請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69094完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳基旺(Ji-Wang Chern) | |
| dc.contributor.author | Hsin-Yi Chiang | en |
| dc.contributor.author | 蔣心怡 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:51:37Z | - |
| dc.date.available | 2022-09-14 | |
| dc.date.copyright | 2017-09-14 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-15 | |
| dc.identifier.citation | Reference
1. Yeatman, T. J., A renaissance for SRC. Nat Rev Cancer 2004, 4 (6), 470-480. 2. Martin, G. S., The hunting of the Src. Nat Rev Mol Cell Biol 2001, 2 (6), 467-475. 3. Zhang, S.; Yu, D., Targeting Src family kinases in anti-cancer therapies: turning promise into triumph. Trends Pharmaco Sci 2012, 33 (3), 122-128. 4. Finn, R. S., Targeting Src in breast cancer. Ann Oncol 2008, 19 (8), 1379-1386. 5. Kim, L. C.; Song, L.; Haura, E. B., Src kinases as therapeutic targets for cancer. Nat Rev Clin Oncol 2009, 6 (10), 587-595. 6. Brunton, V. G.; Frame, M. C., Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol 2008, 8 (4), 427-432. 7. Giaccone, G.; Zucali, P. A., Src as a potential therapeutic target in non-small-cell lung cancer. Annals of Oncology 2008, 19 (7), 1219-1223. 8. Herynk, M. H.; Beyer, A. R.; Cui, Y.; Weiss, H.; Anderson, E.; Green, T. P.; Fuqua, S. A. W., Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor–positive human breast cancer cells. Mol. Cancer Ther 2006, 5 (12), 3023-3031. 9. Mazurenko, N. N.; Zborovskaya, I. B.; Kisseljov, F. L.; Kogan, E. A., Expression of pp60c-src in human small cell and non-small cell lung carcinomas. Eur J Cancer 1992, 28 (2), 372-377. 10. Salgia, R.; Li, J. L.; Ewaniuk, D. S.; Pear, W.; Pisick, E.; Burky, S. A.; Ernst, T.; Sattler, M.; Chen, L. B.; Griffin, J. D., BCR/ABL induces multiple abnormalities of cytoskeletal function. J Clin Invest 1997, 100 (1), 46-57. 11. Ren, R., The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model. Oncogene 2002, 21 (56), 8629-8642. 12. Wertheim, J. A.; Miller, J. P.; Xu, L.; He, Y.; Pear, W. S., The biology of chronic myelogenous leukemia:mouse models and cell adhesion. Oncogene 2002, 21 (56), 8612-8628. 13. Ren, R., Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer 2005, 5 (3), 172-183. 14. Liu, X.; Kung, A.; Malinoski, B.; Prakash, G. K. S.; Zhang, C., Development of alkyne-containing pyrazolopyrimidines to overcome drug resistance of bcr-abl kinase. J Med Chem 2015, 58 (23), 9228-9237. 15. Hehlmann, R., Introduction: CML in the imatinib era. Best Pract Res Clin Haematol 2009, 22 (3), 283-284. 16. Ren, X.; Pan, X.; Zhang, Z.; Wang, D.; Lu, X.; Li, Y.; Wen, D.; Long, H.; Luo, J.; Feng, Y.; Zhuang, X.; Zhang, F.; Liu, J.; Leng, F.; Lang, X.; Bai, Y.; She, M.; Tu, Z.; Pan, J.; Ding, K., Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region–abelson (bcr-abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinib. J Med Chem 2013, 56 (3), 879-894. 17. Manley, P. W.; Cowan-Jacob, S. W.; Mestan, J., Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 2005, 1754 (1), 3-13. 18. Rubbi, L.; Titz, B.; Brown, L.; Galvan, E.; Komisopoulou, E.; Chen, S. S.; Low, T.; Tahmasian, M.; Skaggs, B.; Müschen, M.; Pellegrini, M.; Graeber, T. G., global phosphoproteomics reveals crosstalk between bcr-abl and negative feedback mechanisms controlling src signaling. Sci Signal 2011, 4 (166), ra18-ra18. 19. Moslehi, J. J.; Deininger, M., Tyrosine kinase inhibitor–associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 2015, 33 (35), 4210-4218. 20. Copeland, R. A., The drug-target residence time model: a 10-year retrospective. Nat Rev Drug Discov 2016, 15 (2), 87-95. 21. Jin, M.; Petronella, B. A.; Cooke, A.; Kadalbajoo, M.; Siu, K. W.; Kleinberg, A.; May, E. W.; Gokhale, P. C.; Schulz, R.; Kahler, J.; Bittner, M. A.; Foreman, K.; Pachter, J. A.; Wild, R.; Epstein, D.; Mulvihill, M. J., Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics. ACS Med Chem Lett 2013, 4 (7), 627-631. 