. Bull. 2005, 28, 399–408. Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses. 3. Preziosi, P. Expert Opin. Pharmacother. 2011, 12, 1523–1549. Influenza pharmacotherapy: present situation, strategies and hopes. 4. von Itzstein, M. Nat. Rev. Drug Discov. 2007, 6, 967–974. The war against influenza: discovery and development of sialidase inhibitors. 5. Wilson, I. A.; Skehel, J. J.; Wiley, D. C. Nature 1981, 289, 366–373. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 [Å] resolution. 6. (a) Skehel, J. J.; Wiley, D. C. Annu. Rev. Biochem. 2000, 69, 531–69. Receptor binding and membrane fusion in virus entry : the influenza hemagglutinin. (b) Neumann, G.; Noda, T.; Kawaoka, Y. Nature 2009, 459, 931–939. Emergence and pandemic potential of swine-origin H1N1 influenza virus. 7. Rogers, G. N.; Paulson, J. C.; Daniels, R. S.; Skehel, J. J.; Wilson, I. A.; Wiley, D. C. Nature 1983, 304, 76–78. Single amino acid substitutions influenza haemagglutinin change receptor binding specificity. 8. Matrosovich, M. N.; Matrosovich, T. Y.; Gray, T.; Roberts, N. A.; Klenk, H. D. Proc. Natl. Acad. Sci. U.S.A 2004, 101, 4620–4624. Human and avian influenza viruses target different cell types in cultures of human airway epithelium. 9. Varghese, J. N.; Laver, W. G.; Colman, P. M. Nature 1983, 303, 35–40. Structure of the influenza virus, glycoprotein antigen neuraminidase at 2.9 Å resolution. 10. (a) Baker, A. T.; Varghese, J. N.; Laver, W. G.; Air, G. M.; Colman, P. M. Proteins Struct. Func. Genet. 1987, 2, 111–117. Three-dimensional structure of neuraminidase of subtype N9 from an avian influenza virus. (b) Russell, R. J.; Haire, L. F.; Stevens, D. J.; Collins, P. J.; Lin, Y. P.; Blackburn, G. M.; Hay, A. J.; Gamblin, S. J.; Skehel, J. J. Nature 2006, 443, 45–49. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. 11. Moscona, A. N. Engl. J. Med. 2005, 353, 1363–1373. Neuraminidase inhibitors for influenza. 12. Varghese, J. N.; McKimm-Breschkin, J. L.; Caldwell, J. B.; Kortt, A. A.; Colman, P. M. Proteins Struct. Func. Genet. 1992, 14, 327–332. The structure of the complex between influenza virus neuraminidase and sialic acid, the viral receptor. 13. Chong, A. K. J.; Pegg, M. S.; Taylor, N. R.; von Itzstein, M. Eur. J. Biochem. 1992, 207, 335–343. Evidence for a sialosyl cation transition-state complex in the reaction of sialidase from influenza virus. 14. Taylor, N. R.; von Itzstein, M. J. Med. Chem. 1994, 37, 616–624. Molecular modeling study on ligand binging to sialidase from influenza virus and the mechanism of catalysis. 15. Sugrue, R. J.; Hay, A. J. Virology 1991, 180, 617–624. Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel. 16. Schnell, J. R.; Chou, J. J. Nature 2008, 451, 591–595. Structure and mechanism of the M2 proton channel of influenza A virus. 17. Davis, W. L.; Grunert, R. R.; Haff, R. F.; McGahen, J. W.; Neumayer, E. M.; Paulshock, M.; Watts, J. C.; Wood, T. R.; Hermann, E. C.; Hoffmann, C. E. Sicence 1964, 144, 862–863. Antiviral activity of 1-adamantanamine (amantadine). 