請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/21632
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
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 | 2021-06-08T03:40:28Z | - |
dc.date.copyright | 2021-01-20 | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021-01-18 | |
dc.identifier.citation | 1. M. L. Nierodzik, F. Kajumo and S. Karpatkin, Cancer Res, 1992, 52, 3267-3272. 2. M. Konstantoulaki, P. Kouklis and A. B. Malik, Am. J. Physiol. Lung Cell. Mol. Physiol., 2003, 285, L434-442. 3. G. J. Villares, M. Zigler and M. Bar-Eli, Oncotarget, 2011, 2, 8-17. 4. P. S. Gandhi, Z. W. Chen, F. S. Mathews and E. Di Cera, Proc. Natl. Acad. Sci. U.S.A., 2008, 105, 1832-1837. 5. A. P. Elste and I. Petersen, J. Mol. Histol., 2010, 41, 89-99. 6. C.-D. T. Yu, Canyon Pharmaceuticals, Inc., Hunt Valley, MD (US7795205B2) 2010. 7. M. A. Corral-Rodriguez, S. Macedo-Ribeiro, P. J. Barbosa Pereira and P. Fuentes-Prior, Insect Biochem. Mol. Biol., 2009, 39, 579-595. 8. A. O. Pineda, Z. W. Chen, F. Marino, F. S. Mathews, M. W. Mosesson and E. Di Cera, Biophys. Chem., 2007, 125, 556-559. 9. S. T. Olson and Y. J. Chuang, Trends Cardiovasc. Med., 2002, 12, 331-338. 10. T. E. Warkentin, Best Pract. Res. Clin. Haematol., 2004, 17, 105-125. 11. R. G. Macfarlane, Nature, 1964, 202, 498-499. 12. S. J. Tai, R. W. Herzog, P. Margaritis, V. R. Arruda, K. Chu, J. A. Golden, P. A. Labosky and K. A. High, J. Thromb. Haemost., 2008, 6, 339-345. 13. D. Knesek, T. C. Peterson and D. C. Markel, Thrombosis, 2012, 2012, 837896. 14. N. E. Tsopanoglou, E. Pipili-Synetos and M. E. Maragoudakis, Am. J. Physiol. Renal Physiol., 1993, 264, C1302-1307. 15. V. Ollivier, J. Chabbat, J. M. Herbert, J. Hakim and D. de Prost, Arterioscler. Thromb. Vasc. Biol., 2000, 20, 1374-1381. 16. Y. Q. Huang, J. J. Li and S. Karpatkin, Blood, 2000, 95, 1993-1999. 17. E. A. Nutescu, N. L. Shapiro and A. Chevalier, Cardiol. Clin., 2008, 26, 169-187, v-vi. 18. F. Markwardt, B. Kaiser and M. Richter, Thromb Res, 1992, 68, 475-482. 19. J. I. Weitz, M. Hudoba, D. Massel, J. Maraganore and J. Hirsh, J. Clin. Investig., 1990, 86, 385-391. 20. J. I. Weitz, B. Leslie and M. Hudoba, Circulation, 1998, 97, 544-552. 21. Wallis RB, Fidler IJ, Esumi N. Munich, Germany: European Patent Office, issued September 16; 1992. European Patent No. EP 0503829 22. F. Markwardt, Semin. Thromb. Hemost., 1989, 15, 269-282. 23. A. M. Abdualkader, A. M. Ghawi, M. Alaama, M. Awang and A. Merzouk, Indian J. Pharm. Sci., 2013, 75, 127-137. 24. S. R. Coughlin, Nature, 2000, 407, 258-264. 25. M. T. Garcia-Lopez, M. Gutierrez-Rodriguez and R. Herranz, Curr. Med. Chem., 2010, 17, 109-128. 