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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民,(Jim-Min Fang) | |
| dc.contributor.author | Chun-Lin Chen | en |
| dc.contributor.author | 陳俊霖 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:09:07Z | - |
| dc.date.available | 2015-06-21 | |
| dc.date.copyright | 2013-06-21 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-04-23 | |
| dc.identifier.citation | 1. Beveridge, W. I. Influenza: The Last Great Plague: An Unfinished Story of Discovery, New York: Prodist, 1977.
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Lessons learned from marketed and investigational prodrugs. 88. (a) He, G.; Massarella, J.; Ward, P. Clin. Pharmacokinet. 1999, 37, 471–484. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite. (b) Dutkowski, R.; Thakrar, B.; Froehlich, E. Suter, P.; Oo, C.; Ward, P. Drug safety 2003, 26, 787–801. Safety and pharmacology of oseltamivir in clinical use. (c) Davies, B. E. J. Antimicrbo. Chemother. 2010, 65, ii5–ii10. Pharmacokinetics of oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. 89. (a) Anand, B. S.; Mitra, A. K. Pharmt. Res. 2002, 19, 1194–1202. Mechanism of corneal permeation of L-valyl ester of acyclovir: Targeting the oligopeptide transporter on the rabbit cornea. (b) Charrier, L.; Merlin, D. Laboratory Investigation 2006, 86, 538–546. The oligopeptide transporter hPepT1: gateway to the innate immune reponse. (c) Han, H.-K.; De Vrueh, R. L. A.; Rhie, J. K.; Covitz, K.-M.Y..; Smith, P. L.; Lee, C.-P.; Oh, D.-M.; Sadee, W.; Amidon, G. L. Pharm. Res. 1998, 15, 1154–1159. 5’-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. (d) Li, F.; Hong, L.; Mau, C.-I.; Chan, R.; Hendricks, T.; Dvorak, C.; Yee, C.; Harris, J.; Alfredson, T. J. Pharm. Sci. 2006, 95, 1318–1325. Transport of Levovirin prodrug in the human intestinal Caco-2 cell line. 90. (a) De Vrueh, R. L. A.; Smith, P. L.; Lee, C.-P. J. Pharmacol. Exp. Ther. 1998, 286, 1166–1170. Transport of L-Valine-Acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2. (b) Hilfinger, J.; Amidon, G. US 2012/0058937 A9. Prodrugs of neuraminidase inhibitors. (c) Gupta, S. V.; Gupta, D.; Sun, J.; Dahan, A.; Tusme, Y.; Hilfinger, J.; Lee, K.-D.; Amidon, G. L. Mol. Pharm. 2011, 8, 2358–2367. Enhancing the intestinal membrane permeability of zanamivir: A carrier mediated prodrug approach. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62742 | - |
| dc.description.abstract | 流行性感冒是影響人類健康的主要疾病之一。流感病毒是一種RNA病毒，流感病毒的生命週期中，新形成的流感病毒在離開宿主細胞的時候，神經胺酸酶必須水解血液凝集酶與宿主細胞上唾液酸之間的聯繫，才可以離開宿主細胞而感染其他細胞。神經胺酸酶水解時形成oxonium中間體，而克流感與瑞樂沙的環己烯結構便模擬此中間體以達到抑制流感病毒的效果，其中結構上的羧酸基會與神經胺酸酶的活性中心的精胺酸形成靜電力(Arg118, Arg292 and Arg371)來結合。所以我們實驗室便開發磷酸基團的零流感化合物來取代羧酸基團的oseltamivir以達到更佳結合來有效抑制流感病毒，由實驗結果發現對於H1N1，H5N1與突變H274Y H1N1都較羧酸機化合物更佳。但是零流感化合物的脂溶性低造成生物獲得率較差，為了改善這缺點，我們合成單磷脂零流感化合物來增加脂溶性之外，以可以增加部分的凡德瓦力來加強結合的能力，以達到抑制感冒病毒的目的。在合成上我們使用市售的克流感膠囊先進行Boc保護得到化合物59，接著使用Barton反應得到碘化物76，我們使用不同亞磷酯化合物如二乙基、二丁基、二己基或是二苯丙基亞磷酸與化合物76進行鈀金屬的催化得到不同二磷酯之零流感化合物，將胺基上的Boc去掉之後再與硫脲化物反應得到胍基零流感化合物。接著在鹼性條件之下反應得到單酯零流感化合物之後，最後在移除Boc保護基之後便可獲得零流感與胍基零流感化合物。在分配係數測驗上，我們發現胍基零流感己基單酯95較胍基零流感乙基單酯83有較好的脂溶性，而且胍基零流感己基單酯95也較胍基零流感乙基單酯83與胍基零流感3-苯丙基單酯110有較好的細胞穿透性。然而在生體可用率實驗裡，胍基零流感己基單酯95 (F = 12.6%)之生體可用率略高於胍基零流感乙基單酯83 (F = 12%)。初期在H1N1流感病毒口服投藥的小鼠保護測試上胍基零流感己基單酯95並沒有較胍基零流感乙基單酯83有較好的保護效果，但是胍基零流感己基單酯95與胍基零流感乙基單酯83在鼻吸入方式投藥上都有明顯的保護效用。 | zh_TW |
