Please use this identifier to cite or link to this item:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62657Full metadata record
| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 翁啟惠(Chi-Huey Wong) | |
| dc.contributor.author | Yu-Hsuan Chang | en |
| dc.contributor.author | 張雨萱 | zh_TW |
| dc.date.accessioned | 2021-06-16T16:06:43Z | - |
| dc.date.available | 2018-07-25 | |
| dc.date.copyright | 2013-07-25 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-06-13 | |
| dc.identifier.citation | (1) Nierodzik, M. L.; Karpatkin, S. Cancer Cell 2006, 10, 355.
(2) Elste, A. P.; Petersen, I. J Mol Histol 2010, 41, 89. (3) Gandhi, P. S.; Chen, Z.; Mathews, F. S.; Di Cera, E. Proc Natl Acad Sci U S A 2008, 105, 1832. (4) Di Cera, E.; Guinto, E. R.; Vindigni, A.; Dang, Q. D.; Ayala, Y. M.; Wuyi, M.; Tulinsky, A. J Biol Chem 1995, 270, 22089. (5) Pineda, A. O.; Chen, Z. W.; Marino, F.; Mathews, F. S.; Mosesson, M. W.; Di Cera, E. Biol. Chem. 2007, 125, 556. (6) Pineda, A. O.; Carrell, C. J.; Bush, L. A.; Prasad, S.; Caccia, S.; Chen, Z. W.; Mathews, F. S.; Di Cera, E. J Biol Chem 2004, 279, 31842. (7) Corral-Rodriguez, M. A.; Macedo-Ribeiro, S.; Pereira, P. J. B.; Fuentes-Prior, P. Insect Biochem Molec 2009, 39, 579. (8) Olson, S. T.; Chuang, Y. J. Trends cardiovasc. med. 2002, 12, 331. (9) Warkentin, T. E. Best Pract Res Clin Haematol 2004, 17, 105. (10) Macfarlane, R. G. Nature 1964, 202, 498. (11) Tai, S. J.; Herzog, R. W.; Margaritis, P.; Arruda, V. R.; Chu, K.; Golden, J. A.; Labosky, P. A.; High, K. A. J Thromb Haemost 2008, 6, 339. (12) Knesek, D.; Peterson, T. C.; Markel, D. C. Thrombosis 2012, 2012, 837896. (13) Tsopanoglou, N. E.; Pipili-Synetos, E.; Maragoudakis, M. E. Am J Physiol 1993, 264, C1302. (14) Ollivier, V.; Chabbat, J.; Herbert, J. M.; Hakim, J.; de Prost, D. Arterioscler Thromb Vasc Biol 2000, 20, 1374. (15) Huang, Y. Q.; Li, J. J.; Hu, L.; Karpatkin, S. Blood 2000, 96, 34a. (16) Markwardt, F.; Kaiser, B.; Richter, M. Thrombosis research 1992, 68, 475. (17) Weitz, J. I.; Hudoba, M.; Massel, D.; Maraganore, J.; Hirsh, J. J. Clin. Invest. 1990, 86, 385. (18) Weitz, J. I.; Leslie, B.; Hudoba, M. Circulation 1998, 97, 544. (19) Wirsching, F.; Keller, M.; Hildmann, C.; Riester, D.; Schwienhorst, A. Mol Genet Metab 2003, 80, 451. (20) Markwardt, F. Semin Thromb Hemost 1989, 15, 269. (21) Nutescu, E. A.; Shapiro, N. L.; Chevalier, A. Cardiol Clin 2008, 26, 169. (22) Dery, O.; Corvera, C. U.; Steinhoff, M.; Bunnett, N. W. Am J Physiol 1998, 274, C1429. (23) Macfarlane, S. R.; Seatter, M. J.; Kanke, T.; Hunter, G. D.; Plevin, R. Pharmacol Rev 2001, 53, 245. (24) Steinberg, S. F. Mol Pharmacol 2005, 67, 2. (25) Molino, M.; Barnathan, E. S.; Numerof, R.; Clark, J.; Dreyer, M.; Cumashi, A.; Hoxie, J. A.; Schechter, N.; Woolkalis, M.; Brass, L. F. J Biol Chem 1997, 272, 4043. (26) Camerer, E.; Huang, W.; Coughlin, S. R. Proc Natl Acad Sci U S A 2000, 97, 5255. (27) Garcia-Lopez, M. T.; Gutierrez-Rodriguez, M.; Herranz, R. Curr Med Chem 2010, 17, 109. (28) Vu, T. K.; Hung, D. T.; Wheaton, V. I.; Coughlin, S. R. Cell 1991, 64, 