26. M. Molino, E. S. Barnathan, R. Numerof, J. Clark, M. Dreyer, A. Cumashi, J. A. Hoxie, N. Schechter, M. Woolkalis and L. F. Brass, J. Biol. Chem., 1997, 272, 4043-4049. 27. S. R. Macfarlane, M. J. Seatter, T. Kanke, G. D. Hunter and R. Plevin, Pharmacol. Rev., 2001, 53, 245-282. 28. T. K. Vu, D. T. Hung, V. I. Wheaton and S. R. Coughlin, Cell, 1991, 64, 1057-1068. 29. P. S. Gandhi, Z. Chen, E. Appelbaum, F. Zapata and E. Di Cera, IUBMB life, 2011, 63, 375-382. 30. B. D. Blackhart, L. Ruslim-Litrus, C. C. Lu, V. L. Alves, W. Teng, R. M. Scarborough, E. E. Reynolds and D. Oksenberg, Mol. Pharmacol., 2000, 58, 1178-1187. 31. O. Dery, C. U. Corvera, M. Steinhoff and N. W. Bunnett, Am. J. Physiol., 1998, 274, C1429-1452. 32. M. L. Nierodzik and S. Karpatkin, Cancer Cell, 2006, 10, 355-362. 33. E. Camerer, Thromb Res, 2007, 120 Suppl 2, S75-81. 34. H. Wang, J. J. Ubl, R. Stricker and G. Reiser, Am. J. Physiol., 2002, 283, C1351-1364. 35. S. Nystedt, K. Emilsson, C. Wahlestedt and J. Sundelin, Proc. Natl. Acad. Sci. U.S.A., 1994, 91, 9208-9212. 36. S. Nystedt, K. Emilsson, A. K. Larsson, B. Strombeck and J. Sundelin, Eur. J Agron., 1995, 232, 84-89. 37. N. Vergnolle, N. W. Bunnett, K. A. Sharkey, V. Brussee, S. J. Compton, E. F. Grady, G. Cirino, N. Gerard, A. I. Basbaum, P. Andrade-Gordon, M. D. Hollenberg and J. L. Wallace, Nat. Med., 2001, 7, 821-826. 38. H. Ishihara, A. J. Connolly, D. Zeng, M. L. Kahn, Y. W. Zheng, C. Timmons, T. Tram and S. R. Coughlin, Nature, 1997, 386, 502-506. 39. W. F. Xu, H. Andersen, T. E. Whitmore, S. R. Presnell, D. P. Yee, A. Ching, T. Gilbert, E. W. Davie and D. C. Foster, Proc. Natl. Acad. Sci. U.S.A., 1998, 95, 6642-6646. 40. M. L. Kahn, M. Nakanishi-Matsui, M. J. Shapiro, H. Ishihara and S. R. Coughlin, J. Clin. Investig., 1999, 103, 879-887. 41. N. E. Tsopanoglou and M. E. Maragoudakis, Semin. Thromb. Hemost., 2004, 30, 63-69. 42. L. Hu, M. Lee, W. Campbell, R. Perez-Soler and S. Karpatkin, Blood, 2004, 104, 2746-2751. 43. J. Zain, Y. Q. Huang, X. S. Feng, M. L. Nierodzik, J. J. Li and S. Karpatkin, Blood, 2000, 95, 3133-3138. 44. M. Franchini, M. Montagnana, E. J. Favaloro and G. Lippi, Semin. Thromb. Hemost., 2009, 35, 644-653. 45. M. Popovic, K. Smiljanic, B. Dobutovic, T. Syrovets, T. Simmet and E. R. Isenovic, Mol. Cell Biochem., 2012, 359, 301-313. 46. A. Falanga and A. Piccioli, Curr. Opin. Pulm. Med., 2005, 11, 403-407. 47. A. Falanga and M. Marchetti, Semin. Thromb. Hemost, 2007, 33, 688-694. 48. D. Hanahan and R. A. Weinberg, Cell, 2000, 100, 57-70. 49. L. V. M. Rao, Cancer Metast. Rev, 1992, 11, 249-266. 50. M. Konstantoulaki, P. Kouklis and A. B. Malik, Am. J. Physiol. Lung Cell Mol. Physiol., 2003, 285, L434-L442. 