18. Whittaker, G. R. Expert. Rev. Molec. Med. 2001, 3, 1–13. Intracellular trafficking of influenza virus: clinical implications for molecular medicine. 19. De Clercq, E. Nat. Rev. Drug Discov. 2006, 5, 1015–1025. Antiviral agents active against influenza A viruses. 20. Bright, R. A.; Shay, D. K.; Shu, B.; Cox, N. J.; Klimov, A. I. J. Am. Med. Assoc. 2006, 295, 891–894. Amantadine resistance among influenza A viruses isolated early during the 2005－2006 influenza season in the United States. 21. Schnell, J. R.; Chou, J. J. Nature 2008, 451, 591–595. Structure and mechanism of the M2 proton channel of influenza A virus. 22. Stouffer, A. L.; Acharya, A.; Salom, D.; Levine, A. S.; Di Costanzo, L.; Soto1, C. S.; Tereshko, V.; Nanda, V.; Stayrook, S.; DeGrado, W. F. Nature 2008, 451, 596–599. Structural basis for the function and inhibition of an influenza virus proton channel. 23. (a) Kozakov, D.; Chuang, G. Y.; Begloc, D.; Vajda, S. Trends Biochem.Sci. 2010, 35, 471–475. Where does amantadine bind to the influenza virus M2 proton channel? (b) Pielak, R. M.; Schnell, J. R.; Chou, J. J. Proc. Nat. Acad. Sci. U. S. A. 2009, 106, 7379–7384. Mechanism of drug inhibition and drug resistance of influenza A virus M2 channel. (c) Jing, X.; Ma, C.; Ohgashi, Y.; Oliveira, F. A.; Jardetzky, T. S.; Pinto, L. H.; Lamb, R. A. Proc. Nat. Acad. Sci. U. S. A. 2008, 105, 10967–10972. Fuctional studies indicated amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel. 24. Cady, S. D.; Schmidt-Rohr, K.; Wang, K.; Soto, C. S.; DeGrado, W. F.; Hong, M. Nature 2010, 463, 689–692. Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. 25. Pinto, L. H.; Lamb, R. A. Trends Microbiol. 1995, 3, 271. Understanding the mechanism of action of the anti-influenza virus drug amantadine. 26. Colman, P. M.; Varghese, J. N.; Laver, W. G. Nature 1983, 303, 41–44. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. 27. Meindl, P. M.; Bodo, G.; Palese, P.; Schulman, J.; Tuppy, H. Virology 1974, 58, 457–463. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. 28. Bossart-Whitaker, P.; Carson, M.; Babu, Y.S.; Smith, C. D.; Laver, W.G.; Air, G. M. J. Mol. Biol. 1993, 232, 1069–1083. Three-dimensional structure of influenza A N9 neuraminidase and its complex with inhibitor 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. 29. von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Olover, R. C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Nature 1983, 363, 418–423. Rational design of potent sialidase-based inhibitors of influenza virus replication. 30. Holzer, C. T.; von Itzstein, M.; Jin, B.; Pegg, M. S.; Stewaart, W. P.; Wu, W.-Y. Glycoconj. J. 1993, 10, 40–44. Inhibition of sialidases from viral, bacterial and mammalian sources by analogues of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid modified at C-4 position. 