請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77771
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 方俊民(Jim-Min Fang) | |
dc.contributor.author | Chien-Liang Chen | en |
dc.contributor.author | 陳建良 | zh_TW |
dc.date.accessioned | 2021-07-11T14:34:32Z | - |
dc.date.available | 2028-07-24 | |
dc.date.copyright | 2018-08-01 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-07-24 | |
dc.identifier.citation | 1. Taubenberger, J. K.; Morens, D. M. The pathology of influenza virus infections. Annu. Rev. pathol. 2008, 3, 499–522.
2. Bouvier, N. M.; Palese, P. The biology of influenza viruses. Vaccine. 2008, 26 (Suppl 4), D49–D53. 3. Karlsson Hedestam, G. B.; Fouchier, R. A. M.; Phogat, S.; Burton, D. R.; Sodroski, J.; Wyatt, R. T. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat. Rev. Microbiol. 2008, 6, 143–155. 4. Von Itzstein, M. The war against influenza: Discovery and development of sialidase inhibitors. Nat. Rev. Drug Discov. 2007, 6, 967–974. 5. Wagner, R.; Matrosovich, M.; Klenk, H. D. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev. Med. Virol. 2002, 12, 159–166. 6. Wu, Y.; Wu, Y.; Tefsen, B.; Shi, Y.; Gao, G. F. Bat-derived influenza-like viruses H17N10 and H18N11. Trends Microbiol. 2014, 22, 183–191. 7. Wiley, D. C.; Skehel, J. J. The structure and function of the hemagglutinin membrane glycoprotein of influenza virus. Annu. Rev. Biochem. 1987, 56, 365–394. 8. Skehel, J. J.; Wiley, D. C. Receptor binding and membrane fusion in virus entry: The influenza hemagglutinin. Annu. Rev. Biochem. 2000, 69, 531–569. 9. Carr, C. M.; Kim, P. S. Aspring-loaded mechanism for the conformational change of influenza hemagglutinin. Cell 1993, 73, 823–832. 10. Boriskin, Y. S.; Leneva, I. A.; Pecheur, E. I.; Polyak, S. J. Arbidol: A broad-spectrum antiviral compound that blocks viral fusion. Curr. Med. Chem. 2008, 15, 997–1005. 11. Shen, X.; Zhang, X.; Liu, S. Novel hemagglutinin-based influenza virus inhibitors. J. Thorac. Dis. 2013, 5, S149–S159. 12. Russell, R. J.; Kerry, P. S.; Stevens, D. J.; Steinhauer, D. A.; Martin, S. R.; Gamblin, S. J.; Skehel, J. J. Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17736–17741. 13. Das, K.; Aramini, J. M.; Ma, L. C.; Krug, R. M.; Arnold, E. Structures of influenza A proteins and insights into antiviral drug targets. Nat. Struct. Mol. Biol. 2010, 17, 530–538. 14. Pinto, L. H.; Lamb, R. A. The M2 proton channels of influenza A and B viruses. J. Biol.l Chem. 2006, 281, 8997–9000. 15. Schnell, J. R.; Chou, J. J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 2008, 451, 591–595. 16. Pielak, R. M.; Schnell, J. R.; Chou, J. J. Mechanism of drug inhibition and drug resistance of influenza A M2 channel Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 7379–7384.. 17. Varghese, J. N.; Laver, W. G.; Colman, P. M. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 Å resolution. Nature 1983, 303, 35–40. 18. Taylor, N. R.; von Itzstein, M. Molecular modeling studies on ligand binding to sialidase from influenza virus and the mechanism of catalysis. J. Med. Chem. 1994, 37, 616–624. 19. Darapaneni, V.; Prabhaker, V. K.; Kukol, A. Large-scale analysis of influenza A virus sequences reveals potential drug target sites of non-structural proteins. J. Gen. Virol. 2009, 90, 2124–2133. 20. von Itzstein, M.; Wu, W. Y.; Kok, G. B.; Pegg, M. S.; Dyason, J. C.; Jin, B.; Van Phan, T.; Smythe, M. L.; White, H. F.; Oliver, S. W.; Colman, P. M.; Varghese, J. N.; Ryan, D. M.; Woods, J. M.; Bethell, R. C.; Hotham, V. J.; Cameron, J. M.; Penn, C. R. