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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 | Jui-Yin Yu | en |
dc.contributor.author | 俞瑞胤 | zh_TW |
dc.date.accessioned | 2021-07-11T14:34:28Z | - |
dc.date.available | 2028-12-31 | |
dc.date.copyright | 2018-07-31 | |
dc.date.issued | 2018 | |
dc.date.submitted | 2018-07-25 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77767 | - |
dc.description.abstract | 在治療細菌的感染上,抗生素的使用扮演舉足輕重的角色,然而面對具有多重抗藥性的細菌威脅,必須不斷探索新穎的抗生素及新的藥物作用標靶來對抗。轉醣酶與轉胜肽酶是兩個參與細菌細胞壁生合成的重要酵素。藉由這兩種酵素的催化,單體lipid II可以進行聚合而生成網狀聚合物“肽聚醣”。肽聚醣的生成可以幫助細菌對抗內部所產生的滲透壓,進而保持細菌的形狀與完整性。除了像β-內醯胺類抗生素等針對轉胜肽酶的抑制劑,由於轉醣酶在細胞壁生合成中扮演不可或缺的角色及具有藥物易達性,使得以轉醣酶為目標而開發的新型抗生素是極具吸引力的,而且轉醣酶裸露在細菌細胞膜外側,使得藥物在與酵素結合的過程中不會遇上阻礙。
依據天然抑制劑moenomycin的結構為基礎,我們設計並合成出一系列phosphorylpropanoate衍生物作為具有潛力的轉醣酶抑制劑。設計的抑制劑具有一些帶有不同取代基的芳香烴基團、一個比phosphoglycerate更穩定並連接有一段由triazole為架構之長直脂鏈的phosphorylpropanoate基團,以及一段用來連結上述兩基團的高絲胺酸、胺基或醯胺基連接鏈。期望這些抑制劑可以用來模擬單體lipid II在進行轉醣化過程中所形成過渡態之電荷與結構。 在成功合成出一系列具有潛力的轉醣酶抑制劑後,我們透過高效液相層析–轉醣酶活性分析法及最低抑菌濃度檢測來確認所合成之抑制劑是否具有良好的抑菌效果。根據活性測試的結果,phosphorylpropanoate化合物具有長直脂鏈(例如63a、63c及63e)或聯苯基鏈(63g)的衍生物顯示比具有膽固醇鏈、含支鏈之脂鏈和不飽和脂鏈的衍生物擁有更高的轉醣酶抑制活性,然而這些phosphorylpropanoate化合物卻喪失了抗菌活性。在所有合成的phosphorylpropanoate衍生物中,帶有聯苯基團及胺基連接鏈的化合物(例如94及123)具有較顯著的轉醣酶抑制活性,推論是由於化合物與轉醣酶活性中心產生特定π系統間的作用力。此外化合物94可有效抑制金黃色葡萄球菌,並擁有最低抑菌濃度值為6.3 μM。若將氟取代基引入聯苯基團上(例如112e及112f)可更加提升化合物的抗菌活性。然而若在聯苯基團上3號或5號位置引入R3取代基將會使聯苯的立體構形改變,進而降低與轉醣酶活性中心之間所產生特定π系統間的作用力。相較於化合物94,雙碳鏈長的化合物118預期其正電胺離子將更接近轉醣化過渡態中所形成之電荷的位置,而具有更好的轉醣酶抑制活性。此外,具有三級胺基化合物121及123則具有提升此正電胺離子的生成能力,而活性測試結果也顯示出這類化合物均具有比化合物94更高的轉醣酶抑制活性。若將連接鏈換成較為剛性的piperidine(例如127及128),則維持一樣的轉醣酶抑制活性。 除了利用轉醣酶分子模擬的方式,我們也希望用光親和性標示法來確立聯苯基phosphorylpropanoate衍生物與轉醣酶活性中心的結合區域。此外,綜合本文設計的所有轉醣酶抑制劑,顯示其phosphorylpropanoate基團、聯苯基團及能產生正價性質之胺基連接鏈是提供與轉醣酶活性中心之間作用力的重要區域,這些結構上的重要特性將是一個基礎去開發出具有更佳效果的轉醣酶抑制劑和抗菌劑。 | zh_TW |
dc.description.abstract | The use of antibiotics has a great impact on the treatment of bacterial infections. However, emergence of multi-drug resistant bacteria requires discovery of new antibacterial targets and drugs. Transglycosylase (TGase) and transpeptidase (TPase) are two important enzymes involved in bacteria cell wall biosynthesis. By catalysis of TGase and TPase, the substrate lipid Ⅱ is polymerized to form the netlike polymer peptidoglycan, which can resist internal osmotic pressure to maintain the cell shape and integrity. In addition to TPase inhibitors (e.g. β-lactam antibiotics), TGase has become an attractive target for development of new antibiotics because of its indispensable function and accessibility. As TGase is located on the external surface of bacterial membrane, the inhibitor would bind to TGase without any obstacle.
