臺灣博碩士論文加值系統

最近許多研究指出活化的轉錄因子NF-E2 相關因子2 ( Nuclear factor erythroid-2-related factor, Nrf2)，透過與氧化反應元件(antioxidant response element, ARE) 相互作用，進而活化許多代謝解毒酵素與抗氧化蛋白，在抗氧化與抑制正常癌化等細胞防禦保護中發揮重要的作用。相反的，在臨床上抑制過度活化的轉錄因子NF-E2 相關因子2，卻有阻止癌細胞在化、放療時產生之抗藥性。因此，研發作用強及新穎Nrf2/ARE活化劑當作癌症防護物質(chemoprevention)及研發Nrf2/ARE 抑制劑來防止化療藥物產生的抗藥性(resistance)，已成為癌症研究領域上具有很大的潛力。
本論文已合成一系列新穎的香豆素和萘衍生物。其中，香豆素衍物以化合物17a顯示出比t-BHQ更具有活化Nrf2的活性；而萘的衍生物則是以化合物34a表現最佳。令人興奮的是，這些衍生物對細胞都沒有顯著的毒性。化合物17a已完成體內與體外活性試驗，已知該化合物能同時增加Nrf2/ARE路徑下的AKR1C1、GCLC及Prx1的mRNA濃度，體內試驗中得知其能夠增加小鼠肝臟中II期酵素AKR1C1、GR與HO-1的濃度；化合物34a在西方墨點法分析中得知齊無法向上調解Nrf2的表現濃度，但卻能誘導Nrf2蛋白在絲氨酸40的磷酸化作用使Nrf2轉錄活性受到活化。因此這一系列新穎的香豆素和萘衍生物已知其對ROS/RNS具有清除和化學預防能力並了解其作用機制。本論文中已開發出作用強及新穎的Nrf2活化劑，以期能應用於疾病預防上，當作具有潛力的防護物質。

Recently studies demonstrated that activation of the Nuclear factor erythroid-2-related factor (Nrf2) signaling pathway could reduce the oxidative stress damage and also prevent the normal cell transformation. However, in clinical, over expression of the Nrf2/ARE- regulated detoxification/antioxidation genes has been closely relative to the cancer cells for developing the resistance to chemotherapy and radiotherapy. Therefore, identification of potent Nrf2/ARE signaling activators for chemoprevention as well as Nrf2/ARE signaling inhibitors for overcome tumor cells to develop resistance become very attractive subjects for cancer research.
In this dissertation, a series of novel coumarin and naphthalene derivatives have been synthesized. Among them, the coumarin derivative showed higher activity than t-BHQ in the presence of compound 17a, while Naphthalene derivative was the best in compound 34a. It is exciting that these derivatives are not significantly cytotoxicity. Compound 17a has been assay for in vivo and in vitro activity, and it is known that the compound can simultaneously increase mRNA levels of AKR1C1, GCLC and Prx1 in the Nrf2 / ARE pathway. In vivo, it is known that it can increase AKR1C1, GR And HO-1 concentration. Compound 34a was found to be unable to up-regulate the expression of Nrf2 in Western blot analysis, but could induce Nrf2 protein activation in serine 40 phosphorylation. Therefore, this series of novel coumarin and naphthalene derivatives are known to have the ability to scavenge and chemoprevent ROS / RNS and to understand its mechanism of action. In this dissertation, we have developed a strong and novel Nrf2 activator, which can be used as a potential protective agent for disease prevention.