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 1993, 363, 418–423. 21. 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. 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. J. Am. Chem. Soc. 1997, 119, 681–690. 22. 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. BCX-1812 (RWJ-270201): Discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J. Med. Chem. 2000, 43, 3482–3486. 23. Meindl, P.; Bodo, G.; Palese, P.; Schulman, J.; Tuppy, H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virol.1974, 58, 457–463. 24. Colman, P. M.; Varghese, J. N.; Laver, W. G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 1983, 303, 41–44. 25. Bossart-Whitaker, P.; Carson, M.; Babu, Y. S.; Smith, C. D.; Laver, W. G.; Air, G. M. Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid. J. Mol. Biol. 1993, 232, 1069–1083. 26. Cass, L. M. R.; Efthymiopoulos, C.; Bye, A. Pharmacokinetics of Zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin. Pharmacokinet. 1999, 36, 1–11. 27. Yamamoto, T.; Kumazawa, H.; Inami, K.; Teshima, T.; Shiba, T. Syntheses of sialic acid isomers with inhibitory activity against neuraminidase. Tetrahedron Lett. 1992, 33, 5791–5794. 28. Alame, M. M.; Massaad, E.; Zaraket, H. Peramivir: A novel intravenous neuraminidase inhibitor for treatment of acute influenza infections. Front. Microbiol. 2016, 7, 450. 29. Taylor, S. J. C.; Sutherland, A. G.; Lee, C.; Wisdom, R.; Thomas, S.; Roberts, S. M.; Evans, C. Chemoenzymatic synthesis of (–)-carbovir utilizing a whole cell catalysed resolution of 2-azabicyclo[2.2.1]hept-5-en-3-one. J. Chem. Soc., Chem. Commun. 1990, 0, 1120–1121. 30. Chand, P.; Kotian, P. L.; Dehghani, A.; El-Kattan, Y.; Lin, T. H.; Hutchison, T. L.; Babu, Y. S.; Bantia, S.; Elliott, A. J.; Montgomery, J. A. Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J. Med. Chem. 2001, 44, 4379–4392. 31. Jia, F.; Hong, J.; Sun, P. H.; Chen, J. X.; Chen, W. M. Facile synthesis of the neuraminidase inhibitor peramivir. Synth. Commun. 2013, 43, 2641–2647. 32. Mineno, T.; Miller, M. J. Stereoselective total synthesis of racemic BCX-1812 (RWJ-270201) for the development of neuraminidase inhibitors as anti-influenza agents. J. Org. Chem. 2003, 68, 6591–6596. 33. Chand, P.; Bantia, S.; Kotian, P. L.; El-Kattan, Y.; Lin, T. H.; Babu, Y. S. Comparison of the anti-influenza virus activity of cyclopentane derivatives with oseltamivir and zanamivir in vivo. Bioorg. Med. Chem. 2005, 13, 4071–4077. 34. Chiu, D. C.; Lin, T. C.; Huang, W. I.; Cheng, T. J.; Tsai, K. C.; Fang, J. M. Peramivir analogues bearing hydrophilic side chains exhibit higher activities against H275Y mutant than wild-type influenza virus. Org. Biomol. Chem. 2017, 15, 9910–9922. 35. Laborda, P.; Wang, S. Y.; Voglmeir, J. Influenza neuraminidase inhibitors: Synthetic approaches, derivatives and biological activity. Molecules 2016, 21, 1513. 36. Mukaiyama, T.; Hoshino, T. The reactions of primary nitroparaffins with isocyanates. J. Am. Chem. Soc. 1960, 82, 5339–5342. 37. Liu, K. C.; Shelton, B. R.; Howe, R. K. A particularly convenient preparation of benzohydroximinoyl chlorides (nitrile oxide precursors). J. Org. Chem. 1980, 45, 3916–3918. 38. Kesornpun, C.; Aree, T.; Mahidol, C.; Ruchirawat, S.; Kittakoop, P. Water-assisted nitrile oxide cycloadditions: Synthesis of isoxazoles and stereoselective syntheses of isoxazolines and 1,2,4-oxadiazoles. Angew. Chem. Int. Ed. 2016, 55, 3997–4001. 