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研究生:張瑜
研究生(外文):CHANG,YU
論文名稱:新型1,4-Benzodiazepine-2,5-diones應用為內皮素受體拮抗劑
論文名稱(外文):Novel 1,4-Benzodiazepine-2,5-diones as the Antagonists of Endothelin Receptor
指導教授:方俊民方俊民引用關係蔡蘊明蔡蘊明引用關係何東英何東英引用關係羅禮強
指導教授(外文):Fang, Jim-MinTsai, Yeun-MinHo, Tong-IngLo, Lee-Chiang
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:化學研究所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:159
中文關鍵詞:拮抗劑內皮素受體抗高血壓藥物分子模擬生物檢測
外文關鍵詞:14-benzodiazepine-25-dionesfura-2pharmacophore
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本研究為合成具有1,4-benzodiazepine-2,5-diones架構之化合物,其可能成為具有高活性之內皮素受體拮抗劑。化合物之合成起始於isoatoic anhydride及L-aspartic acid dimethyl ester,兩者加熱得到benzodiazepine架構及其acid side chain,然後經由適當之alkylation, side chain modification及水解步驟來得到最終產物。再將此化合物以鈣離子吸收方式來測試其生物活性,而鈣離子濃度的改變由fura-2作為indicator來偵測,結果在一系列合成之具有1,4-benzodiazepine-2,5-diones架構之化合物,其中有11個化合物作如上述的bioassay,論文編號104,115等二個化合物有較好的拮抗效果。
The synthesis of the benzodiazepine analogues 29 was basically started from 5-chloroisoatoic anhydride 80 and L-aspartic acid dimethyl ester hydrochloride 81, and the synthetic work was through the construction of the backbone of 1,4-benzodiazepine- 2,5-dione, then two times of N-benzylation, followed by the modification of the side chain, ended to the step of hydrolysis to obtain the target compounds with 20 % yield.
To evaluate the efficiency of the endothelin receptor antagonists, we use fura-2 as a ratiometric Ca2+ indicator to measure the ET-1 dose-dependent increase of intracellular free [Ca2+] in intact cells. The binding of Ca2+ to fura-2 causes an increase in fluorescence intensity and a shift of the peak of its excitation spectrum from 380 nm to 340 nm. The internal free [Ca2+] is determined from the relative intensities of fluorescence measured at 380 nm and 340 nm. Eleven of the synthesized 1,4-benzodiazepine-2,5-diones were evaluated for the test of free [Ca2+], and both compound 104 and 115 had the better inhibition.
Chapter 1. Introduction p.1
Chapter 2. Synthesis p.19
Chapter 3. Bioassay p.55
Chapter 4. Experiment p.73
References p.106
Spectrum p.112
1. Watanabe, T., Itoh, Y., Ogi, K., Kimura, C., Suzuki, N., Onda, H. FEBS Lett. 1989, 251, 257.
2. Yanagisawa, M., Masaki, T. Trends Pharmacol. Sci. 1989, 10, 374.
3. Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M.; Mitsui, Y., Yazaki, Y., Goto, K., Masaki, T. Nature 1988, 332, 411.
4. Yanagisawa, M. Circulation 1994, 89, 1320.
5. Fukami, T., Nagase, T., Mase. T., Naya, A., Fujita, K., Niiyama, K. Ishikawa, K. Bioorg. Med. Chem. Lett. 1994, 4, 1613.
6. Itoh, S., Sasaki, T., Ide, K., Ishikawa, K., Nishikibe, M., Yano, M. Biochem. Biophys. Res. Commun. 1993, 195, 969.
7. Aramori, I., Nirei, H., Shoubo, M., Sogabe, K., Nakamura, K., Kojo, H., Notsu, Y., Ono, T., Nakanishi, S. Mol. Pharmacol. 1993, 43, 127.
8. Fujimoto, M., Mihara, S.-I., Najajima, S., Ueda, M., Nakamura, M., Sakurai, K. FEBS Lett. 1992, 305, 41.
9. Mihara, S.-I., Nakajima, S., Matumura, S., Kohnoike, T., Fujimoto, M. J. Pharmacol. Exp. Ther. 1994, 268, 1.
10. Clozel, M., Breu, V., Burri, K., Cassal, J.-M., Fischli, W., Gray, G. A., Hirth, G., Loffler, B.-M., Muller, M., Neidhart, W., Ramuz, H. Nature 1993, 365, 759.
11. Breu, V., Loffler, B.-M, Clozel, M. FEBS Lett. 1993, 334, 210.
12. Seo, B., Oemar, B. S., Siebenmann, R., von Segesser, L., Luscher, T. F. Circulation 1994, 89, 1320.
13. Kanda, Y., Kawanishi, Y., Oda, K., Sakata, T., Mihara, S.-I, Asakura, K., Kanemasa, T., Ninomiya, M., Fujimoto, M., Konoike, T. Bioorg. Med. Chem. 2001, 9, 897.