1057. (29) Gandhi, P. S.; Chen, Z. W.; Appelbaum, E.; Zapata, F.; Di Cera, E. Iubmb Life 2011, 63, 375. (30) Blackhart, B. D.; Ruslim-Litrus, L.; Lu, C. C.; Alves, V. L.; Teng, W.; Scarborough, R. M.; Reynolds, E. E.; Oksenberg, D. Mol Pharmacol 2000, 58, 1178. (31) Camerer, E. Thrombosis research 2007, 120 Suppl 2, S75. (32) Wang, H.; Ubl, J. J.; Stricker, R.; Reiser, G. Am J Physiol Cell Physiol 2002, 283, C1351. (33) Buresi, M. C.; Buret, A. G.; Hollenberg, M. D.; MacNaughton, W. K. Faseb J 2002, 16, 1515. (34) Nystedt, S.; Emilsson, K.; Wahlestedt, C.; Sundelin, J. Proc Natl Acad Sci U S A 1994, 91, 9208. (35) Nystedt, S.; Emilsson, K.; Larsson, A. K.; Strombeck, B.; Sundelin, J. Eur J Biochem 1995, 232, 84. (36) Xiang Y, M.-H. K., Sekine T, Nakamura H, Yudoh K, Nishioka K, Kato T Osteoarthritis Cartilage 2006, 11. (37) Vergnolle, N.; Bunnett, N. W.; Sharkey, K. A.; Brussee, V.; Compton, S. J.; Grady, E. F.; Cirino, G.; Gerard, N.; Basbaum, A. I.; Andrade-Gordon, P.; Hollenberg, M. D.; Wallace, J. L. Nat Med 2001, 7, 821. (38) Ishihara, H.; Connolly, A. J.; Zeng, D.; Kahn, M. L.; Zheng, Y. W.; Timmons, C.; Tram, T.; Coughlin, S. R. Nature 1997, 386, 502. (39) Xu, W. F.; Andersen, H.; Whitmore, T. E.; Presnell, S. R.; Yee, D. P.; Ching, A.; Gilbert, T.; Davie, E. W.; Foster, D. C. Proc Natl Acad Sci U S A 1998, 95, 6642. (40) Kahn, M. L.; Nakanishi-Matsui, M.; Shapiro, M. J.; Ishihara, H.; Coughlin, S. R. J. Clin. Invest. 1999, 103, 879. (41) L, D. B. S. Arch Gen Med 1823, 17. (42) Tsopanoglou, N. E.; Maragoudakis, M. E. Semin Thromb Hemost 2004, 30, 63. (43) Hu, L.; Lee, M.; Campbell, W.; Perez-Soler, R.; Karpatkin, S. Blood 2004, 104, 2746. (44) Zain, J.; Huang, Y. Q.; Feng, X.; Nierodzik, M. L.; Li, J. J.; Karpatkin, S. Blood 2000, 95, 3133. (45) Franchini, M.; Montagnana, M.; Favaloro, E. J.; Lippi, G. Semin Thromb Hemost 2009, 35, 644. (46) Popovic, M.; Smiljanic, K.; Dobutovic, B.; Syrovets, T.; Simmet, T.; Isenovic, E. R. Molecular and cellular biochemistry 2012, 359, 301. (47) Falanga, A.; Piccioli, A. Curr Opin Pulm Med 2005, 11, 403. (48) Falanga, A.; Marchetti, M. Semin Thromb Hemost 2007, 33, 688. (49) Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57. (50) Rao, L. V. M. Cancer Metast Rev 1992, 11, 249. (51) Konstantoulaki, M.; Kouklis, P.; Malik, A. B. Am J Physiol-Lung C 2003, 285, L434. (52) Liao, F.; Li, Y. W.; O'Connor, W.; Zanetta, L.; Bassi, R.; Santiago, A.; Overholser, J.; Hooper, A.; Mignatti, P.; Dejana, E.; Hicklin, D. J.; Bohlen, P. Cancer Res 2000, 60, 6805. (53) Ishihara, H.; Zeng, D.; Connolly, A. J.; Tam, C.; Coughlin, S. R. Blood 1998, 91, 4152. (54) Sabri, A.; Short, J.; Guo, J. F.; Steinberg, S. F. Circ Res 2002, 91, 532. (55) Darmoul, D.; Gratio, V.; Devaud, H.; Peiretti, F.; Laburthe, M. Mol Cancer Res 2004, 2, 514. (56) Arora, P.; Cuevas, B. D.; Russo, A.; Johnson, G. L.; Trejo, J. Oncogene 2008, 27, 4434. (57) Holden, K. G.; Mattson, M. N.; Cha, K. H.; Rapoport, H. J Org Chem 2002, 67, 5913. (58) Koeller, K. M.; Smith, M. E. B.; Wong, C. H. Bioorgan Med Chem 2000, 8, 1017. (59) Yang, Y. Y.; Ficht, S.; Brik, A.; Wong, C. H. J