39. Ono, F.; Ohta, Y.; Hasegawa, M.; Kanemasa, S. Molecular sieve 4Å generates nitrile oxides from hydroximoyl chlorides. Development of catalyzed enantioselective nitrile oxide cycloadditions to monosubstituted alkenes. Tetrahedron Lett. 2009, 50, 2111–2114. 40. Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. Origin of reactivity, regioselectivity, and periselectivity in 1,3-dipolar cycloadditions. J. Am. Chem. Soc. 1973, 95, 7301–7315. 41. Becker, N.; Carreira, E. M. Hydroxyl-directed nitrile oxide cycloaddition reactions with cyclic allylic alcohols. Org. Lett. 2007, 9, 3857–3858. 42. Kim, J. N.; Kim, H. R.; Ryu, E. K. Regioselectivity and stereoselectivity in nitrile oxide cycloaddition to 1,5-hexadien-3-ol. The study on the hydrogen bonding effect and magnesium chelation effect in nitrile oxide cycloaddition. Synth. Commun. 1993, 23, 1673–1682. 43. Kanemasa, S. Metal-assisted stereocontrol of 1,3-dipolar cycloaddition reactions. Synlett. 2002, 9, 1371–1387. 44. Suga, H.; Hashimoto, Y.; Toda, Y.; Fukushima, K.; Esaki, H.; Kikuchi, A. Amine-urea-mediated asymmetric cycloadditions between nitrile oxides and o-hydroxystyrenes by dual activation. Angew. Chem. Int. Ed. 2017, 56, 11936–11939. 45. Sibi, M. P.; Itoh, K.; Jasperse, C. P. Chiral Lewis acid catalysis in nitrile oxide cycloadditions. J. Am. Chem. Soc. 2004, 126, 5366–5367. 46. Mayo, P.; Hecnar, T.; Tam, W. 1,3-Dipolar cycloaddition of nitrile oxides with unsymmetrically substituted norbornenes. Tetrahedron 2001, 57, 5931–5941. 47. Poulsen, P. H.; Vergura, S.; Monleon, A.; Jorgensen, D. K.; Jorgensen, K. A. Controlling asymmetric remote and cascade 1,3-dipolar cycloaddition reactions by organocatalysis. J. Am. Chem. Soc. 2016, 138, 6412–6415 48. Popov, K.; Somfai, P. Synthesis of imidates: TFA-mediated regioselective amide alkylation using Meerwein's reagent. J. Org. Chem. 2016, 81, 3470–3472. 49. Mendelsohn, B. A.; Lee, S.; Kim, S.; Teyssier, F.; Aulakh, V. S.; Ciufolini, M. A. Oxidation of oximes to nitrile oxides with hypervalent iodine reagents. Org. Lett. 2009, 11, 1539–1542. 50. Wang, P. C.; Fang, J. M.; Tsai, K. C.; Wang, S. Y.; Huang, W. I.; Tseng, Y. C.; Cheng, Y. S.; Cheng, T. J.; Wong, C. H. Peramivir phosphonate derivatives as influenza neuraminidase inhibitors. J. Med. Chem. 2016, 59, 5297–5310. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77771 | - |
dc.description.abstract | 針對近來流感的流行問題,經過多年來眾多科學家的藥物開發,發現神經胺酸酶抑制劑可以用於流感的疫情控制,而在2000年,Babu等人開發出新型克流感藥物:帕拉米弗,它也在2014年被美國食品暨藥物管理局核准使用。這支藥物在合成過程中會經過一個1,3-偶極環加成反應,由於起始物「文斯內醯胺」缺少適當的導引基團,位置與立體選擇性的問題在近二十年來都未能被妥善解決。
在此研究中我們著重在1,3-偶極環加成反應的選擇性。我們一樣選擇以文斯內醯胺為起始物,單純透過適當的分子設計與條件最佳化,特別是使用N-三氟醋醯基來誘導位置選擇性,成功使選擇性大幅提升至94%(根據核磁共振光譜分析),幾乎比原方法增加30%,經單一次管柱層析分離的產率也提升至77%,與傳統方法相比有將近三倍半的提升,這不僅有效的提升產率,更能大幅降低分離的複雜度。除此之外,我們搭配理論計算來輔佐運用,並且依據實驗結果提出模型來描述高選擇性的成因。這個方法除了改進傳統合成帕拉米弗使用的1,3-偶極環加成反應,同時也提供科學家一個便於在帕拉米弗的側鏈上修飾的方法,以進行結構與活性關係之研究。 | zh_TW |
dc.description.abstract | Due to the influenza epidemic, many scientists devoted in the drug development and found that the neuraminidase inhibitors could be used for controlling the influenza outbreak. Peramivir, a FDA approved anti-influenza drug, was first synthesized by Babu and coworkers in 2000, and approved by FDA in 2014. The most common synthetic route involved a 1,3-dipolar cycloaddition from Vince lactam derivative. Due to lack of a directing group, the problem in regio- and stereoselectivity could not be solved properly in the past 20 years.