中文摘要 I
英文摘要 II
誌 謝 III
目 錄 V
圖目錄 VII
表目錄 VIII
壹、前言 1
貳、研究動機 8
參、研究方法 17
第一節 含肟及醯胺之香豆素衍生物合成大綱 17
第二節 含肟及醯胺之香豆素衍生物合成方法與步驟 18
第三節 含肟之萘衍生物合成大綱 20
第四節 含肟之萘衍生物合成方法與步驟 21
肆、生物活性評估 24
第一節 含肟及醯胺之香豆素衍生物誘導NF-E2 相關因子2 (Nrf2)活性試驗 24
第二節 1、2位含肟之萘衍生物誘導Nrf2之活性試驗 42
伍、結論 49
陸、實驗部分 50
第一節 儀器與試藥 50
一、儀器 50
二、試藥 51
第二節 各化合物的製備 52
一、側鏈含1-(萘-2-基)乙基[1-(naphthalen-2-yl)ethanyl]之香豆素中間產物的裝備 52
二、3位含肟之香豆素衍生物的裝備 56
三、4位含肟之香豆素衍生物的製備 62
四、6位含肟之香豆素衍生物的製備 68
五、7位含肟之香豆素衍生物的製備 74
六、3位含醯胺之香豆素衍生物的製備 80
七、4位含醯胺之香豆素衍生物的製備 85
八、6位含醯胺之香豆素衍生物的製備 90
九、7位含醯胺之香豆素衍生物的製備 95
十、1位與2位含酮基側鏈之萘衍生物的製備 100
十一、1位含肟之萘衍生物的裝備 107
十二、2位含肟之萘衍生物的裝備 118
柒、論文目錄 129
捌、參考文獻 132
附錄 138

1. Yager, J. D.; Davidson, N. E. N. Eng. J. Med. 2006, 354, 270.
2. Kim, J. W.; Tchernyshyov, I.; Semenza, G. L.; Dang, C. V. Cell Metab. 2006, 3, 177.
3. Franco, R.; Sanchez-Olea, R.; Reyes-Reyes, E.M.; Panayiotidis, M. I. Mutat. Res. 2009, 674, 3.
4. Migliore, L.; Coppede, F. Mutat. Res. 2009, 674, 73.
5. Giordano, F. J. J. Clin. Invest. 2005, 115, 500.
6. Andersen, J. K. Nat. Med. 10 Suppl. 2004, S18.
7. Valko, M.; Rhodes, C. J.; Moncol, J.; Izakovic, M.; Mazur, M. Chem. Biol. Interact. 2006, 160, 1.
8. Hur, W.; Gray, N.S. Curr. Opin. Chem. Biol. 2011, 15, 162.
9. Rao, C. V.; Reddy, B. S. Curr. Cancer Drug Targets 2004, 4, 29.
10. Lau, A.; Villeneuve, N.F.; Sun, Z.; Wong, P. K.; Zhang, D. D. Pharmacol. Res. 2008, 58, 262.
11. Ma, Q. Annu. Rev. Pharmacol. Toxicol. 2013, 53, 401.
12. Motohashi, H.; Yamamoto, M. Mol. Med. 2004, 10, 549-557.
13. Moon, E. J.; Giaccia, A. Free Radic. Biol. Med. 2015, 79, 292.
14. Kang, M. I.; Kobayashi, A.; Wakabayashi, N.; Kim, S. G.; Yamamoto, M.; Proc. Natl. Acad. Sci. U S A 2004, 101, 2046.
15. Vriend, J.; Reiter, R. J. Mol. Cell. Endocrinol. 2015, 401, 213.
16. Baird, L.; Dinkova-Kostova, A. T. Arch. Toxicol. 2011, 85, 241.
17. Wijst, G. van der; Brown, R.; Rots, M.G. Biochim. Biophys. Acta. 2014, 1846, 494.
18. Huang, H. C.; Nguyen, T.; Pickett, C. B. J. Biol. Chem. 2002, 277, 42769.
19. Jain, A. K.; A.K. Jaiswal, J. Biol. Chem. 2006, 281, 12132.
20. Jain, A. K.; Jaiswal, A. K. J. Biol. Chem. 2007, 282, 16502.
21. Cullinan, S.B.; Zhang, D.; Hannink, M.; Arvisais, E.; Kaufman, R. J.; Diehl, J. A. Mol. Cell. Biol. 2003, 23, 7198.
22. Yu, R.; Lei, W.; Mandlekar, S.; Weber, M. J.; Der, C. J.; Wu, J.; Kong, A.N. J. Biol. Chem. 1999, 274, 27545.
23. Yu, R.; Mandlekar, S.; Lei, W.; Fahl, W. E.; Tan, T. H.; Kong, A. N. J. Biol .Chem. 2000, 275, 2322.
24. Papp, D.; Lenti, K.; Modos, D.; Fazekas, D.; Dul, Z.; Turei, D.; Foldvari-Nagy, L.; Nussinov, R.; Csermely, P.; Korcsmaros, T. FEBS. Lett. 2012, 586, 1795.
