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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林俊宏(Chun-Hung Lin),方俊民(Jim-Min Fang) | |
| dc.contributor.author | Ying-Chu Chen | en |
| dc.contributor.author | 陳盈曲 | zh_TW |
| dc.date.accessioned | 2021-05-20T20:19:03Z | - |
| dc.date.available | 2012-06-30 | |
| dc.date.available | 2021-05-20T20:19:03Z | - |
| dc.date.copyright | 2009-06-30 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-06-19 | |
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W.; Wittmann, V.; Burkartm, M. D. ; Hung, S. C.; Wong, C. H., Mechanism of human alpha-1,3-fucosyltranferase V: Glycosidic cleavage occurs prior to nucleophilic attack. Biochemistry 1997, 36, 823-831. 42. Gosselin, S.; Palcic, M. M., Acceptor hydroxyl group mapping for human milk alpha-1,3 and alpha-1,3/4-fucosyltrnaferase. Bioorg. Med. Chem. 1996, 4, 2023-2028. 43. Hindsgaul, O.; Kaur, K. J.; Srivastava, G.; Magdalena, B. T.; Crawley, S. C.; Heerze, L. D.; Palcic, M. M., Evaluation of deoxygenated oligosaccharide acceptor analogs as specific inhibitors of glycosyltranferase. J. Biol. Chem. 1991, 266, 17858-17862. 44. Wong, C. H.; Dumas, D. P.; Ichikawa, Y.; Koseki, K.; Danishefsky, S. J.; Weston, B. W.; Lowe, J. B., Specificity, inhibition, and synthetic utility of a recombinant human alpha-1,3-fucosyltranferase. J. Am. Chem. Soc. 1992, 114, 7321-7322. 45. Burkart, M. D.; Vincent, S. P.; Duffels, A.; Murray, B. W.; Ley, S. V.; Wong, C. 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H.; Tomohiro, T.; Kodaka, M.; Okuno, H., Selective synthesis and kinetic measurement of 1:1 and 2:2 cylic compounds containing 1,4,7,10-tetraazacyclododecane and azobenzene units. J. Org. Chem. 2000, 65, 8979-8987. 66. Moffatt, J. G.; Khorana, H. G., Nucleoside polyphosphates: The synthesis and some reactions of nucleoside-5’-phosphoromorpholidates and related compounds. Improved methods for the preparation of nucleoside-5’-polyphosphates. J. Am. Soc. Chem. 1961, 83, 649-658. 67. Dei, S.; Bellucci, C.; Buccioni, M.; Ferraroni, M.; Gualtieri, F.; Guandalini, L.; Manetti, D.; Matucci, R.; Romanelli, M. N.; Scapecchi, S.; Teodori, E., Synthesis and cholinergic affinity of diastereomeric and enantiomeric isomers of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)-pyrrolidine, 1-methyl-2-(-methyl-1,3-oxa- thiolan-5-yl)pyrrolidine and of their iodomethylates. Bioorg. Med. Chem. 2003, 11, 3153-3164. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9359 | - |
| dc.description.abstract | 生物體中岩藻醣轉移酶常催化最後一個轉醣步驟，而形成如Lewis y與sialyl Lewis x含有岩藻醣的寡醣。由於這些寡醣的重要生理活性 (諸如與癌細胞轉移及細菌感染的關聯性)，使得這類酵素常被視為藥物開發的目標。此篇碩士論文即針對岩藻醣轉移酶抑制劑的設計、合成及其應用作探討。
根據先前所報導的X-ray晶體結構及其反應機轉，在抑制劑的設計上有三項特點。二磷酸鳥苷 (guanosine diphosphate) 在與岩藻醣轉移酶間的作用力上，扮演重要的角色；酵素反應的過渡態 (transition state)具有正電荷的特徵；醣受體結合部位附近之疏水區域。針對這些特點，設計出具有比咯啶 (pyrrolidine)、吡咯烷(piperidine)、嘧唑 (imidazole) 的二磷酸鳥苷衍生物為細菌及人類岩藻醣轉移酶抑制劑，並探討其分子結構與活性間的關係。 除此之外，本實驗室先前合成一系列具有二磷酸鳥苷的岩藻醣抑制劑，以篩選三唑環上不同衍生基團對生物活性的影響，將此結果中效果最好的衍生基團連結到比咯啶環抑制劑YCC-7 (化合物61)。此化合物對胃幽門桿菌的岩藻醣轉移酶抑制效果最好，IC50及Ki值分別為44.1 micromolar及29.5 micromolar，我們進一步以電腦模擬計算解釋抑制劑YCC-7與該酵素間的作用力。 | zh_TW |
| dc.description.abstract | α-Fucosyltransferases (FucTs) usually catalyze the final steps in the biosynthesis of fucose-containing oligosaccharides. Owing to the related biological significance (such as tumor metastasis and bacterial infection), these enzymes are considered as the targets for therapeutic intervention. This thesis is mainly focused on the design, synthesis and evaluation of FucT inhibitors. On the basis of the reported x-ray crystal structures and mechanistic studies, the molecules were designed to include guanosine diphosphate (GDP) that offers major binding affinity, a negative-containing group to mimic the positive-charge character of the transition state, and a hydrophobic group to acquire additional affinity. Several GDP-conjugated pyrrolidines, piperidines and imidazoles were prepared and evaluated as the inhibitors against the FucTs from Helicobacter pylori and human. The structure and activity relationship was also discussed.