31. Woods, J. M.; Bethell, R. C.; Coates, J. A.; Healy, N.; Hiscox, S. A.; Pearson, B. A.; Ryan, D. M.; Ticehurst, J.; Tilling, J.; Walcott, S. M. Antimicrob. Agents Chemother. 1993, 37, 1473–1479. 4-guanidino-2,4-dehydro-2,3-dehydro-N- acetylneuraminic acid is ahighly effective inhibitor both of sialidase (neuraminidase) and of growth of a wide range of influenza A and B viruses in vitro. 32. (a) Dunn, C. J.; Goa, K. L. Drugs 1999, 57, 761－784. Zanamivir; A review of its use in influenza. (b) Elliott, M. Philos. Trams. Royal. Soc. B: Bio. Sci. 2011, 356, 1885–1893. Zanamivir: from drug design to the clinic. 33. Liu, Z.-y.; Wang, B.; Zhao, L.-x.; Li, Y. -h.; Shao, H. -y.; Yi, H.; You, X. -f.; Li, Z. -r. Bioorg. Med. Chem. Lett. 2007, 17, 4851–4854. Synthesis and anti-influenza activities of carboxyl alkoxyalkyl esters of 4-guanidino-Neu5Ac2en (zanamivir). 34. Honda, T.; Kubo, S.; Masuda, T.; Arai, M.; Kobayashi, Y.; Yamashita, M. Bioorg. Med. Chem. Lett. 2009, 19, 2938–2940. Synthesis and in vivo influenza virus-inhibitory effect of ester prodrug of 4-guanidino-7-O-methyl-Neu5Ac2en. 35. Kubo, S.; Tomozawa, T.; Kakuta, M.; Tokumitsu, A.; Yamashita, M. Antimicrob. Agents Chemother. 2010, 54, 1256–1264. Laninamivir prodrug CS-8958, a long acting neuraminidase inhibitor, shows superior anti-influenza virus activity after a single administration. 36. Ishizauka, H.; Yoshiba, S.; Okabe, H.; Yoshihara, K. J. Clin. Pharmacol. 2010, 50, 1319–1329. Clinical Pharmacokinetics of laninamivir, a novel long-acting neuraminidase inhibitor, after single and multiple inhaled doses of its prodrugs. 37. Mammen, M.; Choi, S.-k.; Whiteside, G. M. Angew. Chem. Int. Ed. 1998, 37, 2754–2794. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. 38. Murti, K. G.; Webster, R. G. Virology 1986, 149, 36–43. Distribution of hemagglutinin and neuraminidase on influenza virions as revealed by immunoelectron microscopy. 39. Watson, K. G.; Cameron, R.; Fenton, R. J.; Gower, D.; Hamilton, S.; Jin, B.; Krippner, G. Y.; Luttick, A.; McConnell, D.; MacDonald, S. J. F.; Mason, A. M.; Nguyen, V.; Tucker, S. P.; Wu, W.-Y. Bioorg. Med. Chem. Lett. 2004, 14, 1589–1592. Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase. 40. MacDonald, S. J. F.; Watson, K. G.; Cameron, R.; Chalmers, D. K.; Demaine, D. A.; Fenton, R. J.; Gower, D.; Hamblin, J. N.; Hamilton, S.; Hart, G. J.; Inglis, G. G. A.; Jin, B.; Jones, H. T.; McConnell, D. B.; Mason, A. M.; Nguyen, V.; Owens, I. J.; Parry, N.; Reece, P. A.; Shanahan, S. E.; Smith, D.; Wu, W.-Y.; Tucker, S. P. Antimicrob. Agents Chemother. 2004, 48, 4542–4549. Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a once-weekly dosing regimen. 41. MacDonald, S. J. F.; Cameron, R.; Demaine, D. A.; Fenton, R. J.; Foster, G.; Gower, D.; Hamblin, J. N.; Hamilton, S.; Hart, G. J.; Hill, A. P.; Inglis, G. G. A.; Jin, B.; Jones, H. T.; McConnell, D. B.; McKimm-Breschkin, J.; Mills, G.; Nguyen, N.; Owens, I. J.; Parry, N.; Shanahan, S. E.; Smith, D.; Watson, K. G.; Wu, W.