14. Kanda, Y., Takahashi, T., Araki, Y., Konoike, T., Mihara, S.-I., Fujimoto, M. Bioorg. Med. Chem. Lett. 2000, 10, 1875.
15. Astles, P. C., Brealey, C., Brown, T. J., Facchini, V., Handscombe, C., Harris, N. V., McCarthy, C., Mclay, I. M., Porter, B., Roach, A. G., Sargent, C., Smith, C., Walsh Roger J. A. J. Med. Chem. 1998, 41, 2732.
16. Astles, P. C., Brown, T. J., Halley, F., Handscombe, C. M., Harris, N. V., Majid, T. N., McCarthy, C., Mclay, I. M., Morley, A., Porter, B., Roach, A. G., Sargent, C., Smith, C., Walsh Roger J. A. J. Med. Chem. 1998, 41, 2745.
17. Astles, P. C., Brown, T. J., Halley, F., Handscombe, C. M., Harris, N. V., Majid, T. N., McCarthy, C., Mclay, I. M., Morley, A., Porter, B., Roach, A. G., Sargent, C., Smith, C., Walsh Roger J. A. J. Med. Chem. 2000, 43, 900.
18. Zhang, J., Didierlaurent, S., Fortin, M., Lefrancois, D., Uridat, E., Vevert, J.-P. Bioorg. Med. Chem. Lett. 2000, 10, 2575.
19. Morimoto, H., Fukushima, C., Yamauchi, R., Hosino, T., Kikkawa, K., Yasuda, K., Yamada K. Bioorg. Med. Chem. 2001, 9, 255.
20. Elliott, J. D., Lago, M. A., Cousins, R. D., Gao, A., Leber, J. D., Erhard, K. F., Nambi, P., Elshourbagy, N. A., Kumar, C., Lee, J. A., Bean, J. A., DeBrosse, C. W., Eggleston, D. S., Brooks, D. P., Feuerstein, G., Ruffolo, R. R., Jr., Weinstock, J., Gleason, J. G., Peishoff, C. E., Ohlstein, E. H. J. Med. Chem. 1994, 37, 1553.
21. Keating, T. A., Armstrong, R. W. J. Org. Chem. 1996, 61, 8935.
22. Wright, W. B., Jr., Brabander, H. J., Greenblatt, E. N., Day, I. P., Hardy, R. A., Jr. J. Med. Chem. 1978, 21, 1087.
23. Hu, Wan-Ping, Wang, Jeh-Jeng, Lin, Fu-Lung, Lin, Yu-Chen, Lin, Shinne-Ren, Hsu, Mei-Hui J. Org. Chem. 2001, 66, 2881.
24. Ananthan, S, Clayton, S. D., Ealick, S. E., Wong, G, Evoniuk, G. E., Skolnick, P. J. Med. Chem. 1993, 36, 479.
25. Wong, G, Koehler, K. F., Skolnick, P., Gu, Z.-Q, Ananthan, S, Schonholzer, P, Hunkeler, W., Zhang, W, Cook, J. M. J. Med. Chem. 1993, 36, 1820.
26. Hirschmann, R., Sprengeler, P. A., Kawasaki, T., Leahy, J. W., Shakespeare, W. C., Smith, A. B., III. J. Am. Chem. Soc. 1992, 114, 9699.
27. McDowell, R. S., Blackburn, B. K., Gadek, T. R., McGee, L. R., Rawson, T., Reynolds, M. E., Robarge, K. D., Somers, T. C., Thorsett, E. D., Tischler, M., Webb, R. R., II, Venuti, M. C. J. Am. Chem. Soc. 1994, 116, 5077.
28. Hsu, M. -C., Schutt, A. D., Holly, M., Slice, L. W., Sherman, M. I., Richman, D. D., Potash, M. J., Volsky, D. J. Science 1991, 254, 1799.
29. Pauwels, R., Andries, K., Desmyter, J., Schols, D., Kukla, M. J., Breslin, H. J., Raeymaeckers, A., Gelder, J. V., Woestenborghs, R., Heykants, J., Schellekens, K., Janssen, M. A. C., Clercq, E. D., Janssen, P. A. J. Nature 1990, 343, 470.
30. (a) Arai, H., Hori, S., Aramori, I., Ohkubo, H., Nakanishi, S. Nature 1990, 348, 730. (b) Sakurai, T., Yanagisawa, M., Takuwa, Y., Miyazaki, H., Kimura, S., Goto, K., Masaki, T. Nature 1990, 348, 732.
31. (a) Gu, Z.-Q., Wong, G., Dominguez, C., Brain R. de Costa, Rice, K. C., Skolnick, P. J. Med. Chem. 1994, 36, 1001. (b) Zhang, P., Zhang, W., Liu, R., Harris, B., Skolnick, P., Cook, J. M. J. Med. Chem. 1995, 38, 1679.
