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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 方俊民 | |
| dc.contributor.author | Chen-Yu Liu | en |
| dc.contributor.author | 劉朕與 | zh_TW |
| dc.date.accessioned | 2021-06-14T16:48:17Z | - |
| dc.date.available | 2013-08-06 | |
| dc.date.copyright | 2008-08-06 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-07-29 | |
| dc.identifier.citation | (1) (a) Walsh, C. T.; Wright, G. Chem. Rev. 2005, 105, 391–393. Introduction: antibiotic resistence. (b)吳天鳴，朱延和，細菌的抗藥性：科學發展，九二年，三六四期，64–73。
(2) (a) Sanders, C. C.; Sanders, W. E. Jr. Adv. Exp. Med. Biol. 1995, 390, 15–23. Resistence to antibacterial agents. (b)許家偉，張智培，了解微生物抗藥性的機制：科學月刊，八六年，三二五期。 (3) Liu, H.; Ritter, T. K.; Sadamoto, R.; Sears, P. S.; Wu, M.; Wong, C.-H. ChemBioChem 2003, 4, 603–609. Acceptor specificity and inhibition of the bacterial cell-wall glycosyltransferase MurG. (4) (a) Kahne, D.; Leimkuhler, C.; Lu, W.; Walsh, C. T. Chem. Rev. 2005, 105, 425–448. Glycopeptide and lipoglycopeptide antiobiotics. (b) Williams, D. H.; Williamson, M. P.; Butcher, D. W.; Hammond, S. J. J. Am. Chem. Soc. 1983, 105, 1332–1339. Detailed binding sites of the antibiotics vancomycin and ristocetin A: determination of intermolecular distancesin antibiotic/substrate complexes by use of the time-dependent NOE. (5) (a) Bugg, T. D.; Wright, G. D.; Dutka-Malen, S.; Arthur, M.; Courvalin, P.; Walsh, C. T. Biochemistry 1991, 30, 10408–10415. 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Inhibition of transglycosylation involved in bacterial peptidoglycan synthesis. (10) Sofia, M. J.; Allanson, N.; Hatzenbuhler, N. T.; Jain, R.; Kakarla, R.; Kogan, N.; Liang, R.; Liu, D.; Silva, D. J.; Wang, H.; Gange, D.; Anderson, J.; Chen, A; Chi, F.; Dulina, R.; Huang, B.; Kamau, M.; Wang, C.; Baizman, E.; Branstrom, A.; Bristol, N.; Goldman, R.; Han, K.; Longley, C.; Midha, S.; Axelrod, H. R. J. Med. Chem. 1999, 42, 3193–3198. Discovery of novel disaccharide antibacterial agents using a combinational library approach. (11) Liu, H.; Wong, C.-H. Bioorg. Med. Chem. 2006, 14, 7187–7195. Characterization of a transglycosylase domain of Streptococcus pneumoniae PBP1b. (12) van Heijenoort, Y.; Gomez, M.; Derrien, M.; Ayala, J.; van Heijenoort, J. J. Bacteriol. 1992, 174, 3549–3557. Membrane intermediates in the peptidoglycan metabolism of Escherichia coli: possible roles of PBP 1b and PBP 3. (13) VanNieuwenhze, M. S.; Mauldin, S. C.; Zia-Ebrahimi, M.; Aikins, J. A.; Blaszczak, L. C. J. Am. Chem. Soc. 2001, 123, 6983–6988. The total synthesis of Lipid I. (14) (a) VanNieuwenhze, M. S.; Mauldin, S. C.; Zia-Ebrahimi, M.; Winger, B. E.; Hornback , W. J.; Saha, S. L.; Aikins, J. A.; Blaszczak, L. C. J. Am. Chem. Soc. 2002, 124, 3656–3660. The