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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 羅禮強(Lee-Chiang Lo) | |
dc.contributor.author | Min-Shiang Liao | en |
dc.contributor.author | 廖敏翔 | zh_TW |
dc.date.accessioned | 2021-06-08T04:32:02Z | - |
dc.date.copyright | 2009-10-05 | |
dc.date.issued | 2009 | |
dc.date.submitted | 2009-09-17 | |
dc.identifier.citation | 參考文獻
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22884 | - |
dc.description.abstract | 龐大且具多樣性的蛋白質族群在許多人體生理反應中扮演著舉足輕重的角色,蛋白質失調經常牽涉到許多疾病的發生,例如癌症或糖尿病等等,而化學探針的發展則為蛋白質體學研究提供了有效的工具。
氟化磷酸酯是目前已知能有效標示絲胺酸水解酶的化學探針,其屬於親電性試劑,利用辨識端來進入特定蛋白質族群的受質結合區,使之能與其附近蛋白質上的親核基作用而在蛋白質催化活性部位形成共價鍵結,達到標示的目的。在本論文中,我們以苯甲基氟化磷酸酯為基礎,於其上進行一系列烷基之修飾,為了探討烷基長度與空間立體性質對於探針活性及選擇性的影響,我們合成了包含乙烷基、丁烷基、辛烷基以及環己烷基修飾的苯甲基氟化磷酸酯辨識端,並藉由具較高親水性的聚乙二醇衍生連接橋結合三種不同的發報端,分別有疊氮基團、生物素及螢光基團來構成不同的化學探針組合,這一系列苯甲基氟化磷酸酯類化學探針將可被應用於不同的生物測試策略。在此同時,我們也合成了由相同聚乙二醇衍生連接橋鏈結生物素發報端的氟化磷酸酯,進而與苯甲基氟化磷酸酯類化學探針進行對照比較。 | zh_TW |
dc.description.abstract | Numerous and diverse protein families play a very important role in a lot of human physiological processes. Disorder of proteins always involves in many diseases, such as cancer and diabetes, etc.. Therefore, the development of chemical probes has offered efficient tools for studying protein functions and structures.
It is known that fluorophosphonate is an effective chemical probe for serine hydrolases, which belongs to an electrophilic reagent and enters substrate binding site of specific protein with its recognition head. When being attacked by nearby nucleophile on the protein, there would form the covalent binding at protein active site to achieve labeling. In this thesis, we did modifications of alkyl groups upon benzyl fluorophosphonate. In order to study the influence of alkyl length and steric effect on activity and selectivity of probes, we synthesized benzyl fluorophosphonate recognition heads with modifications including ethyl, butyl, octyl and cyclohexyl. By way of connecting different kinds of tag like azido group, biotin and rhodamine with recognition heads separately through a higher hydrophilic ethylene glycol derived linker, a series of benzyl fluorophosphonate probes were made up. And they will apply to various biological testing strategies. At the same time, we also synthesized the known fluorophosphonate with biotin tag through an identical ethylene glycol derived linker. And then carry on contrast to compare with the benzyl fluorophosphonate chemical probes. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T04:32:02Z (GMT). No. of bitstreams: 1 ntu-98-R96223217-1.pdf: 17193398 bytes, checksum: dab09e5f11ad71289a30c8a2fe59961d (MD5) Previous issue date: 2009 | en |
dc.description.tableofcontents | 目 錄
英文縮寫……………………………………………………………………………...i 中文摘要…………………………………………………………………………….iii 英文摘要…………………………………………………………………………….iv 第一章 緒論………………………………………………………………………....1 1.1前言…………………………….……….…..……………………………….1 1.2蛋白質體學研究方法……………..………..………..……………...………2 1.3化學探針於蛋白質體學之應用…………..…………...…..……………….2 1.4化學探針之基本架構與作用機制……….....………...………………........4 1.4.1辨識端…………………………..……………..……………………..4 1.4.1.1直接利用反應性親電子基團與蛋白質形成共價修飾的化 學探針…………………………………………...…..…………4 1.4.1.2經由蛋白質催化作用而產生高活性中間體的化學探針....6 1.4.2連接橋………...……………….……………..……………………..8 1.4.3發報端………………………………………..……………………..9 1.4.3.1螢光團………………..………………………...…………..9 1.4.3.2生物素………………..…………..…………...…………..10 1.4.3.3疊氮基團……………..………………..……...…………..11 第二章 目標化合物設計背景……..…………….………………………………..13 2.1有機磷化合物於酵素抑制劑之應用……….…………………….………13 2.2氟化磷酸酯類化合物之應用與發展……………….…………….………15 2.3苯甲基氟化磷酸酯類化學探針之開發…………………..………………17 第三章 結果與討論…………...………..……………...……….…………...……20 3.1目標化合物之合成策略……………....….…..….……….………………20 3.2目標化合物之逆合成分析……………...…..….………….…………..…20 3.3目標化合物之合成方法…………….......…..….………….…………..…23 3.3.1辨識端前驅物(化合物9)之合成方法….………..…..……..…23 3.3.2聚乙二醇衍生連接橋(化合物6)之合成方法…...…..……..…27 3.3.3辨識端前驅物與連接橋之銜接..…………………...………….…29 3.3.4辨識端上不同烷基之修飾..………………………...………….…30 3.3.5氟基之建構與發報端之連接..……………………..………….…33 3.3.5.1目標化合物A1之合成方法………………....……….…36 3.3.5.2目標化合物B1及R1之合成方法………….…....….…38 3.4化合物24之逆合成分析……………......…………..…..….………..…46 3.5化合物24之合成方法………………......…………..…..….………..…46 3.6結論…………….................................…………..……….….………..…53 第四章 實驗部分………………………..…………………………………...……54 4.1一般敘述………........................................…………..…….…….……..…54 4.1.1測定及實驗儀器...............…………..…………...….…….……..…54 4.1.2反應試劑...........…………..…………...….……………….……..…55 4.2有機合成實驗步驟及光譜數據............…....………..…….…….……..…56 參考文獻……………..………...……...……………………………………..……89 附錄 化合物之核磁共振光譜圖...…...…………….…………………………….93 圖目錄 圖1-1活性探針作用示意圖:(a)可針對具有活性之蛋白質進行標示(b)對於不具活性之蛋白酶原或被抑制之蛋白質無標示效果…………………...…3 圖1-2化學探針之基本架構…………………………………………………………4 圖1-3 Acyloxymethylketone(AOMK)之作用機制….…………………………...5 圖1-4化學探針LCL2之(a)結構與(b)作用機制….………………………....7 圖1-5不同的潛在性反應基團(latent reactive group)與其作用對象…...……....8 圖1-6(a)生物素與(b)生物素類似物iminobiotin之化學結構………..….....11 圖1-7二階段標示策略………….