51. F. Liao, Y. W. Li, W. O'Connor, L. Zanetta, R. Bassi, A. Santiago, J. Overholser, A. Hooper, P. Mignatti, E. Dejana, D. J. Hicklin and P. Bohlen, Cancer Res., 2000, 60, 6805-6810. 52. H. Ishihara, D. Z. Zeng, A. J. Connolly, C. Tam and S. R. Coughlin, Blood, 1998, 91, 4152-4157. 53. K. Tantivejkul, R. D. Loberg, S. C. Mawocha, L. L. Day, L. S. John, B. A. Pienta, M. A. Rubin and K. J. Pienta, J. Cell Biochem., 2005, 96, 641-652. 54. A. Sabri, J. Short, J. F. Guo and S. F. Steinberg, Circ. Res. 2002, 91, 532-539. 55. D. Darmoul, V. Gratio, H. Devaud, F. Peiretti and M. Laburthe, Mol. Cancer Res., 2004, 2, 514-522. 56. P. Arora, B. D. Cuevas, A. Russo, G. L. Johnson and J. Trejo, Oncogene, 2008, 27, 4434-4445. 57. B. Zhao, M. F. Wu, Z. H. Hu, Y. X. Ma, W. Qi, Y. L. Zhang, Y. R. Li, M. Yu, H. J. Wang and W. Mo, Signal Transduct. Tar., 2020, 5. 58. K. G. Holden, M. N. Mattson, K. H. Cha and H. Rapoport, J. Org. Chem., 2002, 67, 5913-5918. 59. K. M. Koeller, M. E. Smith and C. H. Wong, Bioorg. Med. Chem., 2000, 8, 1017-1025. 60. Y. Y. Yang, S. Ficht, A. Brik and C. H. Wong, J. Am. Chem. Soc., 2007, 129, 7690-7701. 61. E. Meinjohanns, M. Meldal, A. Schleyer, H. Paulsen and K. Bock, J. Chem. Soc. Perk T 1, 1996, DOI: Doi 10.1039/P19960000985, 985-993. 62. R. K. Jain and K. L. Matta, Carbohyd Res., 1992, 226, 91-100. 63. N. O. Elmagbari, R. D. Egleton, M. M. Palian, J. J. Lowery, W. R. Schmid, P. Davis, E. Navratilova, M. Dhanasekaran, C. M. Keyari, H. I. Yamamura, F. Porreca, V. J. Hruby, R. Polt and E. J. Bilsky, J. Pharmacol. Exp .Ther., 2004, 311, 290-297. 64. D. Crich, V. Subramanian and T. K. Hutton, Tetrahedron, 2007, 63, 5042-5049. 65. S. J. T. Mao, M. T. Yates, T. J. Owen and J. L. Krstenansky, Biochemistry-Us, 1988, 27, 8170-8173. 66. Y. S. Hsieh, D. Taleski, B. L. Wilkinson, L. C. Wijeyewickrema, T. E. Adams, R. N. Pike and R. J. Payne, ChemComm., 2012, 48, 1547-1549. 67. M. Elofsson, S. Roy, L. A. Salvador and J. Kihlberg, Tetrahedron Lett, 1996, 37, 7645-7648. 68. L. A. Salvador, M. Elofsson and J. Kihlberg, Tetrahedron, 1995, 51, 5643-5656. 69. G. A. Winterfeld, Y. Ito, T. Ogawa and R. R. Schmidt, Eur. J. Org. Chem., 1999, 1999, 1167-1171. 70. G. B. Fields, Curr. Protoc. Immunol, 2002, Chapter 9, Unit 9 1. 71. C. A. Spek, H. H. Versteeg and K. S. Borensztajn, Thromb. Haemost., 2015, 114, 530-536. 72. N. Yokota, A. Zarpellon, S. Chakrabarty, V. Y. Bogdanov, A. Gruber, F. J. Castellino, N. Mackman, L. G. Ellies, H. Weiler, Z. M. Ruggeri and W. Ruf, Thromb. Haemost., 2014, 12, 71-81. 73. C. J. Reddel, J. D. Allen, A. Ehteda, R. Taylor, V. M. Y. Chen, J. L. Curnow, L. Kritharides and G. Robertson, Thromb. Haemost. 2017, 15, 477-486. 74. M. Riewald, R. J. Petrovan, A. Donner, B. M. Mueller and W. Ruf, Science, 2002, 296, 1880-1882. 