first total synthesis of Lipid II: the final monomeric intermediate in bacterial cell wall synthesis. (b) Schwartz, B.; Markwalder, J. A.; Wang, Y. J. Am. Chem. Soc. 2001, 123, 11638–11643. Lipid II: total synthesis of the bacterial cell wall precursor and utilization as a substrate for glycosyltransfer and transpeptiation by penicillin binding protein (PBP) 1b of Escherichia coli. (c) Narayan, R. S.; VanNieuwenhze, M. S. Eur. J. Org. Chem. 2007, 1399–1414. Synthesis of substrate and biochemical probes for study of the peptidoglycan biosynthetic pathway. (15) Hitchcock, S. A.; Eid, C. N.; Aikins, J. A.; Zia-Ebrahimi, M.; Blaszczak, L. C. J. Am. Chem. Soc. 1998, 120, 1916–1917. The first total synthesis of bacterial cell wall precursor UDP-N-acetylmuramyl-pentapeptide (Park nucleotide). (16) Warren, C. D.; Jeanloz, R. W. Biochemistry 1972, 11, 2565–2572. Chemical synthesis of pyrophosphodiesters of carbohydrates and isoprenoid alcohols. Lipid intermediates of bacterial cell wall and antigenic polysaccharide biosynthesis. (17) Imperiali, B.; Zimmerman, J. W. Tetrahedron Lett. 1990, 31, 6485–6488. Synthesis of dolichylpyrophosphate-linked oligosaccharide. (18) Danilov, L. L.; Maltsev, S. D.; Shibaev, V. N.; Kochetkov, N. K. Carbohydr. Res. 1981, 88, 203–211. Synthesis of polyprenyl pyrophosphate sugars from unprotected mono- and oligo-saccharide phosphates. (19) Men, H.; Park, P.; Ge, M.; Walker, S. J. Am. Chem. Soc. 1998, 120, 2484–2485. Substrate synthesis and activity assay for MurG. (20) Ye, X.-Y.; Lo, M.-C.; Brunner, L.; Walker, D.; Kahne, D.; Walker, S. J. Am. Chem. Soc. 2001, 123, 3155–3156. Better substrates for bacterial transglycosylases. (21) Schwartz, B.; Markwalder, J. A.; Seitz, S. P.; Wang, Y.; Stein, R. L. Biochemistry 2002, 41, 12552–12561. A kinetic characterization of the glycosyltransferase activity of Eschericia coli PBP1b and development of a continuous fluorescence assay. (22) (a) Stembera, K.; Vogel, S.; Buchynskyy, A.; Ayala, J. A.; Wezel, P. ChemBioChem 2002, 3, 559–565. A surface plasmon resonance analysis of the interaction between the antibiotic moenomycin A and penicillin-binding protein 1b. (b) http://www.bioon.com.cn/doc/showarticle.asp?newsid=6446 (23) Walsh, C. T. Science 1999, 284, 442–443. Deconstructing vancomycin. (24) Deacon, J. Fungal Biology ; Blackwell: Oxford, 2005. (25) (a) Osawa, T.; Jeanloz, R. W. J. Org. Chem. 1965, 30, 448–450. An improved, stereoselective synthesis of 2-amino-3-O-(D-1-carboxyethyl)-2-deoxy-D-glucose (muramic acid) (b) Veselý, J.; Ledvina, M.; Jindřich, J.; Šaman, D.; Trnka, T. Collect. Czech. Chem. Commun. 