22. Copeland, R. A.; Pompliano, D. L.; Meek, T. D., Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discov 2006, 5 (9), 730-739. 23. Boschelli, D. H.; Wang, Y. D.; Ye, F.; Wu, B.; Zhang, N.; Dutia, M.; Powell, D. W.; Wissner, A.; Arndt, K.; Weber, J. M.; Boschelli, F., Synthesis and src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44 (5), 822-833. 24. Levinson, N. M.; Boxer, S. G., Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the abl tyrosine kinase domain. PLOS ONE 2012, 7 (4), e29828. 25. Levinson, N. M.; Boxer, S. G., A conserved water-mediated hydrogen bond network defines bosutinib's kinase selectivity. Nat Chem Biol 2014, 10 (2), 127-132. 26. Deau, E.; Hédou, D.; Chosson, E.; Levacher, V.; Besson, T., Convenient one-pot synthesis of N3-substituted pyrido[2,3-d]-, pyrido[3,4-d]-, pyrido[4,3-d]-pyrimidin-4(3H)-ones, and quinazolin-4(3H)-ones analogs. Tetrahedron Lett 2013, 54 (27), 3518-3521. 27. Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B.; Greenberger, L. M.; Gruber, B. C.; Johnson, B. D.; Mamuya, N.; Nilakantan, R.; Reich, M. F.; Shen, R.; Tsou, H.-R.; Upeslacis, E.; Wang, Y. F.; Wu, B.; Ye, F.; Zhang, N., 4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile Inhibitors of Epidermal Growth Factor Receptor Kinase and Their Bioisosteric Relationship to the 4-Anilino-6,7- dialkoxyquinazoline Inhibitors. J Med Chem 2000, 43 (17), 3244-3256. 28. Rao, V. R.; Muthenna, P.; Shankaraiah, G.; Akileshwari, C.; Babu, K. H.; Suresh, G.; Babu, K. S.; Chandra Kumar, R. S.; Prasad, K. R.; Yadav, P. A.; Petrash, J. M.; Reddy, G. B.; Rao, J. M., Synthesis and biological evaluation of new piplartine analogues as potent aldose reductase inhibitors (ARIs). Eur J Med Chem 2012, 57, 344-361. 29. Gibson, K. H.; Grundy, W.; Godfrey, A. A.; Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.; Barker, A. J.; Brown, D. S., Epidermal growth factor receptor tyrosine kinase: Structure-activity relationships and antitumour activity of novel quinazolines. Bioorg Med Chem Lett 1997, 7 (21), 2723-2728. 30. Hennequin, L. F.; Thomas, A. P.; Johnstone, C.; Stokes, E. S. E.; Plé, P. A.; Lohmann, J.-J. M.; Ogilvie, D. J.; Dukes, M.; Wedge, S. R.; Curwen, J. O.; Kendrew, J.; Lambert-van der Brempt, C., Design and structure−activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. J Med Chem 1999, 42 (26), 5369-5389. 31. Smaill, J. B.; Rewcastle, G. W.; Loo, J. A.; Greis, K. D.; Chan, O. H.; Reyner, E. L.; Lipka, E.; Showalter, H. D. H.; Vincent, P. W.; Elliott, W. L.; Denny, W. A., Tyrosine kinase inhibitors. 17. irreversible inhibitors of the epidermal growth factor receptor: 4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides Bearing Additional Solubilizing Functions. J Med Chem 2000, 43 (7), 1380-1397. 32. Wu, X.; Li, M.; Tang, W.; Zheng, Y.; Lian, J.; Xu, L.; Ji, M., Design, synthesis, and in vitro antitumor activity evaluation of novel 4-pyrrylamino quinazoline derivatives. Chem Biol Drug Des 2011, 78 (6), 932-940. 33. Yin, X. J.; Xu, G. H.; Sun, X.; Peng, Y.; Ji, X.; Jiang, K.; Li, F., Synthesis of bosutinib from 3-methoxy-4-hydroxybenzoic acid. Molecules 2010, 15 (6), 4261. 34. Chen, X.; Sassano, M. F.; Zheng, L.; Setola, V.; Chen, M.; Bai, X.; Frye, S. V.; Wetsel, W. C.; Roth, B. L.; Jin, J., Structure–functional selectivity relationship studies of β-arrestin-biased dopamine D2 receptor agonists. J Med Chem 2012, 55 (16), 7141-7153. 35. Ilies, M. A.; Vullo, D.; Pastorek, J.; Scozzafava, A.; Ilies, M.; Caproiu, M. T.; Pastorekova, S.; Supuran, C. T., Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogenophenylaminobenzolamide derivatives. J Med Chem 2003, 46 (11), 2187-2196. 37. Bauer, R. A., Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discov Today 2015, 20 (9), 1061-1073. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69094 | - |