Based on the structure of moenomycin, we designed and synthesized some potential TGase inhibitors of phosphorylpropanoate derivatives that contain the aromatic moieties with different substituents, a phosphorylpropanoate moiety, which is expected to increase the stability of phosphoglycerate, bearing a triazole-based straight lipid chain, and two above-mentioned moieties are connected by homoserine, amide or amine linkers. These inhibitors were expected to mimic the oxonium transition state during the lipid II transglycosylation. The potential TGase inhibitors were synthesized and subjected to HPLC-based TGase fluorescence assay and MIC measurement. The phosphorylpropanoate compounds bearing straight lipids (e.g. 63a, 63c and 63e) or biphenyl group (63g) displayed higher TGase inhibitory activity than the analogous compounds having cholestery, branched or unsaturated lipids. However, these phosphorylpropanoate compounds lost antibacterial activity. Among all the synthesized phosphorylpropanoate derivatives, compounds bearing biphenyl moiety and amine linker (e.g. 94 and 123) showed appreciable TGase inhibition, presumably due to the particular π–π interaction in TGase active site. In addition, compound 94 effectively suppressed the growth of S. aureus with MIC value of 6.3 μM. Introduction of fluorine atoms to biphenyl moiety (e.g. 112e and 112f) did increase antibacterial activity. However, the conformation of biphenyl group may vary by the (R3)n substituents at 3- or 5-positions, and thus may not retain the presumed π–π interaction in the TGase active site. Compound 118 bearing a two-carbon linker, which was expected to place the aminium ion at a closer position to mimic the oxonium ion in the transition state of transglycosylation, had better TGase inhibitory activity than compound 94. Compounds 121 and 123 containing tertiary amine moiety, which could enhance the formation of positively charged aminium ion, also showed higher TGase inhibitory activity than compound 94. Replacing the flexible linker with rigid piperidine (e.g. 127 and 128) retain the TGase inhibitory activity. In addition to molecular docking experiments, the photoaffinity labeling strategy could be used to identify the exact amino acid residues of TGase for binding with phosphorylpropanoate derivatives. Among all of the TGase inhibitors designed in this study, the phosphorylpropanoate, amine linkage and biphenyl group appear to be important moieties to provide the necessary interactions with the active site of TGase. These important elements will serve as a foundation to explore more effective TGase inhibitors and antibacterial agents. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T14:34:28Z (GMT). No. of bitstreams: 1 ntu-107-F99223105-1.pdf: 32796108 bytes, checksum: 259b3eb959bfe724c997b36aa332fa28 (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | Table of Contents
Abstract in Chinese……………………………………...…….......………………………...I Abstract in English……………………………………...…………………........…………III Table of Contents………………………………………..…………………….........……..VII Index of Figures………………………………………...……………………..........…….XII Index of Schemes………………………………………..……………….…..….......…...XVI Index of Tables……………………………………………..…………….……..........…….XIX Abbreviations…………………………………………………………….………..............XXII Chapter 1. Introduction………………………………..…………………….....…..……..1 1.1 Background…………………………………….………………………...........……….1 1.2 Gram-positive Bacteria and Gram-negative Bacteria………..…......................................……………1 1.3 Bacterial Cell Wall Biosynthesis Pathway and Monomer Lipid II…….....................................……3 1.4 Penicillin-binding Proteins (PBPs) and Structure of Transglycosylase….…......................................7 1.5 Mechanism of Transglycosylation……………………………….…...11 1.6 Development of Antibiotics……………………………………….…………..15 1.7 Antibiotics of Peptidoglycan Biosynthesis………………………..............................………….17 1.8 Development of Transglycosylase Inhibitors……………………..………................................….23 1.9 Research of Transglycosylase Inhibitors in Our Laboratory…..…………........................................34 1.10 Analytic Methods for Assessment of Transglycosylase Activity………............................................……37 1.10.1 Radioactive labeling………..…………………………….....………..…….37 1.10.2 Fluorescence labeling for HPLC analysis…………..…...38 1.10.3 Surface plasmon resonance…………………………..…..………...…….40 1.10.4 Fluorescence anisotropy……………………………...…….………..…...41 1.10.5 Förster resonance energy transfer……......………………..42 Chapter 2. Design of TGase Inhibitors…………………………..………………..45 Chapter 3. Results and Discussion…………………………………..……..………….53 3.1 Synthesis of TGase Inhibitors………………………………....……..53 3.1.1 Synthesis of phosphoglycerate containing branched lipid…….…............................................