請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/32549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 | Yu-Ting Li | en |
| dc.contributor.author | 李雨亭 | zh_TW |
| dc.date.accessioned | 2021-06-13T04:11:30Z | - |
| dc.date.available | 2007-07-31 | |
| dc.date.copyright | 2006-07-31 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-07-26 | |
| dc.identifier.citation | 1. WHO.Severe acute respiratory syndrome(SARS).Wkly Epidemiol Rec, 2003, 78, 217.
2. http://www.who.int/csr/sarsarchive/2003_04_16/en/print.html。 3. http://www.cdc.gov/ncidod/sars/sequence.htm。 4. SARS冠狀病毒主要蛋白酶結構晶體資訊如下網頁http://www.biochem.ucl.ac.uk/bsm/pdbsum/1q2w/main.html Structural GenomiX公司所發布之新聞稿內容如下網頁http://www.stromix.com/news/press_release_detail.php?keyID=58。 5. http://www.aps.anl.gov/News/APS_News/2003/20030731a.htm。 6. Urbani, C.; N. Engl. J. Med. 2003, 348, 1951-1952. 7. Marra, M. A.; Jnoes, S. J. M.; Astell, C. R.; Holt, R. A.; Brooks- Wilson, A.; Butterfield, Y. S. N.; Khattra, J.; Asano, J. K.; Barber, S. A.; Chan, S. Y.; Cloutier, A.; Coughlin, S. M.; Freeman, D.; Girn, N.; Griffith, O. L.; Leach, S. R.; Mayo, M.; McDonald, H.; Montgomery, S. B.; Pandoh, P. K.; Petrescu, A. S.; Robertson, A. G.; Schein, J. E.; Siddiqui, A.; Smailus, D. E.; Stott, J. M.; Yang, G. S.; Plummer, F.; Andonov, A.; Artsob, H.; Basrien, N.; Bernard, K.; Booth, T. F.; Bowness, D.; Czub, M.; Drebot, M.; Fernando, L.; Flick, R.; Garbutt, M.; Gray, M.; Grolla, A.; Jones, S.; Feldmann, H.; Meyers, A.; Kabani, A.; Li, Y.; Normand, S.; Stroher, U.; Tipples, G. A.; Tyler, S.; Vogrig, R.; Ward, D.; Watson, B.; Brunham, R. C.; Krajden, M.; Petric, M.; Skowronski, D. M.; Upton, C,; Roper, R. L. Science 2003, 300, 1394-1399. Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome. 8. Shie, J.-J.; Fang, J.-M.; Kuo, C.-J.; Kuo, T.-H.; Liang, P.-H.; Huang, H.-J.; Yang, W.-B.; Lin, C.-H.; Chen, J.-L.; Wu, Y.-T.; Wong, C.-H. J. Med. Chem. 2005, 48, 4469--4473. Discovery of Potent Anilide Inhibitors against the Severe Acute Respiratory Syndrome 3CL Protease. 9. Zhang, H.-Z.; Zhang, H.; Kemnitzer, W.; Tseng, B.; Cinatl, J.; Jr,; Michaelis, M.; Doerr, H. W.; Cai, S. X. J. Med. Chem. 2006, 49, 1198-1201. Design and Synthesis of Dipeptidyl Glutaminyl Fluoromethyl Ketones as Potent Severe Acute Respiratory Syndrome Coronavirus(SARS-CoV) Inhibitors. 10. Anand, K.; Ziebuhr, J.; Wadhwani, P.; Mesters, J. R.; Hilgenfeld, R. Science, 2003, 300, 1763-1767. Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs. 11. Bacha, U.; Barrila. J.; Velazquez-Campoy, A.; Leavitt, S. A.; Freire, E. Biochemistry 2004, 43, 4906-4912. Identification of Novel Inhibitors of the SARS Coronavirus Main Protease 3CLpro. 12. http://www.gancao.com/liaojiegancao/ljgc_gczl.htm.億利資源集團 公司。 13. Hatano, T.; Fukuda. T.; Miyase, T.; and Okuda, T. Chem.Pharm. Bull. 1991, 39, 1238-1243. 14. http://www.cgmh.com.tw/new1/new8805-301.htm. 長庚大學基礎醫 學研究所教授 趙清貴。 15. Kenneth W. Tsang, M.D., Pak L. Ho, M.D., Gaik C. Ooi, M.D., Wilson K. Yee, M.D.,Teresa Wang, M.D., Moira Chan-Yeung, M.D., Wah K. Lam, M.D.,Wing H. Seto, M.D., Loretta Y. Yam, M.D., Thomas M. Cheung, M.D.,Poon C. Wong, M.D., Bing Lam, M.D., Mary S. Ip, M.D., Jane Chan, M.D.,Kwok Y. Yuen, M.D., N. Engl. J. Med, 2003; 348, 1977-1985, A Cluster of Cases of Severe Acute Respiratory Syndrome in Hong Kong. 16. J Cinatl, B Morgenstern, G Bauer, P Chandra, H Rabenau, H W Doerr The Lancet , 2003, 361, 2045-2046, Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. 17. Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359-1472 18. Huang, C.-K.; Wei, P.; Fan, K.; Liu, Y.; Lai, L. Biochemistry. 2004, 43, 4568-4574. 19. Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305-341. 20. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Webber, S. E.; Marakovits, J T.; Fuhrman, S. A.; Patick, A. K.; Matthews, S. A. J. Med. Chem. 1999, 42, 1213-1224. 21. Parik, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505-5507. 22. (a)Hanessian, S.; Bayrakdarian, M.; Luo, X. J. Am. Chem. Soc. 124, 4716-4721. (b) Okamoto, N.; Hara, O.; Makino, K.; Hamada, Y. J. Org. Chem. 2002, 67, 9210-9215. 23. (a)Dragovich, P. S.; Prins, T. J,; Zhou, R.; Brown, E. L.;Maldonado, F. C.; Fuhrman, S. A.; Zalman, L. S.; Tuntaland, T.; Lee, C. A.; Patick, A. K.; Matthews, D. A.; Hendrickson, T. F.; Kosa, M. B.; Liu, B.; Batugo, M. R. J. Med. Chem. 2002, 45, 1607-1623. (b) Lee, K.-Y; Kim Y.-H.; Park, M.-s.; Oh, C.-Y.; Ham, W.-H. J. Org. Chem. 1999, 64, 9450-9458. 24. Hellmann, G.; Opitz, H. alpha-Aminoalkylierung, Verlag Chemine, Weinheim, 1961. 25. (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181. (c) Ugi, I.; Lohberger, S.; Karl, R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 2, pp1083-1109. 26. (a) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem., 1997, 62, 2917-2924. (b) Overman, L. E.; Rabinowitz, M. H.; Renhow, P. A. J. Am. Chem. Soc. 1995, 117, 2657-2658. 27. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27. 28. Strecker, A. Justus Liebigs Ann. Chem. 1854, 91, 349. 29. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474. 30. Biginekki, P. Ber. Dtsch. Chem. Ges. 1891, 24, 2962. 31. Biginekki, P. Ber. Dtsch. Chem. Ges. 1891, 24, 2962. 32. Mannich, C.; Krosche, W. Arch. Phram. ( Weinheim, Ger. ) 1912, 250, 647. 33. Bucherer, H.T.; Fischbeck, H. T. J. Prakt. Chem. 1934, 140, 69. 34. Bucherer, H.T.; Fischbeck, H. T. J. Prakt. Chem. 1934, 140, 24. 35. 謝俊結，國立台灣大學，博士論文，2005 。 36. Kim, D. H.; Jin, Y. Bioorganic and Medicinal Chemistry Letter, 1999, 9, 691-696 , First Hydroxamate Inhibitors for Carboxypeptidase A. N-Acyl-N-Hydroxy-β-Phenylalanines 37. 黃鴻鈞，國立台灣大學，博士論文，2004。 38. Gerold, H.; Lidia, B.; Lia, B.; Jindrich, C. J. Med. Chem. 2005, 48, 1256-1259. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/32549 | - |
| dc.description.abstract | 本篇論文主要在研發對抗嚴重呼吸道症候群(severe acute respiratory syndrome, SARS ) 冠狀病毒的試劑。包括兩部分: 第一部份，合成出alpha羥基醯胺與alpha酮基醯胺衍生物，第二部份，合成出甘草素衍生物。
為了模擬SARS病毒主要蛋白酶催化胜肽水解時，所形成的過渡態結構的特性，而合成了alpha-羥基醯胺與alpha-酮基醯胺等衍生物，如化合物12和13，並使用螢光分析方法去檢測其抑制主要蛋白酶活性的效力，發現抑制效果並沒有先前預想的結果好，高達10 microM。 最近國外學者發現甘草素( Glycyrrhizin ) 能夠抑制SARS冠狀病毒的複製，但是所需的劑量太高，而且甘草素在細胞內的抑制機制仍然不明確，因此希望能找到更有效的抑制劑。甘草素的結構主要分為兩個部份: 18β甘草次酸( Glycyrrhizic acid ) 和雙葡萄糖酸的部份。本論文就甘草次酸進行化學修飾，與胺基酸作偶合反應。利用細胞病變效應 (cytopathic effect assay)的檢測，來進一步找到很有效的SARS冠狀病毒抑制劑。 我們發現甘草次酸衍生物( JMF479 ) 對於抑制SARS冠狀病毒抑制效果甚佳，其 IC50與EC50分別是17和3.3 microM。 | zh_TW |
| dc.description.abstract | The aim of this thesis is to discover the antiviral agents against severe acute respiratory syndrome coronavirus (SARS-CoV). This thesis consists of two parts: (i) synthesis of alpha-hydroxy amide and alpha-keto amide derivatives, and (ii) synthesis of glycyrrhetinic acid derivatives.