…………………………………….…………... 12 圖1-8(a)[3+2] 成環反應與(b)Staudinger ligation示意圖……………….....12 圖2-1(a)沙林與(b)索曼毒氣之化學結構.......................................................13 圖2-2絲胺酸蛋白質水解酶抑制劑(a)DPNP與(b)ethyl hexyl chlorophosphonate之化學結構……………………………………………………………….…15 圖2-3不同類型之氟化磷酸酯化學探針..................................................................16 圖2-4氟化磷酸酯化學探針標示絲胺酸水解酶之作用機制..................................17 圖2-5 芐芳香磷酸酯化學探針之結構.....................................................................17 圖2-6苯甲基氟化磷酸酯類化學探針之結構..........................................................18 圖2-7化合物編號說明及實例..................................................................................19 圖3-1目標化合物之逆合成分析..............................................................................21 圖3-2化合物11與亞磷酸二乙酯之1H光譜疊圖..................................................24 圖3-3化合物11與亞磷酸二乙酯之31P光譜疊圖.................................................24 圖3-4製備化合物10之反應機制............................................................................25 圖3-5化合物10之31P光譜圖.................................................................................25 圖3-6化合物10之1H與13C光譜圖.......................................................................26 圖3-7化合物10與化合物9之1H光譜疊圖..........................................................27 圖3-8化合物7之IR吸收光譜圖............................................................................28 圖3-9常見的耦合試劑及其結構..............................................................................30 圖3-10化合物12與化合物5a之1H光譜疊圖......................................................31 圖3-11化合物5b之1H光譜圖................................................................................33 圖3-12化合物5a與化合物4a之1H光譜疊圖......................................................34 圖3-13環己烯之生成機制........................................................................................35 圖3-14 DAST之反應機制........................................................................................36 圖3-15化合物A1a之31P光譜圖............................................................................37 圖3-16化合物A1a之13C光譜圖............................................................................37 圖3-17常化合物3a之1H光譜圖............................................................................40 圖3-18化合物3a之IR吸收光譜圖........................................................................40 圖3-19化合物2a之19F光譜圖...............................................................................41 圖3-20化合物13a與化合物2a之1H光譜疊圖....................................................43 圖3-21化合物13a之31P光譜圖.............................................................................43 圖3-22化合物B1a水解後之31P光譜圖................................................................45 圖3-23化合物24之逆合成分析..............................................................................47 圖3-24化合物17之1H光譜圖................................................................................50 圖3-25化合物25之1H光譜圖................................................................................52 圖3-26化合物25之31P光譜圖...............................................................................53 表目錄 表1-1一系列具有反應性親電子基團的化學探針....................................................6 表1-2常見之連接橋種類............................................................................................9 表1-3常見之螢光團發報端......................................................................................10 表 2-1一系列有機磷酯解酶抑制劑之化學結構.....................................................14 反應式目錄 式一…………………………………..……………………………………………..23 式二…………………………………..……………………………………………..25 式三…………………………………..……………………………………………..27 式四…………………………………..……………………………………………..28 式五…………………………………..……………………………………………..30 式六…………………………………..……………………………………………..32 式七…………………………………..……………………………………………..32 式八…………………………………..……………………………………………..34 式九…………………………………..……………………………………………..35 式十…………………………………..……………………………………………..37 式十一………………………………..……………………………………………..38 式十二………………………………..……………………………………………..39 式十三………………………………..……………………………………………..41 式十四………………………………..……………………………………………..42 式十五………………………………..……………………………………………..45 式十六………………………………..……………………………………………..49 式十七………………………………..……………………………………………..49 式十八………………………………..……………………………………………..50 式十九………………………………..……………………………………………..51 | |
dc.language.iso | zh-TW | |
dc.title | 苯甲基氟化磷酸酯類化學探針之開發 | zh_TW |
dc.title | Development of Activity Probes based on Benzyl Fluorophosphonate | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蔡蘊明,吳世雄 | |
dc.subject.keyword | 化學探針,苯甲基氟化磷酸酯,烷基,連接橋,疊氮基團,生物素,螢光團, | zh_TW |
dc.subject.keyword | chemical probes,benzyl fluorophosphonate,alkyl groups,linker,azido group,biotin,rhodamine, | en |
dc.relation.page | 93 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2009-09-17 | |
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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