…...54 3.1.2 Synthesis of phosphorylpropanoate inhibitors containing a lipid library…………………………………..…………...………………………56 3.1.2.1 Synthesis of phosphorylpropanoate moiety from D-mannitol…................................................57 3.1.2.2 Synthesis of phosphorylpropanoate moiety from L-serine…….................................................61 3.1.3 Synthesis of phosphorylpropanoate derivatives containing 2,3,4-trihydroxybenzyl group……………………....………...66 3.1.3.1 Synthesis of phosphorylpropanoate derivatives containing L-serine as linker……………………………………………......……...66 3.1.3.2 Synthesis of phosphorylpropanoate derivatives containing L-homoserine as linker…………………………….……...…....……70 3.1.4 Synthesis of phosphorylpropanoate derivatives containing linkers of different lengths………….………………...……….75 3.1.5 Synthesis of phosphorylpropanoate derivatives containing biphenyl moiety……………………......…...…..……………………..76 3.1.6 Synthesis of phosphorylpropanoate conjugates containing substituted biphenyl moieties…………......…………………81 3.1.7 Synthesis of pyrophosphonate 71 and phosphorylpropanoate monoester derivatives……………………….……...83 3.1.8 Synthesis of biphenyl-linked phosphorylpropanoate derivatives containing shorter linker………………....……………………..84 3.1.9 Synthesis of biphenyl-linked phosphorylpropanoate derivatives containing tertiary amine……..…......…………………….85 3.1.10 Synthesis of biphenyl-linked phosphorylpropanoate derivative containing cyclic amine linker…………………………..…...87 3.1.11 Synthesis of biphenyl-linked phosphoglycerate derivative………........................................…..…89 3.1.12 Synthesis of phosphorylpropanoate derivatives 138a–138c containing substituted biphenyl moieties…………………….….…91 3.1.13 Synthesis of salicylanilide-based phosphorylpropanoate derivative….........................94 3.1.14 Synthesis of benzophenone-linked phosphorylpropanoate derivatives as photoaffinity probes…99 3.2 Biological Activity………………………………………..………………...…..101 3.2.1 Transglycosylase activity assay…………………….….....….105 3.2.2 Minimum inhibitory concentration (MIC) assay...…106 3.2.3 Biological activities of phosphoglycerate containing branched lipid...............................106 3.2.4 Biological activities of phosphorylpropanoate containing various lipid substituents………......……...……...107 3.2.5 Biological activities of phosphorylpropanoate derivatives containing different linkers and aromatic groups……………….....…...............................…………...109 3.2.6 Biological activities of phosphorylpropanoate compounds having substituted biphenyl moieties…………………..…112 3.2.7 Biological activities of phosphorylpropanoate derivatives containing shorter linker or tertiary amine, pyrophosphonate and phosphonate esters.....………………………...…114 3.2.8 Biological activities of the derivatives of phosphorylpropanoate 118................................116 3.2.9 Biological activity of salicylanilide-based phosphorylpropanoate derivatives……………........………………………….118 3.2.10 Determination of the IC50 values of some biphenyl-based phosphorylpropanoate derivatives………………..…….…………..…120 3.2.11 TGase inhibition and antibacterial activity of benzophenone-linked phosphorylpropanoate derivatives...…123 3.3 TGase Molecular Modeling…………………………..……………….…...…124 3.4 Conclusions………………………...…………………………….........……………128 Chapter 4. Experimental Section……………………...……………………...…….134 4.1 General Part……………………………...…..……………………………...........134 4.2 HPLC-based TGase Fluorescence Assay………………………………...…135 4.3 Determination of Minimal Inhibition Concentration (MIC)……….…...........................................…..136 4.4 Molecular Modeling…………………………………….......………….………....137 4.5 Synthetic Procedures and Characterization of Compounds...............................................138 References…………………………………………...…….............…………………………..339 Appendix HPLC Diagrams; 1H, 13C and 31P NMR Spectra…..…..………….…….353 | |
dc.language.iso | en | |
dc.title | 以磷酸基甘油酸酯衍生物為架構來設計及合成細菌轉醣酶的抑制劑 | zh_TW |
dc.title | Structure-based design and synthesis of phosphoglycerate–lipid derivatives as the inhibitors against bacterial transglycosylases | en |
dc.type | Thesis | |
dc.date.schoolyear | 106-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 吳世雄(Shih-Hsiung Wu),陳平(Richard P. Cheng),羅禮強(Lee-Chiang Lo),王宗興(Tsung-Shing Wang),鄭婷仁(Ting-Jen Cheng) | |
dc.subject.keyword | 轉醣?,抑制劑,抗生素,磷酸基甘油酸酯,聯苯, | zh_TW |
dc.subject.keyword | transglycosylase,inhibitor,antibiotic,moenomycin,phosphoglycerate,biphenyl, | en |
dc.relation.page | 578 | |
dc.identifier.doi | 10.6342/NTU201801845 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2018-07-26 | |
dc.contributor.author-college | 理學院 | zh_TW |
dc.contributor.author-dept | 化學研究所 | zh_TW |
dc.date.embargo-lift | 2028-12-31 | - |
顯示於系所單位: | 化學系 |
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