| dc.description.abstract | Abstract
To reduce the side effect induced by off-target effect, the concept of the residence time was utilized to design and synthesize three series of quinoline derivative based on lead compound, 4-((2,4-dichloro-5-methoxyphenyl)-amino)-6- methoxy-7-(3-(4 -methyl-1-piperazinyl)-propoxy)-3-quinoline-carbonitrile (2), as potential Bcr-Abl/ c-Src dual inhibitors. An acryloyl functional group was introduced onto the C4 position of quinoline and expected to form the reversible covalent bond to prolong the residence time. After introducing an acryloly functional group onto quinoline, it was found very difficult to identify the structure by NMR. It is considered because of the steric hindrance which made the compound exist in many conformational isomers. Therefore, the compound after a series of studied and the notion finally confirmed. In this investigation, found that the compounds with long chain at C6 or C7 showed better enzymatic inhibitory activity. It was also noted that quinoline (45a, 45b, 46a 46b) with the long chain at C6 showed the good selectivity between Bcr-Abl and C-Src. However, those compounds having the long chain at C7 of quinoline demonstrated good enzymatic inhibitory activity against both the Bcr-Abl and C-Src. Although the compounds with acryloyl group showed 1000-fold weaker activity than those of compounds without acryloyl group, the result of cytotoxicity assay revealed that anti-proliferation activity was in the same category. Furthermore, 37 with acetyl group instead of acryloly was synthesized and did not show any significantly activity against different cancer cell lines, indicating that the acryloyl group played a key role of binding interaction with target enzymes to enhance the inhibitory activity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:51:37Z (GMT). No. of bitstreams: 1 ntu-106-R04423019-1.pdf: 21895529 bytes, checksum: 1925b4b96a43820b22b9b4d691d46711 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 目錄
口試委員審定書 i 中文摘要 ii Abstract iii 圖目錄 vi 表目錄 viii 反應圖示目錄 ix 縮寫表 x 第一章 緒論 1 1.1 V-src與C-src蛋白質激酶 1 1.2 Bcr-abl蛋白質激酶與慢性骨髓性白血病之關聯 4 1.3 Bcr-Abl蛋白質激酶抑制劑的發展 6 第二章 實驗動機與目的 10 2.1 駐留時間之概念 10 2.2 駐留時間概念之應用實例 11 2.2.1長駐留時間藥物 11 2.2.2 藥物駐留時間與選擇性 13 2.3 長駐留時間藥物之優勢 14 第三章 應用延長駐留時間概念於喹啉衍生物作為潛能雙靶點Bcr-Abl/C-Src 蛋白質激酶抑制劑之開發 15 3.1 介紹與理論設計 15 3.2 化學合成 19 3.3 結果與討論 27 3.3.結構異構物 27 3.3.1.1 Kinetic 1H NMR……………………………………………………………….28 3.3.1.2 結構構型能量計算…………………………………………………………..30 3.4 生物活性測試 31 3.4.1體外目標蛋白質激酶活性測試 32 3.4.2細胞毒性測驗 37 3.5 實驗部分 40 3.5.1 Compound Information 40 3.5.2 In vitro C-Abl/C-Src Kinase Activity Assay 84 3.5.3 Cell Culture and Anti-proliferation Assay 86 第四章 總結 87 Reference 88 Appendix A1 | |
| dc.language.iso | zh-TW | |
| dc.subject | Bcr-Abl | zh_TW |
| dc.subject | C-Src | zh_TW |
| dc.subject | 雙把點抑制劑 | zh_TW |
| dc.subject | 結構異構物 | zh_TW |
| dc.subject | C-Src | en |
| dc.subject | dual inhibitor | en |
| dc.subject | quinoline | en |
| dc.subject | conformational isomer | en |
| dc.subject | Bcr-Abl | en |
| dc.title | 應用延長駐留時間概念於喹啉衍生物作為潛能雙靶點Bcr-Abl/C-Src 蛋白質激酶抑制劑之開發 | zh_TW |
| dc.title | Development of Quinolone Derivatives as Potential Dual Kinase Inhibitor of Bcr-Abl /C-Src via Prolonged Residence Time | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王光昭,忻凌偉,梁碧惠,陳香惠 | |
| dc.subject.keyword | Bcr-Abl,C-Src,雙把點抑制劑,??,結構異構物, | zh_TW |
| dc.subject.keyword | Bcr-Abl,C-Src,dual inhibitor,quinoline,conformational isomer, | en |
| dc.relation.page | 152 | |
| dc.identifier.doi | 10.6342/NTU201703265 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-106-1.pdf 未授權公開取用 | 21.38 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。