75. C. Y. Koh, M. Kazimirova, A. Trimnell, P. Takac, M. Labuda, P. A. Nuttall and R. M. Kini, J. Biol. Chem., 2007, 282, 29101-29113. 76. S. Q. Xu, F. J. Fan, H. X. Liu, S. Z. Cheng, M. L. Tu and M. Du, J. Agr. Food Chem., 2020, 68, 3132-3139. 77. V. Trivedi, A. Boire, B. Tchernychev, N. C. Kaneider, A. J. Leger, K. O'Callaghan, L. Covic and A. Kuliopulos, Cell, 2009, 137, 332-343. 78. X. Liu, J. H. Yu, S. J. Song, X. Q. Yue and Q. Li, Oncotarget, 2017, 8, 107334-107345. 79. M. Tatour, M. Shapira, E. Axelman, S. Ghanem, A. Keren-Politansky, L. Bonstein, B. Brenner and Y. Nadir, Thromb. Haemost., 2017, 117, 1391-1401. 80. G. J. Villares, M. Zigler, H. Wang, V. O. Melnikova, H. Wu, R. Friedman, M. C. Leslie, P. E. Vivas-Mejia, G. Lopez-Berestein, A. K. Sood and M. Bar-Eli, Cancer Res., 2008, 68, 9078-9086. 81. L. Pang, J. F. Li, L. P. Su, M. D. Zang, Z. Y. Fan, B. Q. Yu, X. Y. Wu, C. Li, M. Yan, Z. G. Zhu and B. Y. Liu, J. Gastroenterol., 2018, 53, 71-83. 82. N. C. Baker, M. J. Lipinski, T. Lhermusier and R. Waksman, Circulation, 2014, 130, 1287-1294. 83. A. Wang, Expert. Opin. Pharmacother., 2015, 16, 2509-2522. 84. S. Goto, H. Ogawa, M. Takeuchi, M. D. Flather, D. L. Bhatt and J. L. Investigators, Eur. Heart. J., 2010, 31, 2601-2613. 85. A. Chanakira, P. R. Westmark, I. M. Ong and J. P. Sheehan, Gynecol. Oncol., 2017, 145, 167-175. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/21632 | - |
dc.description.abstract | 凝血酶 (thrombin) 於新式抗癌藥物的發展上是關鍵標的。其中一個主要的原因就是與蛋白酶激活受體-1 (protease activated receptors-1) 的結合作用。當凝血酶切割活化蛋白酶激活受體會引發許多血管新生相關因子 (angiogenesis-related genes) 的上調 (up-regulated) 反應,進而促進細胞增殖 (proliferation) 的現象。另外,從多種臨床惡性樣品中也發現凝血酶活化蛋白酶激活受體-1的表現佔據高達77.3% 的比例,顯示蛋白酶激活受體-1在腫瘤生長中扮演主要作用。 在我們的研究中是利用已知的凝血酶直接抑制劑-水蛭素 (hirudin) 作為模板。水蛭素已被證實具有抑制人類胰臟癌細胞生長的效用,但水蛭素抑制凝血的現象為一項嚴重的副作用也是我們所希望排除的。因此,我們設計出一系列的醣胜肽藉由阻擋蛋白酶激活受體-1和凝血酶結合的作用,強調醣胜肽具有抗癌的效果但是不影響正常凝血的作用。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,並對於與凝血酶作用時的功能和穩定性提供關鍵的作用。 | 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. Thrombin activated protease-activated receptor-1 from multiple clinical malignant samples and plays a major role in tumor growth. In our study, we used hirudin as template, which is a well-known direct thrombin inhibitor and is able to reduce cancer growth but the anticoagulant effect is considered as side effect. We have developed a new class of anticancer glycopeptides to target the exosite I of thrombin selectively without affecting the coagulation activity and found that the glycan moiety is important for the function and stability of the glycopeptides in vitro and in vivo. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T03:40:28Z (GMT). No. of bitstreams: 1 U0001-1501202115490300.pdf: 3979178 bytes, checksum: 8f1d9ae78bd3179de54b96b2966a5a15 (MD5) Previous issue date: 2021 | en |
