本論文對於實驗室所開發的方法──經同型半胱氨酸硫內酯(homocysteine thiolactone, HCT)醯基置換進而合成含高半胱胺酸(homocysteine, HCys)胜肽，進行試劑反應量的優化而得到最佳產率，其中優化條件包含了路易士酸、鹼，而後並針對醯基置換方法所使用之胺基酸衍生物結構上的差異來做進一步的探討，並應用於二胜肽、三胜肽及四胜肽的合成。
近年來，組織蛋白去乙醯化酶抑制劑(HDAC inhibitor, HDI)被廣泛的研究並應用在抗腫瘤藥物上，CHAP31 (Cyclic Hydroxamic-acid-containing Peptide 31)即為一種新穎的抑制劑，因其穩定度高與活性測試有不錯的效果，故有越來越多關於此抑制劑的研究，本論文則嘗試著利用實驗室開發的醯基置換方法來進行此抑制劑含硫衍生物的合成。

This thesis focus on the synthesis of homocysteine (HCys)-containing peptides via acyl transfer of homocysteine thiolactone (HCT) . To obtain the best yields, this thesis optimized the reaction under various conditions including changes in Lewis acids, bases, and amino acid derivatives involved in the reaction, further discussions with regard to the structural differences in the amino acids used and the efficiency of acyl transfer was also included. Latter, the optimized conditions were applied to synthesize dipeptides, tripeptides and tetrapeptides.
In recent years, the HDAC inhibitor (HDI) has been widely studied and applied as antitumor drugs. CHAP31 (Cyclic Hydroxamic-acid-containing Peptide 31) is a novel inhibitor. For these reasons, with high stability and good bioactivity, there have been increasing number of studies on this inhibitor. This thesis attempt to apply the acyl transfer method developed by the laboratory to carry out the synthesis of sulfur-containing derivatives of this inhibitor.

論文審定書 i
誌謝 iv
中文摘要 iv
Abstract v
目次 vi
圖目錄 viii
流程目錄 ix
表目錄 x
光譜目錄 xi
縮寫表 xiv
第一章 緒論 1
1.1 組織蛋白在生物中的角色 1
1.1.1 組織蛋白 2
1.1.2 組織蛋白轉譯後修飾 3
1.1.3 離胺酸乙醯化及去乙醯化 4
1.2 去乙醯化酶(HDACs) 6
1.2.1 HDACs的種類介紹 6
1.2.2 HDACs的作用機制 8
1.2.3 HDACs過度表現的缺點 11
1.3 去乙醯化酶抑制劑(HDACI) 13
1.3.1 HDACI基本特徵 13
1.3.2 CHAP inhibitor 16
1.3.2 CHAP 31 18
1.4 環狀胜肽的合成 20
第二章 研究動機 24
第三章 結果與討論 26
3.1 經同型半胱氨酸硫內酯醯基置換方法的優化 26
3.1.1起始物的製備 26
3.1.2 無路易士酸催化下的硫內酯醯基置換方法 28
3.1.3 經路易士酸催化的硫內酯醯基置換方法 29
3.2 應用醯基置換方法於寡肽(oligopeptide)的合成 31
3.2.1 各類胺基酸衍生物進行醯基置換方法的測試(1+1) 31
3.2.2 醯基置換方法於三胜肽合成之應用(2+1) 34
3.2.3醯基置換方法於四胜肽合成之應用(2+2) 35
3.3 CHAP31含硫衍生物的合成 36
3.3.1 CHAP31含硫衍生物的逆合成分析 36
3.3.2 CHAP31含硫衍生物的合成 37
第三節 結論 43
第四章 引用文獻 44
5-1 儀器設備與藥品材料 47
5-2 合成步驟與光譜數據 49
第六章光譜資料 90