2003, 68, 1264–1274. Improved synthesis of 1,2-trans-acetates and 1,2-trans-ethyl 1-thioglycosides derived from 3,4,6-tri-O- acetyl-2-deoxy-2-phthalimido-D-hexopyranosides. (c) Sarkar, S. K.; Roy, N. J. Carbohydr. Chem. 2003, 22, 285–296. Synthesis of the blocked pentasaccharide derivative related to the repeating unit of the O-antigen from Shigella dysenteriae type 3 in the form of its ally glycoside. (26) Maeda, T.; Nishimura, S.-I. Chem. Eur. J. 2008, 14, 478–487. FRET-based direct and continuous monitoring of human fucosyltransferases activity: an efficient synthesis of versatile GDP-L-fucose derivatives from abundant D-galactose. (27) (a) Chen, K.-M.; Semple, J. E.; Joullie, M. M. J. Org. Chem. 1985, 50, 3997–4005. Total synthesis of fungal metabolites and functionalized furanones. (b) Coates, R. M.; Johnson, M. W. J. Org. Chem. 1980, 45, 2685–2697. Stereoselective synthesis of moenocinol and assignment of its carbon-13 nuclear magnetic resonance spectrum. (28) (a) Sato, K.; Miyamoto, O.; Inoue, S.; Furusawa, F.; Matsuhashi, Y. Chem. Lett. 1983, 725–728. Stereoselective synthesis of a cisoid C10 isoprenoid building block and some all-cis-polyprenols. (b) Sato, K.; Miyamoto, O.; Inoue, S.; Furusawa, F.; Matsuhashi, Y. Chem. Lett. 1984, 1105–1108. Genaral method of stereospecific synthesis of natural polyprenols. Synthesis of betulaprenol-6, -7, -8, and -9. (29) Choo, H.; Beadle, J. R.; Chong, Y.; Trahan, J.; Hosterler, K. Y. Bioorg. Med. Chem. 2007, 15, 1771–1779. Synthesis of the 5-phosphono-pent-2-en-1-yl nucleosides: a new class of antiviral acyclic nucleoside phosphonates. (30) Cheng, W.-C.; Lin, C.-C.; Kurth, M. J. Tetrahedron Lett. 2002, 43, 2967–2970. Dimsyl anion in the monoalkylation of solid-phase alkyl sulfones. (31) Liu, H.-J.; Yip, J.; Shia, K.-S. Tetrahedron Lett. 1997, 38, 2253–2256. Reductive cleavage of benzyl ethers with lithium naphthalene. A convenient method of debenzylation. (32) Lee, G.-H.; Choi, E.-B.; Lee, E.; Pak, C.-S. Tetrahedron Lett. 1993, 34, 4541–4542. An efficient desulfonation method mediated by magnesium in ethanol. (33) Keck, G. E.; Savin, K. A.; Weglarz, M. A. J. Org. Chem. 1995, 60, 3194–3204. Use of samarium diiodide as an alternative to sodium/mercury amalgam in the Julia-Lythgoe olefination. (34) Grassi, D.; Lippuner, V.; Aebi, M.; Brunner, J.; Vasella, A. J. Am. Chem. Soc. 1997, 119, 10992–10999. Synthesis and enzymatic phosphorylation of a photoactivatable dolichol analogue. (35) Fujita, Y.; Ishiguro, M.; Onishi, T.; Nishida, T. Bull. Chem. Soc. Jpn. 1982, 55, 1325–1326. A new efficient and stereoselective synthesis of ubiquinone-10. (36) Minutolo, F.; Bertini, S.; Betti, L.; Danesi, R.; Gervasi, G.; Giannaccini, G.; Martinelli, A.; Papini, A. M.; Peroni, E.; Placanica, G.; Rapposelli, S.; Tuccinardi, T.; Macchia, M. ChemMedChem 2006, 1, 218–224. Synthesis of stable analogues of geranylgeranyl diphosphate possesing