跳到主要內容

臺灣博碩士論文加值系統

(3.236.50.201) 您好!臺灣時間:2021/08/05 20:50
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:傅淳
研究生(外文):Chun Fu
論文名稱:以化學合成法合成鮑氏不動桿菌的莢膜五醣並作為免疫抗體評估
論文名稱(外文):Chemical synthesis of pentasaccharide of capsular polysaccharide from Acinetobacter baumannii for immunological evaluation
指導教授:吳世雄吳世雄引用關係
指導教授(外文):Shih-Hsiung Wu
口試委員:鄭偉杰羅禮強施增廉
口試委員(外文):Wei-Chieh ChengLee-Chiang LoTzenge-Lien Shih
口試日期:2015-07-17
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:生化科學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:145
中文關鍵詞:鮑氏不動桿菌莢膜多醣化學合成醣基化醣構築體
外文關鍵詞:Acinetobacter baumanniicapsular polysaccharidechemical synthesisglycosylationsaccharide building blocks
相關次數:
  • 被引用被引用:0
  • 點閱點閱:72
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
鮑氏不動桿菌 (Acinetobacter baumannii) 為好氧性革蘭氏陰性桿菌,是一種伺機性病原體,主要存在於醫院內,被分類為院內感染菌種。雖然它的致病力低,但仍會感染器官移植或免疫系統較差的患者,並誘發其他嚴重疾病 (如敗血症等),甚至危及生命。近年來,由於鮑氏不動桿菌對於抗生素逐漸產生抗藥性,且迅速擴散,使它在全球醫療健保體系中已經成為一種危險的病菌。在預防病菌感染上,細菌的多醣共軛疫苗有一些成功的實例,例如在肺炎鏈球菌 (Streptococcus pneumonia) 和腦膜炎雙球菌 (Neisseria meningitides) 的預防上,都有不錯的成效。所以我們對鮑氏不動桿菌的莢膜研究及醣共軛疫苗的開發深感興趣。最近的文獻報導指出,鮑氏不動桿菌的致病因子包含莢膜多醣 (capsular polysaccharide);另外針對鮑氏不動桿菌ATCC17978菌株的莢膜進一步分析,發現莢膜主要是由五醣為一個單體,並重複單體而組成 (如下圖所示)。由化學結構的觀點來看,這樣的結構非常獨特。目前也沒有文獻探討如何利用化學合成方法去對此菌莢膜中的醣類做研究。
在本論文中,我們設計了一個化學合成方法,可以合成天然物五醣,也從中得到更小片段、類似物、中間物。而我們主要著重於結構較特別的單醣A之化學合成。在A的醣構築體 (saccharide building block) 中,以葡萄糖胺作為骨架。而單醣A中主要的化學轉換有:(1) 將C3位置的水平鍵 (equatorial) 羥基轉換成乙醯胺基。(2) 專一性只在C4位置建構乙醯、C5位置建構羧酸官能基。而這個建構單醣A的合成策略,預期可以被延續應用於合成五醣及其他片段當中。希望在未來,這些合成化合物可以被進一步的應用於抗原表位 (antigenic epitope) 的探討及免疫抗體評估。




Acinetobacter baumannii are an aerobic gram-negative bacillus and an opportunistic bacterial pathogen primarily associated with hospital-acquired infections. It has low virulence but is capable of causing infection in organ transplants and people with compromised immune systems and it can cause serious and life-threatening infections. During recent years, it has become an increasing danger to the global healthcare system as a result of its rapid proliferation and increasing resistance to antibiotics and disinfectants. There are some successful cases of preventing of bacterial infection, like Streptococcus pneumonia and Neisseria meningitides. Recent reports show that the capsular polysaccharide is a virulence factors. Their analytic results show that one of structures of A. baumannii ATCC 17978 CPS is composed by the pentasaccharide as repeating unit (show as below). From the chemical structure point of view, it is not only unique, but also no synthetic method has been reported.
In this work, we would like to design a general and flexible synthetic method to prepare this pentasaccharide and its analogues including new fragments or intermediates. Most importantly, we focused on the synthesis of structurally unique and external monosaccharide A, using glucosamine as a starting material. Besides, the key transformations for preparing the A ring are : (1) the hydroxy group was converted to the acetamido group at the equatorially C3 position, and (2) the acetyl group at the C4 position and the carboxylic acid group at the C5 position were established. Expectedly, this approach toward the preparation of the monosaccharide A might be applied to the synthesis of the pentasaccharide and its derivatives or fragments, which allows us for further biological evaluation and immune response study in the future.