Furthermore, a series of GDP- and triazole-containing compounds were also developed as FucT inhibitors previously. Because 2’-(phenylsulfonyl-methyl)benzyl group was found to be the best hydrophobic group attached to the triazole, the same group was hens coupled with GDP-pyrrolidine to give YCC-7 (61). YCC-7 was found to be a potent inhibitor against H. pylori alpha-1,3-FucT. The corresponding IC50 abd Ki values are 44.1 and 29.5 micromolar, respectively. Computational modeling was further empoyled for the explanation at molecular basis. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T20:19:03Z (GMT). No. of bitstreams: 1 ntu-98-R95223089-1.pdf: 33808996 bytes, checksum: 59ba804779e8ecbc7752be3587012395 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 中文摘要…………………………………………………………… I
英文摘要…………………………………………………………… II 目錄………………………………………………………………… IV 表目錄……………………………………………………………… VI 圖目錄……………………………………………………………… VII 流程目錄…………………………………………………………… IX 簡稱用語對照表…………………………………………………… X 第一章 緒論………………………………………………… 1 1. 岩藻醣轉移酶 (Fucosyltransferase; FucT)的介紹… 2 1.1人類岩藻醣轉移酶的介紹……………………………… 4 1.2幽門螺旋桿菌岩藻醣轉移酶的介紹…………………… 5 2. 岩藻醣轉移酶的功能……………………………………… 6 3. 岩藻醣轉移酶的催化機制………………………………… 8 4. 岩藻醣轉移酶抑制劑的文獻回顧………………………… 10 4.1醣受體類似物 (acceptor substrate analogues) … 11 4.2醣予體類似物 (donor substrate analogues) …… 11 4.3過渡狀態類似物 (transition-state analogues) … 12 4.4變旋異構中心上之立體化學對抑制效果的影響力…… 14 5. 岩藻醣轉移酶抑制劑之設計原則………………………… 16 A. 岩藻醣轉移過程之電性特徵及構型………………… 16 B. 二磷酸鳥苷部分的保留及衍生之疏水區域………… 16 C. 醣苷鍵之修飾………………………………………… 17 6. 研究目標………………………………………………… 17 第二章 結果與討論………………………………………… 20 1.目標產物的逆合成………………………………………… 20 2.以路徑一合成岩藻醣轉移酶之抑制物…………………… 21 3.岩藻醣轉移酶抑制物29 (YCC-1) 及32 (YCC-3) 之合成 22 4.岩藻醣轉移酶抑制物37 (YCC-2) 及38 (YCC-4) 之合成 28 5.岩藻醣轉移酶抑制物51 (YCC-5) 之合成………………… 30 6.岩藻醣轉移酶抑制物56 (YCC-6) 之合成………………… 30 7.生物活性測試……………………………………………… 31 7.1放射線標定法………………………………………… 31 7.2生物活性測試結果……………………………………… 31 8. 疏水基團之衍生…………………………………………… 35 第三章 實驗部分…………………………………………… 40 1. General Method…………………………………………… 40 2. General Procedure for fucosyltransferase activity assay …………………………………………………… 41 3. Computational modeling……………………………… 42 4. Synthetic Procedures and Spectral Data…………… 43 第四章 參考文獻……………………………………………… 76 附錄光譜…………………………………………………………… 87 | |
| dc.language.iso | zh-TW | |
| dc.title | 以結構與反應機轉設計岩藻醣轉移酶之抑制劑 | zh_TW |
| dc.title | Development of α-Fucosyltransferase Inhibitors by Structure- and Mechanism-Based Design | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.advisor-orcid | ,方俊民(jmfang@ntu.edu.tw) | |
| dc.contributor.oralexamcommittee | 楊文彬(Wen-Bin Yang),鄭偉杰(Wei-Chieh Cheng) | |
| dc.subject.keyword | 岩藻醣轉移酶,幽門螺旋桿菌,二磷酸鳥苷,抑制劑, | zh_TW |
| dc.subject.keyword | fucosyltransferase,Helicobacter pylori,GDP inhibitor, | en |
| dc.relation.page | 87 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2009-06-22 | |
| 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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