a (Z,E,E)-geranylgeranyl side chain, docking analysis, and biological assays for prenyl protein transferase inhibition. (37) Feld, B. K.; Weiss, G. A. Bioorg. Med. Chem. Lett. 2006, 16, 1665–1667. Convenient methods for the synthesis of P1-farnesyl-P2-indicator diphosphates. (38) Inomata, K.; Igarashi, S.; Mohri, M.; Yamamoo, T.; Kinoshita, H.; Kotake, H. Chem. Lett. 1987, 707–710. Regio- and stereoselective synthesis of allylic and homoallylic alcohols by the reductive desulfonation of allylic sulfone derivatives. Application to the synthesis of (±)-lavandulol and isolavandulol. (39) Terao, S.; Kato, K.; Shiraishi, M.; Morimoto, H. J. Chem. Soc., Perkin Trans. 1 1978, 1101–1110. Synthesis of ubiquinones. Elongation of the heptaprenyl side-chain in ubiquinone-7. (40) Takanashi, S.-I.; Mori, K. Liebigs Ann./Recl. 1997, 825–838. Synthesis of lurlenic acid and lurlenol, the sex pheromones of the green flagellate Chlamydomonas. (41) Breukink, E.; van Heusden, H. E.; Vollmerhaus, P. J.; Swiezewska, E.; Brunner, L.; Walker, S.; Heck, A. J. R.; de Kruijff, B. J. Biol. Chem. 2003, 278, 19898–19903. Lipid II is an intrinsic component of the pore induced by nisin in bacterial membranes. (42) (a) Chehade, K. A. H.; Andres, D. A.; Morimoto, H.; Spielmann, H. P. J. Org. Chem. 2000, 65, 3027–3033. Design and synthesis of a transferable farnesyl pyrophosphate analogue to ras by protein farnesyltransferase. (b) Prisic, S.; Xu, J.; Coates, R. M.; Peters, R. J. ChemBioChem 2007, 8, 869–874. Probing the role of the DXDD motif in class II diterpene cyclases. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/40461 | - |
| dc.description.abstract | 自從八十幾年前弗萊明發現青黴素以後，抗生素一直被用來對抗細菌感染所造成的疾病。然而，即使是萬古黴素，人類用來對抗細菌的最後一樣武器，也因細菌的突變而產生抗藥性。因此，發展新一代的抗生素以對抗細菌是當今全民健康的重大課題。
轉醣酶(TG)是一個極具發展價值以研發新一代抗生素的重要目標。因為它裸露在細胞膜的外側，藥物不需進入細菌細胞內側，較不易受到其他干擾。它的功能為催化lipid II聚合而形成細菌的細胞壁。 研究TG的困難處有幾點，其中最難以解決的是缺乏lipid II的來源。從細菌的細胞利用分離而獲得研究所需的量，是困難且步驟繁雜的。我們利用化學合成的方法合成了lipid II以及只含有四個Z-form脂肪鏈的lipid II衍生物，試著解決這個問題。 之後，我們更進一步的將所合成的lipid II和其衍生物利用化學方法連結螢光團(dansyl，fluorescein和naphthalene)。再與Clostridium difficile的penicillin-binding protein 1b (PBP1b)混合反應，以HPLC和螢光偵測器以研究它們和TG之間的相互作用關係。由實驗的結果可知，因Fluorescein-LII的胜肽鏈上所含的fluorescein較Dansyl分子結構大了許多，造成TG無法辨識。但是，Dansyl-LII, D-C20-LII, and FRET-LII則仍為TG的受質。因此，我們可於D-C20-LII與PBP1b的反應中加入內標準品，以定量分析的方法初步篩選TG抑制劑。 | zh_TW |
| dc.description.abstract | Since the discovery of penicillin by Fleming more than 80 years ago, antibiotics have been needed to treat infections caused by bacteria. However, even vancomycin, a potent antibiotic as the final weapon against bacterial infections, has encountered the problem of drug resistance. The development of new antibiotic to treat resistant bacterial infections is an important issue for public health.