誌謝 I
中文摘要 II
英文摘要 III
目錄 IV
圖目錄 VII
表目錄 VIII
流程目錄 IX
中英文對照表 XI
簡稱與對照 XIV
第一章 緒論 1
1.1鮑氏不動桿菌(Acinetobacter baumannii) 1
1.2抗藥性 2
1.3莢膜多醣 (capsular polysaccharide) 3
1.4 醣共軛疫苗(Glycoconjugate Vaccine) 4
1.5實驗室先前對於莢膜的研究 5
1.6莢膜片段之單醣A生合成 6
1.7 研究目的與動機 7
第二章 結果與討論 8
2.1 鮑氏不動桿菌ATCC17978的莢膜五醣之逆合成分析 8
2.2 設計分析以及合成策略 10
2.3 單醣化合物1和2的合成 11
2.3.1中間產物9、11的製備 11
2.3.2中間產物14與15的製備 15
2.3.3中間產物18與19的製備 16
2.3.4中間產物31的製備 17
2.3.5中間產物34的製備之兩種路徑探討 21
2.3.6化合物1和2的合成路徑 24
2.4 雙醣3和4的合成 25
2.4.1醣受體41的製備 25
2.4.2醣基化反應合成以及醣予體的製備 26
2.4.3醣受體44的製備 28
2.4.4醣基化反應合成雙醣體中間物45 29
2.4.5 三醣之醣受體的製備 30
2.4.6醣受體51的製備 30
2.4.7醣基化反應合成雙醣體中間物52 31
2.4.8中間產物57的製備 32
2.4.9中間產物58的製備 34
2.4.10化合物3和4的合成 35
2.5 三醣5和6的合成 36
2.5.1 醣受體61的製備 36
2.5.2 醣予體64的製備 36
2.5.3 醣基化反應合成三醣體中間物65 37
2.5.4 化合物5和6的製備 38
2.6 總結 39
第三章 實驗部分 40
3.1實驗藥品 40
3.2 實驗儀器 40
3.3 實驗步驟與光譜數據 41
參考文獻 71
附錄 79


1.Baumann, P., Isolation of Acinetobacter from Soil and Water. J. Bacteriol. 1968, 96, 39–42.
2.Elliot J., Interspecies Transformation of Acinetobacter: Genetic Evidence for a Ubiquitous Genus. J. Bacteriol. 1972, 112, 917–931.
3.Scott, P.; Deye, G.; Srinivasan, A.; Murray, C.; Moran, K.; Hulten, E.; Fishbain, J.; Craft, D.; Riddell, S.; Lindler, L.; Mancuso, J.; Milstrey, E.; Bautista, C. T.; Patel, J.; Ewell, A.; Hamilton, T.; Gaddy, C.; Tenney, M.; Christopher, G.; Petersen, K.; Endy, T.; Petruccelli, B., An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus complex infection in the US military health care system associated with military operations in Iraq. Clin. Infect. Dis. 2007, 44, 1577–1584.
4.Camp, C.; Tatum, O. L., A Review of Acinetobacter baumannii as a Highly Successful Pathogen in Times of War. Lab. Med. 2010, 41, 649–657.
5.Peleg, A. Y.; Seifert, H.; Paterson, D. L., Acinetobacter baumannii: emergence of a successful pathogen. Clin. Microbiol. Rev. 2008, 21, 538–582.
6.Sandra I. ; Leigh G.; Dieter H.M., The Inanimate Environment of an Intensive Care Unit as a Potential Source of Nosocomial Bacteria : Evidence for Long Survival of Acinetobactoer calcoaceticus. Infect. Cont. Hosp. Ep. 1989, 10, 402–407.
7.Wendt, C.; Dietze, B.; Dietz, E.; Ruden, H., Survival of Acinetobacter baumannii on Dry Surfaces. J. Clin. Microbiol. 1997, 35, 1394–1397.
8.Towner, K. J., Acinetobacter: an old friend, but a new enemy. J. Hosp. Infect 2009, 73, 355–363.