-Y.; Tucker, S. P. J. Med. Chem. 2005, 48, 2964–2971. Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. 42. Kim, C. U.; Lew, W.; Williams, M. A.; Liu, H.; Zhang, L.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Mendel, D. B.; Tai, C. Y.; Laver, W. G.; Stevens, R. C. J. Am. Chem. Soc. 1997, 119, 681–690. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. 43. Kim, C. U.; Lew, W.; Williams, M. A.; Wu, H.; Zhang, L.; Chen, X.; Escarpe, P. A.; Mendel, D. B.; Laver, W. G.; Stevens, R. C. J. Med. Chem. 1998, 41, 2451–2460. Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors. 44. (a) Li, W.; Escarpe, P. A.; Eisenberg, E. J.; Cundy, K. C.; Sweet, C.; Jakeman, K. J.; Merson, J.; Lew, W.; Williams, M.; Zhang, L.; Kim, C. U.; Bischofberger, N.; Chen, M. S.; Mendel, D. B. Antimicrob. Agents Chemother. 1998, 42, 647–653. Identification of GS-4104 as an orally bioavailable prodrug of influenza virus neuraminidase inhibitor GS-4071. (b) Sidwell, R. W.; Huffman, J. H.; Barnard, D. L.; Bailey, K. W.; Wong, M. H.; Morrison, A.; Syndergaard, T.; Kim, C. U. Antiviral Res.1998, 37, 107–120. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. 45. Sweeny, D. J.; Lynch, G.; Bidgood, A. M.; Lew, W.; Wang, K. Y.; Cundy, K. C. Drug Metab. Dispos. 2000, 28, 737–741. Metabolism of the influenza neuraminidase inhibitor prodrug oseltamivir in the rat. 46. Yamamoto, T.; Kumazawa, H.; Inami, K.; Teshima, T.; Shiba, T. Tetrahedron Lett. 1992, 33, 5791–5794. Syntheses of sialic acid isomers with inhibitory activity against neuraminidase. 47. Babu, Y. S.; Chand, P.; Bantia, S.; Kotian, P.; Dehghani, A.; El-Kattan, Y.; Lin, T. -H.; Hutchison, T. L.; Elliott, A. J.; Parker, C. D.; Ananth, S. L.; Horn, L. L.; Laver, G. W.; Montgomery, J. A. J. Med. Chem. 2000, 43, 3482–3486. BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. 48. Bantia, S.; Parker, C. D.; Ananth, S. L.; Horn, L. L.; Andries, K.; Chand, P.; Kotian, P. L.; Dehghan, A.; El-Kattan, Y.; Lin, T.; Hutchison, T. L.; Montgomery, J. A.; Kellog, D. L.; BaBu, Y. S. Antimicrob. Agents Chemother. 2001, 45, 1162–1167. Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir. 49. Sidwell, R. W., Smee, D. F.; Huffan, J. H.; Barnaard, D. L.; Bailey, K. W.; Morrey, J. D.; Babu, Y. S. Antimicrob. Agents Chemother. 2001, 45, 749–757. In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RWJ-270201. 50. Gubareva, L. V.; Webster, R. G.; Hayden, F. G. Antimicrob. Agents Chemother. 2001, 45, 3403–3408. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant. 51. de Jong, M. D.; Tran, T. T.; Truong, H. K.; Vo, M. H.; Smith, G. J.; Nquyen, V. C.; Bach, V. C.; Phan, T. Q.; Do, Q. H.; Guan, Y.; Peiris, J. S.; Tran, T. H.; Farrar, J. N. Engl. J. Med. 2005, 353, 2667–3672. Oseltamivir resistance during treatment of influenza A (H5N1) infection. 