Transglycosylase (TG) is a potential target for development of new antibiotics. It is located on the extracellular surface of the bacterial cell membrane, where it catalyzes the polymerization of lipid II to establish the bacterial cell wall. One of the difficulties in studying TG is the lack of lipid II, though it can be isolated from bacterial membrane in little amount by tedious procedure. In this thesis, I report a chemical synthesis that provides an alternative method to obtain substantial amounts of lipid II and its analogues containing four cis-isoprene units. Furthermore, the natural lipid II and its analogues were elaborated with fluorescence probes, for example, dansyl, fluorescein, and naphthyl via chemical methods. These fluorescent substrates were used to study the transglycosylation in cell wall formation. The reactivity between lipid II analogs and PBP1b were moitored by HPLC using fluorescence detector. Based on the analysis, fluorescein conjugated with Fluorescein-LII is too bulky to be recognized by TG, but Dansyl-LII, D-C20-LII, and FRET-LII are still the substrates of TG. By normalization with internal standard, we may screen the inhibitors based on the decrease of D-C20-LII monitored by HPLC. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-14T16:48:17Z (GMT). No. of bitstreams: 1 ntu-97-D93223005-1.pdf: 2258799 bytes, checksum: f98e48b1517978a9d47e5355ff48515d (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 誌謝．．．．．．．．．．．．．．．．．．．．．．．．．．I
中文摘要．．．．．．．．．．．．．．．．．．．．．．．．III 英文摘要．．．．．．．．．．．．．．．．．．．．．．．．VI 目錄．．．．．．．．．．．．．．．．．．．．．．．．．．IX 圖目錄．．．．．．．．．．．．．．．．．．．．．．．．．XI 表目錄．．．．．．．．．．．．．．．．．．．．．．．．．XIV 流程目錄．．．．．．．．．．．．．．．．．．．．．．．．XV 反應式目錄．．．．．．．．．．．．．．．．．．．．．．．XVI 簡稱用語對照表．．．．．．．．．．．．．．．．．．．．．XVII 第一章 緒論．．．．．．．．．．．．．．．．．．．．．．．1 1-1 抗生素與抗藥性．．．．．．．．．．．．．．．．．．． 1 1-2 細胞壁合成機制與抗藥性．．．．．．．．．．．．．．． 2 1-3 Penicillin-Binding Protein．．．．．．．．．．．．． 5 1-4 Moenomycin及其衍生物．．．．．．．．．．．．．．．． 5 1-5 Lipid II及其衍生物的合成．．．．．．．．．．．．．． 8 1-6 Lipid II及Dansyl-LII之活性測試．．．．．．．．．．．15 1-7 以Surface Plasmon Resonance作為篩選TG抑制劑之方法． 16 第二章 結果與討論．．．．．．．．．．．．．．．．．．． 19 2-1 Lipid II合成．．．．．．．．．．．．．．．．．．．．19 2-2 胜肽含螢光團Lipid II衍生物之合成．．．．．．．．．．26 2-3 脂肪鏈含螢光團Lipid II衍生物之合成．．．．．．．．．29 2-4 脂肪鏈中含氧原子Lipid II 之合成．．．．．．．．．． 51 2-5 Lipid II及衍生物之活性測試．．．．．．．．．．．．．54 2-5.1 Dansyl-LII和Fluorescein-LII與TG的活性測試．．．． 54 2-5.2 D-C20-LII與TG的活性測試．．．．．．．．．．．．． 58 2-5.3 FRET-LII與TG的活性測試．．．．．．．．．．．．．．62 2-6 結論．．．．．．．．．．．．．．．．．．．．．．．．64 第三章 實驗部份．．．．．．．．．．．．．．．．．．．． 65 3-1 General information．．．．．．．．．．．．．．．． 65 3-2 Assay of transglycosylase activity with Dansyl-LII, Fluorescein-LII, and FRET-LII．．．．．．．．．．． 65 3-3 Assay of transglycosylase activity with D-C20-LII 66 3-4 Synthetic procedures and compound characterizations 66 參考文獻與資料．．．．．．．．．．．．．．．．．．．． 111 附錄：1H及13C NMR光譜．．．．．．．．．．．．．．．．．119 | |
| dc.language.iso | zh-TW | |
| dc.subject | 抗生素 | zh_TW |
| dc.subject | 轉醣酶 | zh_TW |
| dc.subject | 抑制劑 | zh_TW |
| dc.subject | inhibitor | en |
| dc.subject | lipid II | en |
| dc.subject | antibiotic | en |
| dc.subject | transglycosylase | en |
| dc.title | 合成Lipid II及其衍生物以研究細胞壁合成中的轉醣化過程 | zh_TW |
| dc.title | Total Synthesis of Lipid II and Analogs for the Study of Transglycosylation in Cell Wall Formation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 蔡蘊明,羅禮強,林俊宏,馬徹,鄭偉杰 | |
| dc.subject.keyword | 轉醣酶,抗生素,抑制劑, | zh_TW |
| dc.subject.keyword | transglycosylase,inhibitor,antibiotic,lipid II, | en |
| dc.relation.page | 117 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-07-31 | |
| 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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