9.Oncul, O.; Keskin, O. È.; Acarz, H. V.; Kucukardalõx, Y.; Evrenkaya, R.; Atasoyu, E. M.; C. Topx, S. N.; Ozkanz, S.; EmekdasËk, G.; avusËlu, S. C.; Us, M. H.; Pahsa, A.; GoÈkben, M., Hospital-acquired infections following the 1999 Marmara earthquake. J. Hosp. Infect. 2002, 51, 47–51.
10.Garnacho-Montero, J; Ortiz-Leyba, C; Jimenez-Jimenez, F. J.; Barrero-Almodo var, A. E.; Garcıa-Garmendia, J. L.; Bernabeu-Witteii, M.; Gallego-Lara, S. L.; Madrazo-Osuna, J, Treatment of Multidrug-Resistant Acinetobacter baumannii Ventilator- Associated Pneumonia (VAP) with Intravenous Colistin: A Comparison with Imipenem-Susceptible VAP. Treatment of A. baumannii VAP 2003, 36, 1111–1118.
11.(a) Devaud, M.; Kayser, F. H.; Bachi, B., Transposon-Mediated Multiple Antibiotic Resistance in Acinetobacter Strains. Antimicrob. Agents Ch. 1982, 22, 323–329; (b) Gordon, N. C.; Wareham, D. W., Multidrug-resistant Acinetobacter baumannii: mechanisms of virulence and resistance. Int. J. Antimicrob. Ag. 2010, 35, 219–226.
12.Dijkshoorn, L.; Nemec, A.; Seifert, H., An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat. Rev. Microbiol. 2007, 5, 939–951.
13.Kuo, S.-C.; Chang, S.-C.; Wang, H.-Y.; Lai, J.-F.; Chen, P.-C.; Shiau, Y.-R.; Huang, I.-W.; Lauderdale, T.-L. Y.; Hospitals, T., Emergence of extensively drug-resistant Acinetobacter baumannii complex over 10 years: Nationwide data from the Taiwan Surveillance of Antimicrobial Resistance (TSAR) program. BMC Infect. Dis. 2012, 12 ,200.
14.Gales, A. C.; Jones, R. N.; Sader, H. S., Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006-09). J. Antimicrob. Chemother. 2011, 66, 2070–2074.
15.Reinert, R. R.; Low, D. E.; Rossi, F.; Zhang, X.; Wattal, C.; Dowzicky, M. J., Antimicrobial susceptibility among organisms from the Asia/Pacific Rim, Europe and Latin and North America collected as part of TEST and the in vitro activity of tigecycline. J. Antimicrob. Chemother. 2007, 60, 1018–1029.
16.Gaddy, J. A.; Actis, L. A., Regulation of Acinetobacter baumannii biofilm formation. Future microbiol. 2009, 4, 273–278.
17.Costerton, J. W.; Irvin, R. T.,The bacterial glycocalyx in bature and disease. Ann. Rev. Microbiol 1981, 35, 299–324.
18.Roberts, I. S., The Biochemistry and genetics if capsular polysaccharude production in bacteria. Annu. Rev. Microbiol. 1996, 50, 285–315.
19.Pace, D., Glycoconjugate vaccines. Expert Opin. Biol. Ther. 2013, 13, 11–33.
20.Kuberan, B.; Linhardt, R. J., Carbohydrate Based Vaccines Curr. Org. Chem. 2000, 4, 653–677.
21.Stein, K. E., Thymus-Independent and Thymus-Dependent Responses to Polysaccharide Antigens. J. Infect. Dis. 1992, 165, s49–52.
22.Pollard, A. J.; Perrett, K. P.; Beverley, P. C., Maintaining protection against invasive bacteria with protein–polysaccharide conjugate vaccines. Nat. rev. Immunol. 2009, 9, 212–220.
23.Avci, F. Y.; Li, X.; Tsuji, M.; Kasper, D. L., A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design. Nat. med. 2011, 17, 1602–1609.
24.Lees-Miller, R. G.; Iwashkiw, J. A.; Scott, N. E.; Seper, A.; Vinogradov, E.; Schild, S.; Feldman, M. F., A common pathway for O-linked protein-glycosylation and synthesis of capsule in Acinetobacter baumannii. Mol. Microbiol. 2013, 89, 816–830.