| dc.description.abstract | Influenza is a major disease to menace human’s health. Influenza virus is a kind of RNA virus. In the life cycle, the new influenza virus will leave the host cell by cutting off the sialic acid moiety of the glycoprotein receptor on host cell surface. Neuraminidase catalyzes such hydrolysis to form an oxonium intermediate from sialoside. The structure of oseltamivir and zanamivir mimic the (oxa)cyclohexene intermediate to inhibit the activity of neuraminidase. Tamiflu™ is a prodrug, and its ester bond will be hydrolyzed by hepatic esterase to form oseltamivir carboxylate (OC), which binds to the three arginine residues (Arg118, Arg292 and Arg371) in the neuraminidase of influenza virus. Our team has synthesized tamiphosphor (the phosphonate congener of OC) and guanidino-tamiphosphor as potent inhibitors against influenza virus. The phosphonic functional group on C-2 rendered better efficiency against avian H5N1, human H1N1 and oseltamivir-resistant H274Y influenza viruses. However, poor lipophilicity of tamiphosphor and guanidino-tamiphosphor caused low bioavailability. To circumvent this drawback, we synthesized phosphonate monoester compounds to increase the lipophilicity with retention of the inhibitory activity against influenza virus. The N-Boc protected OC 59 was prepared from tamiflu capsule, and then converted to the corresponding iodo compound 76 by halo-decarboxylation reaction using Barton’s procedure. The Pd coupling reactions of iodo compound 76 with various dialkyl phosphite compounds such as diethy, dibuty, dihexyl and di(3-phenylpropyl) phosphites, to give the desired phosphonate products. The N-Boc group was deprotected, and the resulting amino group was treated with N-Boc-thiourea reagent to give the N-Boc-guanidino derivatives. The tamiphosphor and guanidino-tamiphosphor was available by the phosphonate dialkyl esters was treated with alkali to give the phosphonate monoesters. Tamiphosphor monoesters and guanidine-tamiphosphor monoesters were finally synthesized after removal of the Boc group. We found monohexyl phosphonate 95 showed better lipophicility than monoethyl phosphonate 83 in the distribution coefficient measurement. Compound 95 also has better cell permeability than compound 83 and the (3-phenyl)propyl phosphonate analog 110. However, the bioavailability of compound 95 (F = 12.6%) was just slightly higher than that of compound 83 (F = 12%). Our preliminary mice test indicated that compound 95 may not be better than 83 for treatment of H1N1 influenza virus infection by oral gavage. Nontheless, both compounds 83 and 95 showed high efficiency in protection of mice from influenza infection by intranasal administration. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:09:07Z (GMT). No. of bitstreams: 1 ntu-102-D95223013-1.pdf: 23852687 bytes, checksum: 85bd9e2f2bb45b8ff17a82f234ade271 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 口試委員會審定書