25. Magesh, S.; Chen, Y.; Hu, L. Med. Res. Rev. 2012, 32, 687.
26. Kumar, V.; Kumar, S.; Hassan, M.; Wu, H.; Thimmulappa, R. K.; Kumar, A.; Sharma, S. K.; Parmar, V. S.; Biswal, S.; Malhotra, S. V.; J. Med. Chem. 2011, 54, 4147.
27. Gao, B.; Doan, A.; Hybertson, B. M. Clin. Pharmacol. 2014, 6, 19.
28. Kostova, I. Curr. Med. Chem. 2005, 5, 29.
29 Amin, K. M.; Awadalla, F. M.; Eissa, A. A.; Abou-Seri, S. M.; Hassan, G. S. Bioorg. Med. Chem. 2011, 19, 6087.
30. Belluti, F.; Fontana, G.; Dal Bo, L.; Carenini, N.; Giommarelli, C.; Zunino, F. Bioorg. Med. Chem. 2010, 18, 3543.
31. Cai, X.; Yang, J.; Zhou, J.; Lu, W.; Hu, C.; Gu, Z.; Huo, J.; Wang, X.; Cao, P.; Bioorg. Med. Chem. 2013, 21, 84.
32. Carta, F.; Maresca, A.; Scozzafava, A.; Supuran, C. T. Bioorg. Med. Chem. 2012, 20, 2266.
33. Kathuria, A.; Priya, N.; Chand, K.; Singh, P.; Gupta, A.; Jalal, S.; Gupta, S.; Raj, H. G.; Sharma, S. K. Bioorg. Med. Chem. 2012, 20, 1624.
34. Marumoto, S.; Miyazawa, M. Bioorg. Med. Chem. 2012, 20, 784.
35. Matos, M. J.; Teran, C.; Perez-Castillo, Y.; Uriarte, E.; Santana, L.; Vina, D. J. Med. Chem. 2011, 54, 7127.
36. Chen, Y. L.; Lu, C. M.; Lee, S. J.; Kuo, D. H.; Chen, I. L.; Wang T. C. and Tzeng, C. C. Bioorg. Med. Chem, 2005, 13, 5710.
37. Reddy, N. S.; Gumireddy, K.; Mallireddigari, M. R.; Cosenza, S. C.; Venkatapuram, P.; Bell, S. C.; Reddy, E. P. and Ramana Reddy, M. V. Bioorg. Med. Chem. 2005, 13, 3141.
38. Smyth, T.; Ramachandran, V. N. ; Smyth, W. F. Int J. Antimicrob. Agents, 2009, 33, 421.
39. Elshemy, H. A. H.; Zaki, M. A. Bioorg. Med. Chem. 2016, http://dx.doi.org/10.1016/j.bmc.2016.12.019
40. Bouckaert, C.; Serra, S.; Rondelet, G.; Dolusic,E.; Wouters, J.; Dogne, J. M.; Frederick, R.; Pochet, L. 2016, 110, 181
41.Chen, Y. L.; Wang, T. C.; Lee, K. H.; Cheng, Y. L.; Teng, C. M.; Tzeng, C. C. Helv. Chim. Acta. 1996, 79, 651.
42.Chen, Y. L.; Wang, T. C.; Chang, N. C.; Tzeng, C. C. Helv. Chim. Acta. 1999, 82, 191.
43.Chen, Y. L.; Chen, I. L.; Tzeng, C. C.; Wang, T. C. Helv. Chim. Acta. 2000, 83, 989.
44.Chen, Y. L.; Teng, C.M.; Tzeng, C.C. Chinese Pharmaceutical Journal 2001, 53, 85.
45.Chen, Y. L.; Lu, C. M.; Lee, S. J.; Kuo, D. H.; Chen, I. L.; Wang, T. C.; Tzeng, C. C. Bioorg. Med. Chem. 2005, 13, 5710.
