研究生: |
廖振傑 LIAO,JHEN-JIE |
---|---|
論文名稱: |
設計及合成六位具有取代基 3-(β-D-Ribofuranosyl)uracil 的衍生物及其生物活性評估 Design, Synthesis and Biological Evaluation of 6-Substituted-3-(β-D-Ribofuranosyl)uracil Derivatives |
指導教授: |
簡敦誠
Chien, Tun-Cheng |
學位類別: |
碩士 Master |
系所名稱: |
化學系 Department of Chemistry |
論文出版年: | 2009 |
畢業學年度: | 97 |
語文別: | 中文 |
論文頁數: | 89 |
中文關鍵詞: | 六位取代基 |
英文關鍵詞: | Orotidine 5’-monophosphate decarboxylase, 6-substituted 3-ribofuranosyluracil, 6-chloro-3-(b-D-ribofuranosyl)uracil |
論文種類: | 學術論文 |
相關次數: | 點閱:152 下載:0 |
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中文摘要
Orotidine 5’-monophosphate decarboxylase (ODCase) 抑制物的設計及合成為本論文的主要目的,主要分為: (a) 6-substituted uridine 和 (b) 6-substituted 3-ribofuranosyluracil 兩種類型,設計合成類似 ODCase 的受質或抑制劑結構以探討酵素作用機制與活性評估。
首先以6-chloro-1,3-dimethyluracil 作為反應模型測試鹼基上數種的親核取代反應,評估反應性及可行性。6-Chloro-1,3-dimethyluracil 與親核性試劑進行取代反應,如 sodium azide、氰化鈉、正丁基胺、和 imidazole 可得到對應的 6-substituted 1,3-dimethyluracils. 然而,相同的反應應用在 6-iodouridine 時,卻無法合成預期的產物。
此外, 以6-chlorouracil作為起始物, 與1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (TBAR) 在路易士酸下進行醣化反應 (glycosylation) 形成6-chloro-3-(2,3,5-tri-O-benzoyl--D-ribofuranosyl)uracil。利用親核性試劑無法直接對6-chloro-3-(-D-ribofuranosyl)uracil 衍生物做取代反應,因此我們推測 uracil N1上的氫會干擾取代反應。為了證明這個假設,我們在 N1 位置接上甲基或是 Benzyl 取代基,再由N1 有取代基的 6-chloro-3-(-D-ribofuranosyl)uracil 衍生物與親核性試劑(sodium azide、氰化鈉)反應,能得到相對應六位取代基的3-ribofuranosyluracils。這些 uridine 類似物是具有潛力的 ODCase 抑制劑,未來會更進一步研究其生物活性與評估。
Abstract
The main focus of this thesis is the design and synthesis of inhibitors for orotidine 5’-monophosphate decarboxylase (ODCase). The thesis includes two parts: (a) 6-substituted uridine and (b) 6-substituted 3-ribofuranosyluracil. These two types of structures were designed as the analogous structures of substrate / inhibitors for ODCase, in order to study the interactions between the enzyme and substrate / inhibitors.
6-Chloro-1,3-dimethyluracil was chosen as the reaction model to investigate the synthesis of 6-substituted uridine. 6-Chloro-1,3-dimethyluracil underwent nucleophilic substitution reactions with nucleophilic reagents such as sodium azide, sodium cyanide, n-butylamine, and imidazole to afford the corresponding 6-substituted 1,3-dimethyluracils. However, the synthesis was unsuccessful when the same approach was applied to sugar-protected 6-iodouridine.
Glycosylation of silylated 6-chlorouracil with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (TBAR) in the presence of Tin (IV) chloride (SnCl4) as a lewis acid afforded 6-chloro-3-(2,3,5-tri-O-benzoyl--D-ribofuranosyl)uracil. Direct nucleophilic substitution of this 6-chloro-3-(-D-ribofuranosyl)uracil derivative was unsuccessful. We rationalized that the unsubstituted nitrogen at 1-position of uracil interfered the reaction. To prove this hypothesis, methyl and benzyl substituents were introduced to the N1-position. The N1-substituted 6-chloro-3-(-D-ribofuranosyl)uracil derivatives underwent nucleophilic substitution with nucleophilic reagents such as sodium azide, or sodium cyanide to give the corresponding 6-substituted 3-ribofuranosyluracils. The synthesized uridine analogs are potential inhibitors of ODCase. Further biological evaluation will be investigated.