52. Dharan, N. J.; Gubareva, L. V.; Meyer, J. J.; Okomo-Adhiambo, M.; McClinton, R. C.; Marshall, S. A.; St. George, K.; Epperson, S.; Brammer, L.; Klimov, A. I.; Bresee, J. S.; Fry, A. M. J. Am. Med. Assoc. 2009, 301, 1034–1041. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United State. 53. Collins, P. J.; Haire, L. F.; Lin, Y. P.; Liu, J. F.; Russel, R. J.; Walker, P. A.; Skehel, J. J.; Martin, S. R.; Hay, A. J.; Gamblin, S. J. Nature 2008, 453, 1258–1261. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. 54. Shie, J. J.; Fang, J. M.; Wang, S. Y.; Tsai, K. C.; Cheng, Y. S. C.; Yang, A. S.; Hsiao, S. C.; Su, C. Y.; Wong, C. H. J. Am. Chem. Soc. 2007, 129, 11892–11893. Synthesis of tamiflu and its phosphonate congeners possessing potent anti-influenza activity. 55. Cheng, Y.-C.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22, 3099–3108. Relationship between the inhibition constant (Ki) which causes 50 per cent inhibition (I50) of an enzymatic reaction. 56. Lavis, L. D. ACS Chem. Biol. 2008, 3, 203–206. Ester bonds in produgs. 57. Stoimenovski, J.; MacFarlane, D. R.; Bica, K.; and Rogers, R. D. Pharm. Res. 2010, 27, 521–526. Crystalline vs. ionic liquid salt forms of active pharmaceutical ingredients: a position paper. 58. Stahl, P. H.; Wermuth, C. G. Monographs on Acids and Bases, in Handbook of Pharmaceutical Salts Properties, Selection, and Use; Stahl, P. H.; Wermuth, C. G.; Eds.; Verlag Helvetica Chimica Acta: Zürich, 2002, pp. 265–327. 59. Cazzola, M.; Testi, R.; Matera, M. G. Clin. Pharmacokinetics 2002, 41, 19–30. Clinical pharmacokinetics of salmeterol. 60. Miller, J. M.; Dahan, A.; Gupta, D.; Varghese, S.; Amidon, G. L. Mol. Pharm.. 2010, 7, 1223–1234. Enabling the intestinal absorption of highly polar antiviral agents: ion-pair facilitated membrane permeation of zanamivir heptyl ester and guanidino oseltamivir. 61. Straub, J. O. Ecotoxicol. Environ. Saf. 2009, 72, 1625–1634. An environmental risk assessment for oseltamivir (Tamiflu®) for sewage works and surface waters under seasonal-influenza- and pandemic-use conditions 62. Miller, J. M.; Dahan, A.; Gupta, D.; Varghese, S.; Amidon, G. L. J. Control. Release 2009, 137, 31–37. Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs. 63. Fukuto, J. M. Methods in Enzymology 2010, 268, 365–375. Chemistry of N-hydroxy-L-arginine. 64. Clement, B.; Lomb, R.; Moller, W. J. Biol. Chem. 1997, 272, 19615–19620. Isolation and characterization of the protein components of the liver microsomal O2-insensitive NADH- benzamidoxime reductase. 65. Gruenewald, S.; Wahl, B.; Bittner, W.; Hungeling, H.; Kanzow, S.; Kotthaus, J.; Schwering, U.; Mendel, R. R.; Clement, B. J. Med. Chem. 2008, 51, 8173–8177. The fourth molybdenum containing enzyme mARC: cloning and involvement in the activation of N-hydroxylated prodrugs. 66. Clement, B.; Immel, M.; Terlinden, R.; Wingen, F. J. Arch. Pharm. 1992, 325, 61–62. Reduction of amidoxime derivatives to pentamidine in vivo. 67. Wang, P.; Zhang, J. Z. H. J. Phys. Chem. B 2010, 114, 12958–12964. Selective binding of antiinfluenza drugs and their analogues to ‘open’ and ‘closed’ conformations of H5N1 neuraminidase. 68. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373–6374. 2- and 4-Nitrobenzenesulfonamides: Exceptionally versatile means for preparation of secondary amines and protection of amines. 69. Unpublished results. 70. Martin, N. I.; Woodward, J. J.; Marletta, M. A. Org. Lett. 2006, 8, 4035－4038. NG-hydroxyguanidines from primary amines. 71. Lajiness, J. P.; Robertson, W. M.; Dunwiddie, I.; Broward, M. A.; Vielhauer, G. A.; Weir, S. J.; Boger, D. L. J. Med.Chem. 2010, 53, 7731－7738. Design, synthesis, and evaluation of duocarmycin O-amino phenol prodrugs subject to tunable reductive activation. 72. Weiss, S.; Keller, M.; Bernhardt, G.; Buschauer, A.; Konig, B. Bioorg. Med. Chem. 2008, 16, 9858－9866. Modular synthesis of non-peptidic bivalent NPY Y1 receptor antagonists. 73. Fancher, A.-M.; White, P. W.; Brochu, C.; Crand-Maître, C.; Rancourt, J.; Fazal, G. J. Med. Chem. 2004, 47, 18–21. Discovery of small-molecule inhibitors of the ATPase activity of human papillomavirus E1 helicase. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65436 | - |
| dc.description.abstract | 流感屬於上呼吸道的感染，過去曾爆發多起世界性的大流行造成數千萬人的死亡，此外在近幾年中也曾爆發出禽流感H5N1和2009年的新型流感H1N1，有此可知，流感病毒是不斷在進行突變，且隨時有造成大流行的可能性。目前最主要的抗流感藥物為克流感和瑞樂沙，並且在2007年中央基因體研究中心也開發出新一代的神經胺酸酶「零流感」，值得注意的是，胍基克流感GOA (14)和胍基零流感TPG (51)對流感病毒的神經胺酸酶有更好的抑制效果，但由於其衍生物的結構包含極性較大的胍基團，使得生物利用度較差而不易作為口服藥物。有鑒於此，我們設計出一系列GOA和TPG的衍生物，藉此提高其親脂性。
在第一個部分中，我們成功將HNAP修飾在GOA (14)的羧酸上以得到酯基前驅藥物GO－HNAP (27)，其可透過分子內離子對和親脂性基團以提高其親脂性，並且透過離體實驗也証明GO－HNAP (27)可藉由酯水解酶的作用而釋放出活性藥物GOA (14)。 在第二個部分中，我們將羥基胍基、烷基胍基和醯基胍基分別修飾於TPG (51)或其乙基單酯衍生物TPGEt (52)以得到一系列化合物，首先在親脂性的測試中，比較化合物 45和化合物 63的Log D可得知將取代基修飾於胍基的末端(terminal)上對親脂性的提升有較大的幫助。另一方面我們也進一步對衍生物進行抑制NA和抗流感病毒的活性測試，結果顯示烷基胍基化合物 62和63的抑制活性明顯下降許多，而醯基胍基化合物 71則失去活性，但值得注意的是，羥基胍基化合物 46在活性測試實驗中仍對NA有很好的抑制活性(IC50 = 6.1 nM)，然而在親脂性的實驗中，化合物 46因末端羥基的極性過大使得其親脂性只有些微的提升，有鑒於此，在未來可進一步針對羥基胍基進行保護基的修飾，期望透過此方式可有效的提高化合物的親脂性。 | zh_TW |
| dc.description.abstract | Influenza is a respiratory infection. It caused high mortality of annual epidemics and occasional pandemics in the past. Recently, the new type of mutated influenza viruses occurred. The outbreak of H5N1 avian flu and the new type H1N1 human flu in 2009 have increased public awareness of the potential for global influenza pandemics. Zanamivir and oseltamivir are main anti-influenza drugs targeting neuraminidase (NA). Another NA inhibitor tamiphosphor was developed by our group in 2007. Most importantly, guanidino-oseltamivir carboxylic acid (14, GOA) and gaunidino-tamiphosphor (51, TPG) are better inhibitors than oseltamivir against wild-type human H1N1 and avian H5N1 viruses. However, GOA (14) and TPG (51) have low oral bioavailability due to the high polarity of guanidine group. Therefore, my research focused on the synthesis of GOA (14) and TPG (51) derivatives with improved bioavailability.