46.Chen, Y. L.; Wang, T. C.; Liang, S. C.; Teng, C. M.; Tzeng, C. C. Chem. Pharm. Bull. (Tokyo) 1996, 44, 1591
47.Balogun, E.; Hoque, M.; Gong, P.; Killeen, E.; Green, C. J.; Foresti, R.; Alam, J.; Motterlini, R. Biochem. J. 2003, 371, 887.
48.Lee, Y.; Shin, D. H.; Kim, J. H.; Hong, S.; Choi, D.; Kim, Y. J.; Kwak, M. K.; Jung, Y. Eur. J. Pharmacol. 2010, 643, 21.
49.Kachadourian, R.; Day, B. J.; Pugazhenti, S.; Franklin, C. C.; Genoux-Bastide, E.; Mahaffey, G.; Gauthier, C.; Di Pietro, A.; Boumendjel, A. J. Med. Chem. 2012, 55, 1382.
50.Kumar, V.; Kumar, S.; Hassan, M.; Wu, H.; Thimmulappa, R. K.; Kumar, A.; Sharma, S. K.; Parmar, V. S.; Biswal, S.; Malhotra, S. V. J. Med. Chem. 2011, 54, 4147.
51. Rojas, J.; Buitrago, A.; Rojas, L. B.; Morales, A.; Baldovino, S. Nat. Prod. Commun. 2010, 5, 1115.
52. Choi, J.; Bae, S. J.; Ha, Y. M.; No, J. K.; Lee, E. K.; Lee, J. S.; Song, S.; Lee, H.; Suh, H.; Yu, B.P.; Chung, H. Y. Bioorg. Med. Chem. Lett. 2010, 20, 4882.
53. Jeong, S. H.; Jo, W. S.; Song, S.; Suh, H.; Seol. S. Y.; Leem, S. H.; Kwon, T. K.; Yoo, Y. H.; Biochem. Pharmacol. 2009, 77, 1337.
54. Gusman, J.; Malonne, H.; Atassi, G.; Carcinogenesis 2001, 22,1111.
55. Fre’mont, L. Life Sci. 2000, 66, 663.
56. Bertini, S.; Vincenzo Calderone, I.; Carboni, R. M.; Martelli, A.; Martinelli, A.; Minutolo, F.; Rajabi, M.; Testai, L.; Tuccinardi, T.; Ghidoni, R.; Macchia, M. Bioorg. Med. Chem. 2010, 18, 6715.
57. Das, S. K.; Panda, G.; Chaturvedi, V.; Manju, Y. S.; Gaikwad, A. K.; Sinha, S. Bioorg. Med. Chem. Lett. 2007, 17, 5586.
56. Lokhande, T. N.; Viswanathan, C. L.; Joshia A.; Juvekar, A. Bioorg. Med. Chem. 2006, 14, 6022.
58. Chaturvedi, D.; Ray, S.; Srivastavab, A. K.; Chander, R. Bioorg. Med. Chem. 2008, 16, 2489.
59. Kongkathip, B.; Sangma, C.; Kirtikara, K.; Luangkamin, S.; Hasitapan, K.; Jongkon, N.; Hannongbuaa S.; Kongkathipa, N. Bioorg. Med. Chem. 2005, 13, 2167.
60. Walker, K. A.; Wallach, M. B.; Hirschfeld, D. R. J. Med. Chem. 1981, 24, 67
61. Nardi, D.; Tajana, A.; Leonardi, A.; Pennini, R.; Portioli, F.; Magistretti, M. J.; Subissi, A. J. Med. Chem. 1981, 24, 727.
62. Karakurt, A.; Alagoz, M. A.; Sayoglu, B.; Calıs, U.; Dalkara, S. Eur. J. Med. Chem. 2012, 57, 275.
63. Tzeng, C. C.; Lee, K. H.; Wang, T. C.; Han, C. H.; Chen, Y. L. Pharm. Res. 2000, 17, 715.
64. Chen, Y. L.; Wang, T. C.; Chang, N. C.; Chang, Y. L.; Teng, C. M.; Tzeng, C. C. Chem. Pharm. Bull. 1998, 46, 962.
65. Wang, T. C.; Lee, K. H.; Chen, Y. L.; Liou, S. S.; Tzeng, C. C. Bioorg. Med. Chem. Lett. 1998, 8, 2773.
66. Hong, C. Y.; Kim, Y. K.; Lee, Y. H.; Kwak, J. H. Bioorg. Med. Chem. Lett., 1998, 8, 221.
67. Hong, C. Y.; Kim, Y. K.; Chang, J. H.; Choi, S. H.; Nam, D. H.; Kim, Y. Z.; Kwak, J. H. J. Med. Chem. 1997, 40, 3594.