In our work, we focused on the selectivity of 1,3-dipolar cycloaddition and modified the dipolarophile to improve the selectivity. In addition, computational analysis was carried out to support this work. We designed a series of Vince lactam derivatives to conduct 1,3-dipolar cycloadditions. After reaction optimization, especially using N-trifluoroacetyl to induce regioselectivity, we greatly improved the selectivity to 94% by NMR analysis, a nearly 30% increase compared to the conventional method. The isolated yield after single column chromatography was 77%, a 3.5-fold increase. This method was not only beneficial to the yield, but substantially reduced the procedure in purification. Furthermore, we did the computational analysis to support this work, and proposed several models to rationalize the causes of high selectivity based on the experimental data. In addition to improve the 1,3-dipolar cycloaddition leading to peramivir synthesis, our method also provides a convenient way to modify the side chain of peramivir, the structure–activity relationship (SAR) study. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T14:34:32Z (GMT). No. of bitstreams: 1 ntu-107-R05223168-1.pdf: 22333625 bytes, checksum: 365dd43305597d4961b68df1c7bb5f31 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 中文摘要 I
Abstract II Table of Contents IV Index of Figures VII Index of Schemes X Index of Tables XIII Abbreviations XVI Chapter 1. Introduction 1 1.1 Influenza virus 1 1.1.1 The structure of influenza A virus 1 1.1.2 The replication cycle of influenza virus 2 1.1.3 The envelope proteins of influenza virus 3 1.2 Neuraminidase inhibitors 6 1.2.1 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) 7 1.2.2 Zanamivir 8 1.2.3 Oseltamivir 10 1.2.4 Peramivir 13 1.3 1,3-Dipolar cycloaddition (in the isoxazoline/isoxazolidine synthesis) 23 1.3.1 Nitrile oxide cycloaddition 23 1.3.2 Nitrone cycloaddition 30 Chapter 2. Results and Discussion 32 2.1 New strategy of 1,3-dipolar cycloaddition in the peramivir synthesis 32 2.2 Computational analysis 35 2.3 Synthesis of Vince lactam derivatives 39 2.4 Generation methods of 1,3-dipoles 46 2.5 1,3-Dipolar cycloaddition with nitrile oxide 48 2.6 Optimization of reaction conditions 55 2.6.1 The effect of different nitrile oxides 55 2.6.2 The effect of solvent and temperature 57 2.6.3 The effect of generation methods of nitrile oxides 60 2.6.4 The effect of different addition methods 62 2.6.5 The effect of concentration and injection rate 63 2.6.6 The effect of Lewis acid and ligand 68 2.7 1,3-Dipolar cycloaddition with nitrone 70 2.8 Dipolarophile screening and reaction optimization 72 2.9 Models of the hydrogen bond effect and dipole effect 83 2.10 Conclusion 89 2.11 Prospection 92 Chapter 3. Experimental Section 93 3.1 General part 93 3.2 Synthetic procedures and characterization of compounds 95 Chapter 4. References 131 Appendix 139 Molecular orbitals 139 Optimized structures in DFT (CAM-B3LYP/6-31G(d)) 141 X-ray crystallographic data 144 NMR spectra 156 | |
dc.language.iso | en | |
dc.title | "選擇性1,3-偶極環加成用於合成帕拉米弗及其類似物" | zh_TW |
dc.title | Selective 1,3-Dipolar Cycloaddition for Approach to Peramivir and Analogues | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 謝俊結,張哲健,王宗興 | |
dc.subject.keyword | 流感病毒,帕拉米弗,1,3-偶極環加成,選擇性, | zh_TW |
dc.subject.keyword | influenza virus,peramivir,1,3-dipolar cycloaddition,selectivity, | en |
dc.relation.page | 192 | |
dc.identifier.doi | 10.6342/NTU201801857 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-07-25 | |
dc.contributor.author-college | 理學院 | zh_TW |
dc.contributor.author-dept | 化學研究所 | zh_TW |
dc.date.embargo-lift | 2028-07-24 | - |
顯示於系所單位: | 化學系 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-107-R05223168-1.pdf 目前未授權公開取用 | 21.81 MB | Adobe PDF | 檢視/開啟 |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。