In the first approach, GOA (14) was modified with 1-hydroxy-2-naphthoic acid (HNAP) as a possible ester prodrug GO-HNAP (27), which formed intramolecular ion-pair to increase lipophilicity. Besides, our preliminary study showed that GO-HNAP conjugate could release the active anti-influenza drug, GOA (14), by esterase catalyzed hydrolysis in rat plasma. In the second approach, the guanidine group of TPG (51) or TPGEt (52) was modified as alkylguanidine, hydroxyguanidine and acylguanidine. Comparing the log D of compound 45 with compound 63, the modification at the terminal position of guanidine in compound 45 seemed to have better lipophilicity. In addition, these derivatives were subjected to inhibitory assays against influenza NA and viruses. The NA inhibitory activity of compounds 62 and 63 decreased, and compound 71 had no inhibition against NA. Although compound 46 showed better inhibition against NA (IC50 = 6.1 nM), it only slightly improved the lipophilicity. Therefore, modification of the N-hydroxyguanidino proup may lead to better lipophilicity. | en |
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| dc.description.tableofcontents | 謝誌............................................................................................................................... I
中文摘要 .................................................................................................................... III Abstract ........................................................................................................................ V 目錄.......................................................................................................................... VIII 圖目錄 ........................................................................................................................ XI 表目錄 ..................................................................................................................... XIII 流程目錄 ................................................................................................................. XIV 簡稱用語對照表 ....................................................................................................... XV 第一章 緒論.................................................................................................................. 1 第一節 流行性感冒............................................................................................ 1 第二節 流感病毒簡介........................................................................................ 2 2-1 流感病毒的組成 .................................................................................. 2 2-2 流感病毒感染宿主細胞的生命周期(life cycle) ................................. 3 2-3 流感病毒表面重要的膜蛋白 .............................................................. 4 2-3-1 血球凝集素 (Hemagglutinin，HA) ............................................ 4 2-3-2 神經胺酸酶 (Neuraminidase，NA) ............................................ 6 2-4 離子通道蛋白M2 ................................................................................ 7 第三節 流感藥物的開發.................................................................................... 8 3-1 離子通道蛋白抑制劑 .......................................................................... 9 3-2 神經胺酸酶抑制劑 ............................................................................ 10 3-2-1 Zanamivir的開發 ....................................................................... 10 3-2-2 Zanamivir的改進 ....................................................................... 12 3-2-3 Oseltamivir的開發 ..................................................................... 14 3-2-4 Peramivir的開發 ........................................................................ 17 第四節 抗藥性病毒的產生.............................................................................. 18 第二章 結果與討論.................................................................................................... 21 第一節 研究背景－零流感的開發.................................................................. 21 第二節 利用分子內離子對(intramolecular ion-pair)增加分子的親脂性 ...... 23 2-1 設計概念 .............................................................................................. 23 2-2 GO－HNAP (27)的合成 ....................................................................... 24 2-3 親脂性的測試與探討 .......................................................................... 27 2-4 離體培養活性檢測 .............................................................................. 29 2-4-1 活性測試的方法 ........................................................................... 29 2-4-2 抗流感活性的測試與討論 ........................................................... 31 3-5 結論 ...................................................................................................... 33 第三節 胍基前驅藥物...................................................................................... 34 3-1 設計概念 .............................................................................................. 34 3-2 羥基胍基化合物的合成 ...................................................................... 35 3-2-1 Oseltamivir衍生物的合成 ............................................................ 35 3-2-2 Tamiphosphor衍生物的合成 ........................................................ 37 3-3 抗流感活性和親脂性的測試與討論 .................................................. 40 3-4 化合物 31衍生物的合成 ................................................................... 42 3-5 結論 ...................................................................................................... 43 第四節 烷基胍基與醯基胍基化合物.............................................................. 44 4-1 設計概念 .............................................................................................. 44 4-2 化合物 62和63的合成 ..................................................................... 46 4-3 化合物 71的合成 ............................................................................... 48 4-4 抗流感活性和親脂性的測試與討論 .................................................. 51 4-5 結論 ...................................................................................................... 53 第五節 總結...................................................................................................... 53 第三章 實驗部分........................................................................................................ 55 第一節 一般方法.............................................................................................. 55 第二節 活性測試以及實驗步驟...................................................................... 56 第三節 化學合成步驟以及結構鑑定.............................................................. 60 第四章 參考文獻........................................................................................................ 98 附錄化合物之核磁共振光譜.................................................................................... 112 | |
| dc.language.iso | zh-TW | |
| dc.title | 合成胍基克流感與胍基零流感衍生物以改善親脂性 | zh_TW |
| dc.title | Synthesis of Guanidino-Oseltamivir and Guanidino-Tamiphosphor Derivatives with Improved Lipophilicity | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 羅禮強,吳世雄,梁碧惠 | |
| dc.subject.keyword | 克流感,零流感,前驅藥物,胍基, | zh_TW |
| dc.subject.keyword | tamiphosphor,oseltamivir,guanidine,prodrug,150-cavity, | en |
| dc.relation.page | 154 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-07-25 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| 顯示於系所單位： | 化學系 | |
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