臺灣博碩士論文加值系統

NF-κB是一個核轉錄因子，當細胞受到刺激時，NF-κB會透過其訊號傳遞路徑的活化，進入細胞核與DNA結合，促使DNA進行過度的表達，而嚴重時則會導致腫瘤與癌症的發生。我們將IKKβ當作欲抑制的對象，其為NF-κB訊號傳遞路徑中的一個關鍵蛋白質，此研究利用本實驗室所篩選出來的化合物WY5107作為前導化合物，WY5107為一IKKβ的良好抑制劑，為了達到更好的IKKβ抑制活性，我們將其與另一良好的IKKβ抑制劑IMD-0354以不同的橋樑結構相連，IMD-0354為一小分子ATP競爭抑制劑，能選擇性的針對IKKβ形成鍵結。我們期待這些化合物對於IKKβ有更良好的抑制活性，由生物實驗結果發現，化合物Methyl 4-((3-(4-nitrobenzamido)phenyl)amino)benzoate ( 8 ) 具有良好的IKKβ抑制活性；而綜合生物實驗結果，推測在四環化合物附近有能夠形成疏水性交互作用力的胺基酸，可以與酯基形成交互作用力；另外，以胺基橋梁修飾的化合物較以二級醯胺鍵橋梁修飾的化合物，抑制活性來的更為良好。

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA. When it is activated excessively, enhanced expression of pro-inflammatory cytokines such as TNF-α, lead to inflammatory and autoimmune diseases. The target was IKKβ, which play an key role in NF-κB signal pathway. We selected WY5107, which was designed from our Lab and has good inhibitory activity of IKKβ. In order to achieve better IKKβ inhibitory activity, we synthesis different bridges link WY5107 and another IKKβ inhibitor, IMD-0354, as a small-molecule, ATP-competitive inhibitor selectively targeting IKKβ kinase activity. And with the results of biological experiment, within all analogs synthesiszed, compound ( 8 ) exhibited the best IKKβ inhibitory activity. The SAR results showed that amino acids near the tetracyclic compounds which can form hydrophobic interaction, and the compounds modified by amine bridge exhibited better IKKβ
inhibitory activity than amide bridged analogs.

中文摘要
Abstract
目錄
表目錄
圖目錄
第一章 緒論
1.1 NF-κB 的結構與功能
1.2 NF-κB 的訊號傳遞路徑
1.3 NF-κB 的抑制途徑
第二章 研究動機與實驗設計
第三章 實驗材料與方法
3.1 化學試藥、溶劑與儀器介紹
3.2 有機合成
3.2.1 第一系列合成
3.2.2 第二系列合成
3.3 生物實驗
3.4 分子對接軟體操作
第四章 結果與討論
4.1 有機合成的探討
4.1.1 化合物(8)、(9)的合成
4.1.2 化合物(14)、(15)的合成
4.1.3 化合物(16a)、(16b)、(16c)及(16d)的合成
4.1.4 化合物(25)的合成
4.1.4 化合物(27a)、(27b)、(29a)與(29b)的合成
4.2 生物活性
第五章 結論
未來展望
參考文獻
圖譜