32. Ishikura, M., Mori, M., Ikeda, T., Ban, Y. J. Org. Chem. 1982, 47, 2456.
33. Cho, N. S., Song, K. Y. J. Heterocycl. Chem. 1989, 26, 1807.
34. Akssira, M., Boumzebra, M., Kasmi, H., Dahdouh, A., Roumestant, M. L., Ph. Viallefont Synth. Commun. 1993, 23, 2265.
35. Webb, R. R., II, Barker, P. L., Baier, M., Reynolds, M. E., Robarge, K. D., Blackburn, B. K., Tischler, M. H., Weese, K. J. Tetrahedron Lett. 1994, 35, 2113.
36. Karp, G. M. J. Org. Chem. 1995, 60, 5814.
37. Boojamra, C. G., Burow, K. M., Ellman, J. A. J. Org. Chem. 1995, 60, 5742.
38. Goff, D. A., Zuckermann, R. N. J. Org. Chem. 1995, 60, 5744.
39. The unpublished result was carried out by 柯博文.
40. The unpublished result was carried out by 陳文雄.
41. Kim, D. H. J. Heterocycl. Chem. 1975, 12, 1323.
42. (a) Coppola, G. M. Synthesis 1980, 505. (b) Wright, W. B. U. S. Patent 3947408 1976; C. A. 1976, 85, 46771. (c) Carabateas, P. M. U. S. Patent 3732212 1973; C. A. 1973, 79, 42570. (d) Stevens, R. V., Cory, R. M., Rossen, S. J. Chem. Soc. Chem. Commun. 1975, 742.
43. Tsubota, M, Hamashima, M. Heterocycl. 1984, 21, 706.
44. (a) Thompson, L. A., Ellman, J. A. Chem. Rev. 1996, 96, 555. (b) Landi, J. J., Ramig, K., Syn. Commun. 1991, 21, 167.
45. Blass, B. E., Burt, T. M., Liu, S, Portlock, D. E., Swing, E. M. Tetrahedron Lett. 2000, 41, 2063.
46. Hansch, M. J. Org. Chem. 1955, 20, 1026.
47. Williard, P. G., Fryhle, C. B. Tetrahedron Lett. 1980, 21, 3731.
48. Vickery, E. H., Pahler, L. F., Eisenbraun, E. J. J. Org. Chem. 1979, 44, 4444.
49. Svoboda, J, Palecek, J. Chem. Commun. 1991, 56, 1317.
50. (a) Mimoto, T., Kato, R., Takaku, H., Nojima, S., Terashima, K. J. Med. Chem. 1999, 10, 1789. (b) MimoSachweh, V., Langhals, H. Chem. Ber. 1986, 119, 1627.
51. Sakakibara, S. et al. Bull. Chem. Soc. 1967, 40, 2164.
52. Bellmann, E., Shaheen, S. E., Thayumanavan, S., Barlow, S., Grubbs, R. H., Marder, S. R., Kippelen, B, Peyghambarian, N. Chem. Mater. 1998, 10, 1668.
53. Mimoto, T., Kato, R., Takaku, H., Nojima, S., Terashima, K. J. Med. Chem. 1999, 10, 1789.
54. Guthrie, R. D., Shi, B. J. Am. Chem. Soc. 1990, 112, 3136.
55. Rubanyi, G. M. Drugs Future 1992, 17, 915.
56. Sakurai, T., Goto, K. Drugs 1993, 46, 795.
57. Brock, T. A., Danthuluri, N. R. “Endothelin”, Rubanyi, G. M. Ed., Oxford University Press, pp 103-124.
58. Boyer, J. L., Downes, C. P., Harden, T. K. J. Biol. Chem. 1993, 264, 884.
59. Chueh, S. -H., Kao, L. -S. J. Neurochem. 1993, 61, 1782.
60. Nilius, B., Hess, P., Lansmen, J. B., Tsien, R. W. Nature 1985, 316, 443.
61. Blachier, F., Malaisse, W. J. Biochim. Biophys. Acta 1988, 970, 222.
62. Miyamoto, T., Restrepo, D., Vragoe, E. J., Teeter, J. H. J. Mem. Biol. 1992, 127, 173.
63. Hoth, M., Penner, R. Nature 1992, 355, 353.
64. Tsien, R. W. Ann. Rev. Cell Biol. 1990, 6, 751.
65. Gill, D. L., Ueda, T., Chueh, S. H., Noel, M. W. Nature 1986, 342, 16.
66. McPherson, P. S., Campell, K. P. J. Biol. Chem. 1993, 268, 13765.
67. Lee, H. C., Walseth, T. H., Bratt, G. H., Hayes, R. N., Clapper, D. L. J. Biol. Chem. 1989, 264, 1608.
68. Grynkiewicz, G., Poenie, M., Tsien, R. Y. J. Biol. Chem. 1985, 260, 3440.
69. Lin, W, -W., Chuang, D. M. Mol. Pharmacol. 1993, 44, 158.
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