1. Marks, P. A.; Dokmanovic, M., Expert. Opin. Investig. Drugs 2005, 14 (12), 1497-1511.
2. Thiagalingam, S.; Cheng, K. H.; J Lee, H.; Mineva, N.; Thiagalingam, A.; Ponte, J., Academy of Sciences 2003, 983 (1), 84-100.
3. Jenuwein, T.; Allis, C. D., Science 2001, 293 (5532), 1074-1080.
4. Allfrey, V. G.; Mirsky, A. E., Science 1964, 144 (3618), 559-559
5. Yoshida, M.; Furumai, R.; Nishiyama, M.; Komatsu, Y.; Nishino, N.; Horinouchi, S., Cancer Chemoth. Pharm. 2001, 48 (1), S20-S26.
6. Ito, K.; Adcock, I. M., Mole. Biotechno. 2002, 20 (1), 99-106.
7. Cao, D. F.; Yang, N., Prog. Biochem. Biophys. 2015, 42 (11), 978-993
8. Annemieke, J. M.; Albert, H.; Huib, N.; Stephan K.; André B. P., Biochemical Journal 2003, 370 (3), 737-749
9. Bjerling, P.; Silverstein, R. A.; Thon, G.; Caudy, A.; Grewal, S.; Ekwall, K., Mole. Cell Biol. 2002, 22 (7), 2170-2181.
10. Bolden, J. E.; Peart, M. J.; Johnstone, R. W., Nat. Rev. Drug Discov. 2006, 5, 769.
11. Zhang, J.; Zhong, Q., Cell. Mole. Life Sci. 2014, 71 (20), 3885-3901.
12. Feldman, J. L.; Dittenhafer-Reed, K. E.; Denu, J. M., J. Biol. Chem. 2012, 276 (51), 42419-42427.
13. Finnin, M. S.; Donigian, J. R.; Cohen, A.; Richon, V. M.; Rifkind, R. A.; Marks, P. A.; Breslow, R.; Pavletich, N. P., Nature 1999, 401(6749), 188-93
14. Lombardi, P. M.; Cole, K. E.; Dowling, D. P.; Christianson, D. W., Curr. Opin. Struct. Biol. 2011, 21 (6), 735-743.
15. Fraga, M. F.; Ballestar, E.; Villar-Garea, A.; Boix-Chornet, M.; Espada, J.; Schotta, G.; Bonaldi, T.; Haydon, C.; Ropero, S.; Petrie, K.; Iyer, N. G.; Pérez-Rosado, A.; Calvo, E.; Lopez, J. A.; Cano, A.; Calasanz, M. J.; Colomer, D.; Piris, M. Á.; Ahn, N.; Imhof, A.; Caldas, C.; Jenuwein, T.; Esteller, M., Nature Genetics 2005, 37, 391.
16. Kalipso, H.; Luke, G.; Susan, C.; Hing, Y. L.; David E. N.; Craig, N. R.; The Prostate 2004, 59 (2), 177-189.
17. Hoon, C. J.; Jeong, K. H.; Byung, Y.; Hyun, K. J.; Uk, H. S.; Jae, J. H.; Yong, D. K., Japanese Journal of Cancer Research 2001, 92 (12), 1300-1304.
18. Wilson, A.; Byun, D. S.; Popova, N.; Murray, L. B.; L'Italien, K.; Sowa, Y.; Arango, D.; Velcich, A.; Augenlicht, L. H.; Mariadason, J. M., J. Biol. Chem. 2006 281(19), 13548-13558.
19. Zhang, Z.; Yamashita, H.; Toyama, T.; Sugiura, H.; Ando, Y.; Mita, K.; Hamaguchi, M.; Hara, Y.; Kobayashi, S.; Iwase, H., Breast Cancer Res Treat 2005, 94 (1), 11-16.
20. Huang, B. H.; Laban, M.; Leung, C. H. W.; Lee, L.; Lee, C. K.; Salto, T., M.; Raju, G. C.; Hooi, S. C., Cell. Death Differ. 2005, 12, 395.
21. Jaehei, S.; Heon, N. J.; Heun, L. J.; Woo, E. J.; Min, A. Y.; Young, K. S.; Hyung, L. S.; Sang, P. W.; Jin, Y. N.; Young, L. J.; Woo, N. S., APMIS 2005, 113 (4), 264-268.
22. Mann, B.; Johnson, J. R.; Cohen, M H..; Justice, R.; Pazdur, R., The Oncologist 2007, 12 (10), 1247-1252.
23. Florence, F.; Barbora, O.; Michael, S.; Mario, D.; Marc, D., Curr. Nutr. Food Sci. 2010, 6 (1), 78-99.
24. Furumai, R.; Komatsu, Y.; Nishino, N.; Khochbin, S.; Yoshida, M.; Horinouchi, S., Proceedings of the National Academy of Sciences 2001, 98 (1), 87-92.
25. Balasubramanian, S.; Verner, E.; Buggy, J. J., Cancer Letters 2009, 280 (2), 211-221.
26. Komatsu, Y.; Tomizaki, K. Y.; Tsukamoto, M.; Kato, T.; Nishino, N.; Sato, S.; Yamori, T.; Tsuruo, T.; Furumai, R.; Yoshida, M.; Horinouchi, S.; Hayashi, H., Cancer Research 2001, 61 (11), 4459-66.
27. White, C. J.; Yudin, A. K., Nat. Chem. 2011, 3, 509.
28. Liao, J. S. Chemical ligation at methionine via acyl transfer of homocysteine thiolactone. National Sun Yat-sen University, 2015.
29. Nicola, M. P. I., Process for the resolution of homocysteine-thiolactone 2008.
30. Armarego, W. L. F.; Chai, C.; Armarego, W. L. F.; Chai, C., Purification of Laboratory Chemicals. Elsevier Inc., 2009.
31. Llewellyn, D. B.; Wahhab, A., Tetrahedron Letters 2009, 50 (27), 3939-3941.
32. Ho, V. K. K.; Satoshi, M.; Katsunori, T., Chemistry – A European Journal 2016, 22 (52), 18865-18872.
33. Huang, K. J.; Huang, Y. C.; Lin, Y. A., Chemistry –An Asian Journal 2018, 13 (4), 400-403.
34. Sapala, A. R.; Dhawan, S.; Haridas, V., Supramolecular Chemistry 2017, 29 (9), 670-679.
35. Zhang, X.; Yang, X.; Wang, H.; Li, S.; Guo, K.; Jiang, D.; Xiao, J.; Liang, D., Biol. Pharm Bull 2017, 40 (8), 1240-1246.
36. Yu, Y. Y.; Sun, W.; Dong, L.; Liu, H. D.; Jiang, D.; Xiao, J. H.; Yang, X. H.; Li, S., Chinese Chemical Letters 2013, 24 (8), 715-718.
37. McNulty, J.; Vemula, R.; Krishnamoorthy, V.; Robertson, A., Tetrahedron Letters 2012, 68 (27), 5415-5421.
38. Borah, A. J.; Goswami, P.; Barua, N. C.; Phukan, P., Tetrahedron Letters 2012, 53 (52), 7128-7130.
39. Goncalves, M. S. T.; Maia, H. L. S., Organic & Biomolecular Chemistry 2003, 1 (9), 1480-1485.