謝誌………………………………………………………….……………….……… I 目錄………………………………………………………….……………….……… II 圖目錄……………………………………………………………………………...VI 表目錄……………………………………………………………………………..IX 流程目錄…………………………………………………………………….……..XI 中文摘要…………………………………………………………………………..XIV 英文摘要………………………………………………………………………….XVI 目錄 第一章 緒論 1 1-1. 認識流行性感冒 1 1-1-1. 流感的症狀 1 1-1-2. 歷史背景 1 1-1-3. 流感病毒的結構 2 1-1-4. 病毒之生命週期 (life cycle) 3 1-2. 流感病毒的構造 4 1-2-1. 病毒表面之重要蛋白質 5 1-2-2. 病毒之其它重要蛋白質 8 1-3. 流感病毒的抑制劑 8 1-3-1. M2離子通道抑制劑(M2 ion channel inhibitor) 8 1-3-2. 血液凝集素抑制劑(hemagglutinin inhibitor) 10 1-3-3. 神經胺酸酶抑制劑(neuraminidase inhibitor) 11 1-4. Oseltamivir化合物的相關合成研究 19 1-4-1. Gilead的合成流程 19 1-4-2. Roche和其他團隊的合成流程 20 1-4-3. 本實驗室所開發之oseltamivir與tamiphosphor的合成 24 1-5. 新型流感抑制劑的開發 28 1-5-1. 病毒的突變機制 28 1-5-2. 病毒對oseltamivir生成之抗藥性 29 1-5-3. 零流感(Tamiphosphor)新型態抑制劑 31 1-6. 其他流感抑制藥物的設計與開發 34 1-6-1. Oseltamivir羥基胺酸(hydroxamate acid)衍生物的開發 34 1-6-2. 細菌神經胺酸酶(NanA) 35 1-7. 開發抗流感藥物的展望 38 第二章. 結果與討論 2. 流感抑制劑的設計與合成 39 2-1. Oseltamivir羥基醯胺衍生物的開發 39 2-2. 零流感單酯衍生物之合成 45 2-3. 零流感單丁酯與其胍基衍生物之合成 54 2-4. 零流感單己酯與其胍基衍生物之合成 56 2-5. 零流感單辛酯與其胍基衍生物之合成 59 2-6. 零流感單癸酯與其胍基衍生物之合成 61 2-7. 零流感3-苯丙基單酯與其胍基衍生物之合成 63 2-8. 零流感3-吲哚丙基單酯與其胍基衍生物之合成 68 2-9. 其他零流感化合物的合成 71 2-9-1. 零流感5-胺基戊基單酯化合物的合成 71 2-9-2. 零流感3-羧基丙基單酯化合物的合成 75 2-9-3. 零流感3-炔丁基單酯與其胍基衍生物的合成 79 第三章. 化合物特性與藥物動力檢測 3. 抗流感抑制劑之性質與活性檢測 83 3-1. 抑制流感病毒化合物的分配係數(LogD)測試 83 3-2. 流感化合物針對不同型態感冒病毒的抑制活性測試 89 3-3. 零流感單磷酯化合物之代謝穩定性 91 3-4. 零流感單磷酯化合物之細胞穿透實驗 92 3-5. 抑制流感化合物的小鼠存活率實驗 93 3-6. 零流感化合物之生體可用率測試 99 3-7. 細菌神經胺酸酶(NanA)的抑制活性測試 100 3-8. 結論 102 第四章. 測流感病毒突變株之化合物的開發: RABC(Resistance Assessment by Binding Competition) 4-1. 緒論 104 4-2. RABC(Resistance Assessment by Binding Competition) assay的原理 107 4-2-1. 小分子生物感測器的設計 107 4-2-2. RABC assay的設計原理 108 4-3. 零流感衍生物使用於RABC assay 109 4-3-1. 零流感檢測化合物的設計 109 4-3-2. 零流感衍生物的合成與RABC assay 109 第五章. 設計與合成零流感前驅藥物以增加在生物體的吸收 5-1. 緒論: 前驅藥物(prodrug) 112 5-2. 咖啡酸衍生之前驅藥物 114 5-3. L-纈氨酸衍生之前驅藥物 120 5-3-1. L-纈氨酸零流感化合物的合成 123 6. 實驗部分 126 6-1. 一般方法 126 6-2. 活性測試與實驗步驟 127 6-3. 分子模擬 (Molecular modeling) 130 6-4. 化學合成步驟及結構鑑定 132 7. 參考文獻 211 附錄:化合物之核磁共振光譜 分配係數(LogD)之實驗數據 細胞穿透實驗數據 發表文獻 | |
| dc.language.iso | zh-TW | |
| dc.subject | 流感 | zh_TW |
| dc.subject | 抑制劑 | zh_TW |
| dc.subject | 零流感化合物 | zh_TW |
| dc.subject | Influenza | en |
| dc.subject | tamiphoshpor | en |
| dc.title | 發展零流感單磷酯衍生物作為有效的抗流感試劑:
合成、生物活性與藥物動力之研究 | zh_TW |
| dc.title | Development of Tamiphosphor Monoesters as Effective Anti-Influenza Agents: Synthesis, Bioactivity and Pharmacokinetic Study | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 羅禮強,吳世雄,林俊宏,林君榮,詹家琮 | |
| dc.subject.keyword | 流感,抑制劑,零流感化合物, | zh_TW |
| dc.subject.keyword | Influenza,tamiphoshpor, | en |
| dc.relation.page | 373 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-04-24 | |
| 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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