25.Westman, E. L.; Preston, A.; Field, R. A.; Lam, J. S., Biosynthesis of a rare di-N-acetylated sugar in the lipopolysaccharides of both Pseudomonas aeruginosa and Bordetella pertussis occurs via an identical scheme despite different gene clusters. J. Bacteriol. 2008, 190 , 6060–6069.
26.Emmerson, D. P. G.; Howard, J. A. K.; Villard, R.; Hems, W. P.; Mugnaini, C.; Toozec, R. P.; Batsanov, A.; Davis, B. G., Precise structure activity relationships in asymmetric catalysis using carbohydrate scaffolds to allow ready fine tuning: dialkylzinc–aldehyde additions. Org. Biomol. Chem. 2003, 1, 3826–3838.
27.Öberg, C. T.; Noresson, A.-L.; Leffler, H.; Nilsson, U. J., Synthesis of 3-amido-3-deoxy-β-d-talopyranosides: all-cis-substituted pyranosides as lectin inhibitors. Tetrahedron 2011, 67, 9164–9172.
28.Yamaguchi, T.; Hesek, D.; Lee, M.; Oliver, A. G.; Mobashery, S., Sulfonylation-induced N- to O-acetyl migration in 2-acetamidoethanol derivatives. J. Org. Chem. 2010, 75, 3515–3517.
29.Kitamura, Y.; Koshino, H.; Nakamura, T.; Tsuchida, A.; Nitoda, T.; Kanzaki, H.; Matsuoka, K.; Takahashi, S., Total synthesis of the proposed structure for pochonicine and determination of its absolute configuration. Tetrahedron Lett. 2013, 54, 1456–1459.
30.Reckendorf, W. M. z.; Hehenberger, H., Elimination Reactions Accompanying the Synthesis of 2,3-Diamino-2,3-dideoxy-D-glucose. Chem. Ber. 1980, 113, 3089–3093
31.Posakony, J. J.; Ferre-D''Amare, A. R., Glucosamine and glucosamine-6-phosphate derivatives: catalytic cofactor analogues for the glmS ribozyme. J. Org. Chem. 2013, 78, 4730–4743.
32.Aguilera, B.; FernandezMayoralas, A.; Jaramillo, C., Use of cyclic sulfamidates derived from D-allosamine in nucleophilic displacements: Scope and limitations. Tetrahedron 1997, 53 , 5863–5876.
33.Daskhan, G. C.; Jayaraman, N., Increased glycosidic bond stabilities in 4-C-hydroxymethyl linked disaccharides. Carbohydr. Res. 2011, 346, 2394–2400.
34.Wasonga, G.; Tatara, Y.; Kakizaki, I.; Huang, X., Synthesis of N-acetyl Glucosamine Analogs as Inhibitors for Hyaluronan Biosynthesis. J. Carbohydr. Chem. 2013, 32, 392–409.
35.Taylor, J. G.; Xuechen Li; Markus Oberthur; Wenjiang Zhu; Kahne, D. E., The Total Synthesis of Moenomycin A. J. Am. Chem. Soc. 2006, 128, 15084-15085.
36.Iglesias-Guerra, F.; Candela, J. I.; Espartero, J. L.; Vega-Perez, J. M., A novel general method for 2-aminoglycal synthesis. Tetrahedron Lett. 1994, 35, 5031–5034.
37.Walvoort, M. T.; Moggre, G. J.; Lodder, G.; Overkleeft, H. S.; Codee, J. D.; van der Marel, G. A., Stereoselective synthesis of 2,3-diamino-2,3-dideoxy-beta-D-mannopyranosyl uronates. J. Org. Chem. 2011, 76, 7301–7315.
38.Hartman, M. C. T.; Coward, J. K., Synthesis of 5-Fluoro-Acetylglucosamine Glycosides and Pyrophosphates via Epoxide Fluoridolysis: Versatile Reagents for the Study of Glycoconjugate Biochemistry. J. Am. Chem. Soc. 2002, 124, 10036–10053.
39.Öberg, C. T.; Leffler, H.; Nilsson, U. J., Arginine Binding Motifs: Design and Synthesis of Galactose-Derived Arginine Tweezers as Galectin-3 Inhibitors. J. Med. Chem. 2008, 51, 2297–2301.