dc.description.tableofcontents | Contents 口試委員審定書 # 誌謝 i 中文摘要 iii Abstract iv Contents v List of Figures viii List of Tables ix List of Schemes x Abbreviations xi Chapter 1 Introduction 1 1.1 Thrombin 1 1.1.1 The structure of thrombin 1 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 8 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 1.5 Purpose of research 13 Chapter 2 Experimental materials and methods 14 2.1 Molecular modeling and computed binding energies of designed compounds 14 2.2 Chemical synthesis of O-linked glycans 15 2.2.1 Synthesis of Fomc-Serine-OAllyl 16 2.2.2 Synthesis of Fomc-Serine-OBenzyl 17 2.2.3 Synthesis of Fomc-Ser(α-GalNAc)-OH 18 2.2.4 Synthesis of Fmoc-Ser(α-Fucose)-OH 22 2.2.5 Synthesis of Fomc-Ser(β-Fucose)-OH 25 2.2.6 Synthesis of Fmoc-Ser(α-Mannose)-OH 28 2.2.7 Synthesis of Fmoc-Ser(β-Mannose)-OH 30 2.3 Synthesis of peptides and glycopeptides by solid phase peptide synthesis 33 2.3.1 Peptide synthesis 33 2.3.2 Glycopeptide synthesis 34 2.4 Design of N-terminal PAR-1 sequence as thrombin substrate 37 2.5 Enzyme assays 39 2.6 Flow cytometry analysis 39 2.7 Anticancer activity of HS compounds 40 2.7.1 Cell lines and mice 40 2.7.2 Pre-treated compounds in H460 tumor growth assay 41 2.7.3 Treated compounds in H460 tumor growth assay 42 Chapter 3 Results 43 3.1 Molecular modeling of hirudin and new designed compounds 43 3.2 Chemical synthesis of O-linked glycan 49 3.3 Synthesis of peptides and glycopeptide by SPPS 50 3.4 Established an in vitro method for the detection of the thrombin activity 52 3.5 An in vivo experiment to confirm the anticancer activity 55 Chapter 4 Discussions and conclusion 60 Chapter 5 References 64 Appendix: Selected NMR and Mass spectra 71 | |
dc.language.iso | en | |
dc.title | 針對凝血酶與蛋白酶激活受體-1間的作用設計和合成具抗癌的醣胜肽 | zh_TW |
dc.title | Design and Synthesis of Glycopeptides as Anticancer Agents Targeting Thrombin-Protease Activated Receptor-1 Interaction | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 余惠敏(Hui-Ming Yu) | |
dc.contributor.oralexamcommittee | 吳世雄(Shih-Hsiung Wu),方俊民(Jim-Min Fang),陳韻如(Yun-Ru Chen) | |
dc.subject.keyword | 凝血酶,癌症,蛋白酶激活受體,醣胜肽,水蛭素, | zh_TW |
dc.subject.keyword | Thrombin,Cancer,Protease Activated Receptors-1,Glycopeptide,Hirudin, | en |
dc.relation.page | 86 | |
dc.identifier.doi | 10.6342/NTU202100066 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2021-01-19 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
U0001-1501202115490300.pdf 目前未授權公開取用 | 3.89 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。