Am Chem Soc 2007, 129, 7690. (60) Meinjohanns, E.; Meldal, M.; Schleyer, A.; Paulsen, H.; Bock, K. J Chem Soc Perk T 1 1996, 985. (61) Jain, R. K.; Matta, K. L. Carbohydrate research 1992, 226, 91. (62) Elmagbari, N. O.; Egleton, R. D.; Palian, M. M.; Lowery, J. J.; Schmid, W. R.; Davis, P.; Navratilova, E.; Dhanasekaran, M.; Keyari, C. M.; Yamamura, H. I.; Porreca, F.; Hruby, V. J.; Polt, R.; Bilsky, E. J. J Pharmacol Exp Ther 2004, 311, 290. (63) Crich, D.; Subramanian, V.; Hutton, T. K. Tetrahedron 2007, 63, 5042. (64) Fields, G. B. Current protocols in immunology / edited by John E. Coligan ... [et al.] 2002, Chapter 9, Unit 9 1. (65) Lee, H. C.; Gaensslen, R. E. Advances in Fingerprint Technology, Second Edition; Taylor & Francis, 2010. (66) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal Biochem 1970, 34, 595. (67) Bereczky, B.; Gilly, R.; Raso, E.; Vago, A.; Timar, J.; Tovari, J. Clin Exp Metastas 2005, 22, 69. (68) Nierodzik, M. L.; Kajumo, F.; Karpatkin, S. Cancer Res 1992, 52, 3267. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62657 | - |
| dc.description.abstract | 凝血酶 (Thrombin) 於新式抗癌藥物的發展上是關鍵的目標。其中一個主要的原因就是和蛋白酶激活受體 (Protease Activated Receptors) 的結合當凝血酶活化蛋白酶激活受體會觸發一連串對於細胞傳遞上的訊號。例如：生長因子(growth factors)的釋放、免疫調節(immunomodulation)作用和生物上的趨化現象(chemotaxis)。
水蛭素 (Hirudin) 已被證實為凝血酶的直接性抑制劑和具有抑制人類胰臟癌細胞生長的效用.但是，水蛭素抑制凝血的現象是一項嚴重的副作用且短暫的半生期也是我們所關注的地方。因此，我們以水蛭素為模板設計出一系列的HS (HS-1到HS-26) 衍生物，由胜肽或是醣胜肽所組成的。藉由阻擋蛋白酶激活受體和凝血酶結合的現象，HS系列強調具有抗癌的作用但是減低抑制凝血的作用。 由我們的研究結果顯示，藉由添加醣類於胜肽鏈上可以增加其對凝血酶的結合能力，而且添加醣類的結構會影響其抑制癌症的效果。由動物實驗的結果顯示，醣胜肽(HS-14) 可直接抑制腫瘤生長、無抗凝血的作用，極具有發展為抗癌藥物的潛在性。 | zh_TW |
| dc.description.abstract | Thrombin is a potential target for new cancer drug development because it binds to PARs (Protease Activated Receptors) to trigger a cascade of signaling events for cellular communications, such as release of growth factors, chemotaxis, and immunomodulation. The thrombin inhibitor Hirudin has been found to reduce cancer growth but the anticoagulant effect is considered as side effect. We designed HS series (HS-1 to 26) peptides and glycopeptides based on the C-terminal region of hirudin which binds to thrombin exosite I, where is the site that PAR-1 bind to the thrombin. The design HS series are emphasized on anti-cancer effect which is mediated through thrombin exosite I and devoid of anticoagulant properties which is controlled by thrombin active site. We found that the ability of thrombin binding and the inhibitory effect of cancer are increased by adding glycan. The animal experiment results show that glyco-peptide (HS-14) which has the best tumor growth inhibitory effect and has no anticoagulant activity, is a potential candidate for the anti-cancer drug. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T16:06:43Z (GMT). No. of bitstreams: 1 ntu-102-R00223117-1.pdf: 4120400 bytes, checksum: 83a0ffb626939e4e0df6999a72107b1b (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 ii Abstract iii Contents iv List of Figures vii List of Tables viii List of Schemes ix Abbreviations x Chapter1 Introduction 1 1.1 Thrombin 1 1.1.1 The Structure of Thrombin 2 1.1.2 The Role of Thrombin in Coagulation Cascade 3 1.1.3 The Role of Thrombin in Angiogenesis 4 1.2 Hirudin 5 1.3 Protease-Activated Receptors (PARs) 6 1.3.1 PAR-1 7 1.3.2 PAR-2 9 1.3.3 PAR-3 9 1.3.4 PAR-4 10 1.4 The Relation of Thrombin and Cancer 10 Chapter2 Experimental Materials and Methods 13 2.1 The Molecular Computer Modeling of New Designed Compounds 13 2.2 Chemical Synthesis of O-Linked Glycans 14 2.2.1 Synthesis of Fomc-Serine-OAllyl 15 2.2.2 Synthesis of Fomc-Serine-OBenzyl 15 2.2.3 Synthesis of Fomc-Ser(alpha-GalNAc)-OH 15 2.2.4 Synthesis of Fmoc-Ser(alpha-Fucose)-OH 17 2.2.5 Synthesis of Fomc-Ser(beta-Fucose)-OH 19 2.2.6 Synthesis of Fmoc-Ser(alpha-Mannose)-OH 20 2.2.7 Synthesis of Fmoc-Ser(beta-Mannose)-OH 21 2.3 Synthesis of Peptides and Glycopeptides by Solid Phase Peptide Synthesis 23 2.3.1 Peptide Synthesis 25 2.3.2 Glycopeptide Synthesis 29 2.4 Ninhydrin Test 44 2.5 The Activated Partial Thromboplastin Time (aPTT) Assay 45 2.6 Flow Cytometry Analysis 45 2.7 The Animal Model Experiment. 45 2.7.1 The 4T1 Tumor Growth Assay 46 2.7.2 The B16F10 tumor growth assay 46 2.7.3 The H460 tumor growth assay 47 Chapter3 Results and Discussions 50 3.1 Molecular Modeling of Hirudin and New Designed Compounds 50 3.2 Chemical Synthesis of O-Linked Glycans 51 3.2.1 Synthesis of Fomc-Serine-OAllyl 51 3.2.2 Synthesis of Fomc-Serine-OBenzyl 52 3.2.3 Synthesis of Fomc-Ser(alpha-GalNAc)-OH 52 3.2.4 Synthesis of Fmoc-Ser(alpha-Fucose)-OH 53 3.2.5 Synthesis of Fomc-Ser(beta-Fucose)-OH 54 3.2.6 Synthesis of Fmoc-Ser(alpha-Mannose)-OH 55 3.2.7 Synthesis of Fmoc-Ser(beta-Mannose)-OH 56 3.3 Synthesis of peptides and glycopeptide by SPPS 57 3.4 The activated partial thromboplastin time (aPTT) assay 59 3.5 The Animal Model Experiment 60 3.5.1 Designed peptides on 4T1 tumor growth 60 3.5.2 HS compound prevent B16F10 melanoma lung metastasis 61 3.5.3 HS compound prevent H460 human lung cancer cells 62 Chapter4 Conclusion 67 Chapter5 References 69 Appendix Selected NMR and MASS spectra 74 | |
| dc.language.iso | zh-TW | |
| dc.subject | 凝血酶 | zh_TW |
| dc.subject | 癌症 | zh_TW |
| dc.subject | 蛋白?激活受體 | zh_TW |
| dc.subject | 醣胜肽 | zh_TW |
| dc.subject | 水蛭素 | zh_TW |
| dc.subject | Thrombin | en |
| dc.subject | Cancer | en |
| dc.subject | Protease Activated Receptors-1 | en |
| dc.subject | Glycopeptide | en |
| dc.subject | Hirudin | en |
| dc.title | 設計胜肽或醣胜肽的人類凝血酶抑制劑應用於癌症治療 | zh_TW |
| dc.title | Design Peptides or Glycopeptides as Thrombin Inhibitors in Cancer Therapy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 余惠敏(Hui-Ming Yu),林俊宏(Chun-Hung Lin) | |
| dc.subject.keyword | 凝血酶,癌症,蛋白?激活受體,醣胜肽,水蛭素, | zh_TW |
| dc.subject.keyword | Thrombin,Cancer,Protease Activated Receptors-1,Glycopeptide,Hirudin, | en |
| dc.relation.page | 88 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-06-14 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| Appears in Collections: | 化學系 | |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| ntu-102-1.pdf Restricted Access | 4.02 MB | Adobe PDF |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.