68. Cooper, C. S.; Klock, P. L.; Chu, D. T. W.; Hardy, D. J.; Swanson, R. N.; Plattner, J. J. J. Med. Chem. 1992, 35, 1392.
69. Chen, Y. L.; Lu, C. M.; Chen, I. L.; Tsao, L. T.; Wang, J. P. J. Med. Chem., 2002, 45, 4689.
70. Wang, T. C.; Zhao, Y. L.; Liou, S. S. Helv. Chim. Acta. 2002, 85, 1382.
71. Wang, T. C.; Chen, I. L.; Lu, P. J.; Wong, C. H.; Liao, C. H.; Tsiao, K. C.; Chang, K. M.; Chen, Y. L.; Tzeng, C. C. Bioorg. Med. Chem, 2005, 13, 6045.
72. Harris, J. W.; Katki, A.; Anderson, L. W.; Chmurny, G. N.; Paukstelis, J. V.; Collins, J. M. J. Med. Chem. 1994, 37, 706.
73. Bishop, M. J.; Ciufolini, M. A. J. Amer. Chem. Soc. 1992, 114, 10081.
74. Charyulu, G. A.; Mckee, T. C.; Ireland, C. M.; Chris, M. Tetrahedron Lett. 1989, 30, 4201.
75. Chen, I. L.; Chen, J. J.; Lin, Y. C.; Peng, C. T.; Juang, S. H.; Wang, T. C. Euro. J. Med. Chem. 2013, 59, 227.
76. Chen, I. L.; Chen, J. Y.; Shieh, P. C.; Chen, J. J.; Lee, C. H.; Juang, S. H.; Wang, T. C. Bioorg. Med. Chem.2008, 16, 7639.
77. Silverstein, R. M.; Webster, F. X. Spectrometry Identification of Organic compounds, 1998, 6th, 217.
78. Chen, H. H.; Chen, Y. T.; Huang, Y. W.; Tsai, H. J.; Kuo, C.C. Free Radic. Biol. Med. 2012, 52, 1054.
79. Pi, J.; Bai, Y.; Reece, J. M.; Williams, J.; Liu, D.; Freeman, M. L.; Fahl, W. E.; Shugar, D.; Liu, J.; Qu, W.; Collins, S.; Waalkes, M. P.; Free Radic. Biol. Med. 2007, 42, 1797.
80. Hamdulay, S. S.; Wang, B.; Birdsey, G. M.; Ali, F.; Dumont, O.; Evans, P. C.; Haskard, D. O.; Wheeler-Jones, C. P.; Mason, J. C. Free Radic. Biol. Med. 2010, 48, 1013.
81. Martin, D.; Rojo, A. I.; Salinas, M.; Diaz, R.; Gallardo, G.; Alam, J.; De Galarreta, C. M.; Cuadrado, A. J. Biol. Chem. 2004, 279, 8919.
82. Kweon, M. H.; In Park, Y.; Sung, H. C.; Mukhtar, H. Free Radic. Biol. Med. 2006, 40, 1349.
83. Xu, C.; Yuan, X.; Pan, Z.; Shen, G.; Kim, J. H.; Yu, S.; Khor, T. O.; Li, W.; Ma, J.; Kong, A. N. Mol. Cancer Ther. 2006, 5, 1918.
84. Lee, K. M.; Kang, K.; Lee, S. B.; Nho, C. W. Cancer Lett. 2013, 330, 225.
85. Lee, S. E.; Jeong, S. I.; Yang, H.; Park, C. S.; Jin, Y. H.; Park, Y. S. J. Cell. Biochem. 2011, 112, 2352.
86. Buelna-Chontal, M.; Guevara-Ch_avez, J. G.; Silva-Palacios, A.; Medina-Campos, O. N.; Pedraza-Chaverri, J.; Zazueta, C. Free Radic. Biol. Med. 2014, 74, 145.