The derivatives of alpha-hydroxy amide and alpha-keto amide, such as 12 and 13 were synthesized, in order to mimic the tetrahedral transition state in the hydrolysis of the peptide substrate catalyzed by the SARS-CoV main protease. The inhibition assays were carried out using a peptide substrate that contains a fluorophore Edans and a quencher Dabcyl. It has been reported that Glycyrrhizin has the activity to inhibit the replication of the SARS coronavirus, but the inhibition concentration is still high. The mechanism of glycyrrhizic acid in vivo is still unclear. It is thus desirable to find better SARS-CoV inhibitors. The structure of Glycyrrhizin contains two parts: 18 beta glycyrrhetinic acid (GA) and disaccharide acid. A series of GA derivatives were prepared by coupling reactions with amino acid esters, and their anti-SARS activities were measured using the CPE (cytopathic effect) assay. We found that a glycyrrhetinic acid derivative (JMF479) was particularly effective against the SARS coronavirus with the IC50 and CPE values of 17 and 3.3 mucroM. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T04:11:30Z (GMT). No. of bitstreams: 1 ntu-95-R92223017-1.pdf: 7691514 bytes, checksum: a004bfc255a6c456c00a2ad4dc62bac9 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | 目 錄
目錄………………………………………………………… II 圖目錄……………………………………………………… V 表目錄……………………………………………………… VI 簡稱用語對照表…………………………………………… VII 中文摘要…………………………………….......... VIII 英文摘要…………………………………………………… X 壹、緒論 1-1. SARS冠狀病毒的起源與介紹................... 1 1-2. SARS冠狀病毒基因定序 ...................... 5 1-3. SARS冠狀病毒與其他冠狀病毒的比較...............8 1-4. SARS冠狀病毒的繁殖方式………...............11 1-5. SARS冠狀病毒主要水解蛋白酶..................12 1-6. 甘草素的藥理作用及應用.........................15 1-7. 甘草甜素與SARS冠狀病毒..............................21 貳、第一部份結果與討論 2-1. 研究背景 ................ 25 2-2.alpha-羥基醯胺化合物之製備 …………………… 30 2-3. alpha-酮基醯胺化合物之製備 …………… 40 參、第二部份結果與討論 3-1. 研究背景 ........................41 3-2. 甘草素的水解 .......................... 42 3-3. 甘草次酸和胺基酸的偶合反應................... 44 3-3-1. 甘草次酸和甘胺酸的偶合反應 .................. 46 3-3-2. 甘草次酸和絲胺酸的偶合反應................. 48 3-3-3. 甘草次酸和纈胺酸的偶合反應 ................ 49 3-3-4. 甘草次酸和麩醯胺的偶合反應................ 50 3-3-5. 甘草次酸和苯丙胺酸的偶合反應 ................ 51 3-3-6. 甘草次酸和離胺酸的偶合反應 ........52 3-4. 甘草次酸和1-胺基-2-茚醇的偶合反應 ......... 55 肆、 結 論 ...... 61 伍、實驗部份 ... 69 壹、一般敘述 ………………………………………… 69 一、測試及實驗儀器 ……………………………… 69 二、溶劑、試劑之前處理 ………………………… 70 三、實驗前準備要項 ………………………… 71 四、SARS–CoV–3CLpro的抑制效果測試 ………… 72 五、細胞病變（cytopathic effect, CPE）檢測……… 73 貳、光譜數據 …………………………………… 74 陸、 參考文獻 ………………………………………… 97 柒、摘錄之光譜 …………………………………………… 103 捌、附件 ................. 130 | |
| dc.language.iso | zh-TW | |
| dc.title | 設計及合成對抗SARS冠狀病毒
之抑制劑: (一) alpha-羥基醯胺與alpha-酮基醯胺 (二) 甘草素衍生物 | zh_TW |
| dc.title | Design and Synthesis of Inhibitors against
SARS Coronavirus: Ⅰ alpha-Hydroxy Amide and alpha-Ketoamide Ⅱ Glycyrrhizin Derivatives | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蔡蘊明(Yeun-Min Tsai),李文山(Wen-Shan Li) | |
| dc.subject.keyword | 嚴重急性呼吸道症候群,羥基醯胺,酮基醯胺,甘草素, | zh_TW |
| dc.subject.keyword | SARS,hydroxyamide,ketoamide,glycyrrhizin, | en |
| dc.relation.page | 132 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-07-26 | |
| 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 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-95-1.pdf 目前未授權公開取用 | 7.51 MB | Adobe PDF |
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。