40.Limbach, M.; Dalai, S.; Janssen, A.; Es-Sayed, M.; Magull, J. r.; Meijere, A., Addition of Indole to Methyl 2-Chloro-2-cyclopropylideneacetate en Route to Spirocyclopropanated Analogues of Demethoxyfumitremorgine C and Tadalafil. Eur. J. Org. Chem. 2005, 3, 610–617.
41.Nifantiev, N.; Komarova, B.; Maryasina, S.; Tsvetkov, Y., Water-Dependent Reduction of Carbohydrate Azides by Dithiothreitol. Synthesis 2013, 45, 471–478.
42.Hsu, Y.; Ma, H. H.; Lico, L. S.; Jan, J. T.; Fukase, K.; Uchinashi, Y.; Zulueta, M. M.; Hung, S. C., One-pot synthesis of N-acetyl- and N-glycolylneuraminic acid capped trisaccharides and evaluation of their influenza A (H1N1) inhibition. Angew. Chem. Int. Ed. 2014, 53, 2413–2416.
43.Guan, Z.; Zhang, L. H.; Sinay, P.; Zhang, Y., Study on metal-induced reactions of alpha-diazocarbonyl glucosides. J. Org. Chem. 2012, 77, 8888–8895.
44.Rejzek, M.; Kannathasan, V. S.; CorinWing; Preston, A.; L.Westman, E.; Lam, J. S.; Naismith, J. H.; Maskell, D. J.; Field, R. A., Chemical synthesis of UDP-Glc-2,3-diNAcA, a key intermediate in cell surface polysaccharide biosynthesis in the human respiratory pathogens B. pertussis and P. aeruginosa. Org. Biomol. Chem 2009, 7, 1203–1210.
45.Serna, S.; Kardak, B.; Reichardt, N.-C.; Martin-Lomas, M., Synthesis of a core trisaccharide building block for the assembly of N-glycan neoconjugates. Tetrahedron: Asymmetry 2009, 20, 851–856.
46.Kaburag, Y.; Kishi, Y., Operationally Simple and Efficient Workup Procedure for TBAF-Mediated Desilylation: Application to Halichondrin Synthesis. Org. Lett. 2007, 9, 723–726.
47.Wang, C.; Li, Q.; Wang, H.; Zhang, L.-H.; Ye, X.-S., A new one-pot synthesis of Gb3 and isoGb3 trisaccharide analogues. Tetrahedron Lett. 2006, 62, 11657–11662.
48.Ohlin, M.; Johnsson, R.; Ellervik, U., Regioselective reductive openings of 4,6-benzylidene acetals: synthetic and mechanistic aspects. Carbohydr. Res. 2011, 346, 1358–1370.
49.Jung, M. E.; Koch, P., An Efficient Synthesis of the Protected Carbohydrate Moiety of Brasilicardin A. Org. Lett. 2011, 13, 3710–3713.
50.Li, Z.; Gildersleeve, J. C., Mechanistic Studies and Methods To Prevent Aglycon
ransfer of Thioglycosides. J. Am. Chem. Soc. 2006, 128, 11612–11219.
51.Kumar, R.; Maulik, P. R.; Misra, A. K., Concise chemical synthesis of a tetrasaccharide repeating unit of the O-antigen of Hafnia alvei 10457. Glycoconjugate J. 2008, 25, 511–519.
52.Wu, X.; Cui, L.; Lipinski, T.; Bundle, D. R., Synthesis of monomeric and dimeric repeating units of the zwitterionic type 1 capsular polysaccharide from Streptococcus pneumoniae. Chem. Eur. J. 2010, 16, 3476–3488.
53.Ren, Z. X.; Yang, Q.; Price, K. N.; Chen, T.; Nygren, C.; Turner, J. F.; Baker, D. C., Synthesis of a C-linked hyaluronic acid disaccharide mimetic. Carbohydr. Res. 2007, 342, 1668–1679.
54.Huang, L.; Teumelsan, N.; Huang, X., A facile method for oxidation of primary alcohols to carboxylic acids and its application in glycosaminoglycan syntheses. Chem. Eur. J. 2006, 12, 5246–5252.
55.Öberg, C. T.; Leffler, H.; Nilsson, U. J., Arginine Binding Motifs: Design and Synthesis of Galactose-Derived Arginine Tweezers as Galectin-3 Inhibitors. J. Med. Chem. 2008, 51, 2297–2301.


QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top