1. 行政院衛生署, 101 年國人十大死因惡性腫瘤連續31 年第一名,
http://www.kmtth.org.tw/dept/hosptl/News/Details.aspx?id=6574016302955695491&itemId=2.
2. Siomek, A., NF-kappaB signaling pathway and free radical impact. Acta biochimica Polonica 2012, 59 (3), 323-31.
3. Morwick, T.; Berry, A.; Brickwood, J.; Cardozo, M.; Catron, K.; DeTuri, M.; Emeigh, J.; Homon, C.; Hrapchak, M.; Jacober, S.; Jakes, S.; Kaplita, P.; Kelly, T. A.; Ksiazek, J.; Liuzzi, M.; Magolda, R.; Mao, C.; Marshall, D.; McNeil, D.; Prokopowicz, A., 3rd; Sarko, C.; Scouten, E.; Sledziona, C.; Sun, S.; Watrous, J.; Wu, J. P.; Cywin, C. L., Evolution of the thienopyridine class of inhibitors of IkappaB
kinase-beta: part I: hit-to-lead strategies. Journal of medicinal chemistry 2006, 49 (10),2898-908.
4. Makarov, S. S., NF-kappa B in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis research 2001, 3 (4), 200-6.
5. Edwards, M. R.; Bartlett, N. W.; Clarke, D.; Birrell, M.; Belvisi, M.; Johnston, S. L., Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease. Pharmacology & therapeutics 2009, 121 (1), 1-13.
6. Gareus, R.; Kotsaki, E.; Xanthoulea, S.; van der Made, I.; Gijbels, M. J.; Kardakaris, R.; Polykratis, A.; Kollias, G.; de Winther, M. P.; Pasparakis, M., Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis. Cell metabolism 2008, 8 (5), 372-83.
7. Li, X.; Stark, G. R., NFkappaB-dependent signaling pathways. Experimental hematology 2002, 30 (4), 285-96.
8. Hayden, M. S.; Ghosh, S., Signaling to NF-kappaB. Genes & development 2004, 18 (18), 2195-224.
9. Wu, Z. H.; Miyamoto, S., Many faces of NF-kappaB signaling induced by genotoxic stress. Journal of molecular medicine 2007, 85 (11), 1187-202.
10. Baeuerle, P. A., IkappaB-NF-kappaB structures: at the interface of inflammation control. Cell 1998, 95 (6), 729-31.
11. Cramer, P.; Muller, C. W., A firm hand on NFkappaB: structures of the IkappaBalpha-NFkappaB complex. Structure 1999, 7 (1), R1-6.
12. Muller, C. W.; Harrison, S. C., The structure of the NF-kappa B p50:DNA-complex: a starting point for analyzing the Rel family. FEBS letters 1995, 369 (1), 113-7.
13. Roshak, A. K.; Callahan, J. F.; Blake, S. M., Small-molecule inhibitors of NF-kappaB for the treatment of inflammatory joint disease. Current opinion in pharmacology 2002, 2 (3), 316-21.
14. Liang, Y.; Zhou, Y.; Shen, P., NF-kappaB and its regulation on the immune system. Cellular & molecular immunology 2004, 1 (5), 343-50.
15. Zarnegar, B. J.; Wang, Y.; Mahoney, D. J.; Dempsey, P. W.; Cheung, H. H.; He, J.; Shiba, T.; Yang, X.; Yeh, W. C.; Mak, T. W.; Korneluk, R. G.; Cheng, G., Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nature immunology 2008, 9 (12), 1371-8.
16. Mahoney, D. J.; Cheung, H. H.; Mrad, R. L.; Plenchette, S.; Simard, C.; Enwere, E.; Arora, V.; Mak, T. W.; Lacasse, E. C.; Waring, J.; Korneluk, R. G., Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proceedings of the National Academy of Sciences of the United States of America 2008, 105 (33), 11778-83.
17. Dutta, J.; Fan, Y.; Gupta, N.; Fan, G.; Gelinas, C., Current insights into the regulation of programmed cell death by NF-kappaB. Oncogene 2006, 25 (51), 6800-16.
18. Mafuvadze, B.; Liang, Y.; Besch-Williford, C.; Zhang, X.; Hyder, S. M., Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors. Hormones & cancer 2012, 3 (4), 160-71.
19. Kim, S. G.; Veena, M. S.; Basak, S. K.; Han, E.; Tajima, T.; Gjertson, D. W.; Starr, J.; Eidelman, O.; Pollard, H. B.; Srivastava, M.; Srivatsan, E. S.; Wang, M. B., Curcumin treatment suppresses IKKbeta kinase activity of salivary cells of patients with head and neck cancer: a pilot study. Clinical cancer research : an official journal of the American Association for Cancer Research 2011, 17 (18), 5953-61.
20. Ban, J. O.; Hwang, I. G.; Kim, T. M.; Hwang, B. Y.; Lee, U. S.; Jeong, H. S.; Yoon, Y. W.; Kimz, D. J.; Hong, J. T., Anti-proliferate and pro-apoptotic effects of 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyranone through inactivation of NF-kappaB in human colon cancer cells. Archives of pharmacal research 2007, 30 (11), 1455-63.
21. Ban, J. O.; Yuk, D. Y.; Woo, K. S.; Kim, T. M.; Lee, U. S.; Jeong, H. S.; Kim, D. J.; Chung, Y. B.; Hwang, B. Y.; Oh, K. W.; Hong, J. T., Inhibition of cell growth and induction of apoptosis via inactivation of NF-kappaB by a sulfurcompound isolated from garlic in human colon cancer cells. Journal of pharmacological sciences 2007, 104 (4), 374-83.
22. Muto, S. N., T.; Sotome, T.; Itai, A., Inhibitors against the production and release of inflammatory cytokines. Patents WO02 / 49532 A1. 2004.
23. 李宜蓉, 合成轉錄因子NF-κB 小分子抑制劑並探討其構效關係, 碩士論文, 東海大學, 台中. 2011.
24. Hayakawa, Y.; Maeda, S.; Nakagawa, H.; Hikiba, Y.; Shibata, W.; Sakamoto, K.; Yanai, A.; Hirata, Y.; Ogura, K.; Muto, S.; Itai, A.; Omata, M., Effectiveness of IkappaB kinase inhibitors in murine colitis-associated tumorigenesis. Journal of gastroenterology 2009, 44 (9), 935-43.
25. Tanaka, A.; Konno, M.; Muto, S.; Kambe, N.; Morii, E.; Nakahata, T.; Itai, A.; Matsuda, H., A novel NF-kappaB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. Blood 2005, 105 (6), 2324-31.
26. Frank, A. O.; Feldkamp, M. D.; Kennedy, J. P.; Waterson, A. G.; Pelz, N. F.; Patrone, J. D.; Vangamudi, B.; Camper, D. V.; Rossanese, O. W.; Chazin, W. J.; Fesik, S. W., Discovery of a potent inhibitor of replication protein a protein-protein interactions using a fragment-linking approach. Journal of medicinal chemistry 2013, 56 (22), 9242-50.
27. 謝正鴻, 合成 IMD-0354 衍生物以及探討其對於轉錄因子 NF-κB 的抑制效果, 碩士論文, 東海大學, 台中. 2011.
28. 黃志遠, 苯甲醯苯胺及吲哚化合物的合成與抑制NF-κB 之結構活性關係探討, 碩士論文, 東海大學, 台中. 2010.
29. Graziano, G., Hydrophobicity of benzene. Biophysical chemistry 1999, 82 (1), 69-79.