1. Cui, W.; DeWitt, J.; Miller, S.; Wu, W. Biochem. Biophys. Res. Commun, 1999, 259, 133-135.
2. Radzicka, A.; Wolfenden, R. Science, 1995, 267, 90-93.
3. Donovan, W.; Kushner, S. J. Bacteriol, 1983, 156, 620-624.
4. Beak, P.; Siegel, B. J. Am. Chem. Soc, 1973, 95, 7919-7920.
5. Beak, P.; Siegel, B. J. Am. Chem. Soc, 1976, 98, 3601-3606.
6. Rishavy, M.; Cleland, W. Biochemistry, 2000, 39, 4569-4574.
7. Silverman, R.; Groziak, M. J. Am. Chem. Soc, 1982, 104, 6434-6439.
8. Acheson, S. A.; Bell, J. B.; Jones, M. E.; Wolfenden, R. Biochemistry, 1990, 29, 3198-3202.
9. Shostak, K.; Jones, M. E. Biochemistry, 1992, 31, 12155-12161.
10. Lee and, J. K.; Houk, K. N. Science, 1997, 276, 942-945.
11. Lee, T.-S.; Chong, L. T.; Chodera, J. D.; Kollman, P. A. J. Am. Chem. Soc, 2001, 123, 12837-12848.
12. Appleby, T.; Kinsland, C.; Begley, T.; Ealick, S. Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 2005-2010.
13. Fujihashi, M.; Bello, A. M.; Poduch, E.; Wei, L.; Annedi, S. C.; Pai, E. F.; Kotra, L. P. J. Am. Chem. Soc, 2005, 127, 15048-15050.
14. Bello, A. M.; Poduch, E.; Fujihashi, M.; Amani, M.; Li, Y.; Crandall, I.; Hui, R.; Lee, P. I.; Kain, K. C.; Pai, E. F.; Kotra, L. P. J. Med. Chem., 2007, 50, 915-921.
15. Fujihashi, M.; Wei, L.; Kotra, L. P.; Pai, E. F. J. Mol. Biol, 2009, 387, 1199-1210.
16. Levine, H. L.; Brody, R. S.; Westheimer, F. H. Biochemistry, 1980, 19, 4993-4999.
17. Miller, B.; Snider, M.; Wolfenden, R.; Short, S. J. Biol. Chem, 2001, 276, 15174-15176.
18. David P. Ringer, B. A. H., Janet L. Etheredge, J. Biol chem. Toxicol, 1991, 6, 19-27.
19. Cadman, E.; Dix, D.; Handschumacher, R. Cancer Res, 1978, 38, 682-688.
20. Kotra, L.; Meza-Avina, M.; Wei, L.; Buhendwa, M.; Poduch, E.; Bello, A.; Pai, E. Mini-Rev. Med. Chem, 2008, 8, 239-247.
21. Poduch, E.; Bello, A. M.; Tang, S.; Fujihashi, M.; Pai, E. F.; Kotra, L. P. J. Med. Chem., 2006, 49, 4937-4945.
22. Bello, A. M.; Poduch, E.; Liu, Y.; Wei, L.; Crandall, I.; Wang, X.; Dyanand, C.; Kain, K. C.; Pai, E. F.; Kotra, L. P. J. Med. Chem., 2008, 51, 439-448.
23. Lewis, C. A.; Wolfenden, R. Biochemistry, 2007, 46, 13331-13343.
24. Cope, A. C.; Heyl, D.; Peck, D.; Eide, C.; Arroyo, A. J. Am. Chem. Soc, 1941, 63, 356-358.
25. Ashley, J.; Harris, J.; Dalgliesh, C.; Stephenson, E.; Albert, A.; Magrath, D.; Baddiley, J.; Topham, A.; Reed, R. J. Chem. Soc, 1944, 677-679.
26. Kundu, N.; Sikdar, S.; Hertzberg, R.; Schmitz, S.; Khatri, S. J. Chem. Soc., Perkin Trans. 1, 1985, 1295-1300.
27. Peter Siemsen; Robert C. Livingston; Franis Diederich Angew. Chem. Int. Ed, 2000, 39, 2632-2657.
28. Castro, C. E. Org. Synth, 1972, 52, 128.
29. Sayer, J. M.; DePecol, M. J. Am. Chem. Soc, 1977, 99, 2665-2671.
30. Senda, S.; Hirota, K.; Asao, T.; Maruhashi, K. J. Am. Chem. Soc, 1978, 100, 7661-7664.
31. Senda, S.; Hirota, K.; Asao, T. J. Org. Chem, 1975, 40, 353-356.
32. Senda, S.; Hirota, K.; Asao, T. Chem. Pharm. Bull, 1975, 23, 1708-1713.
33. da Silva, E. T.; Lima, E. L. S. Tetrahedron Lett, 2003, 44, 3621-3624.
34. Chinchilla, R.; Najera, C. Chem. Rev, 2007, 107, 874-922.
35. Tanaka, H.; Haraguchi, K.; Koizumi, Y.; Fukui, M.; Miyasaka, T. Can. J. Chem, 1986, 64, 1560-1563.
37. Winkley, M. W.; Robins, R. K. J. Org. Chem, 1968, 33, 2822-2827.
38. Winkley, M.; Robins, R. J. Chem. Soc., Perkin Trans. 1, 1969, 5, 791.
39. Niedballa, U.; Vorbrueggen, H. J. Org. Chem, 1974, 39, 3660-3663.
40. Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber, 1981, 114, 1234-1255.
41. 史諭樵 國立台灣師範大學化學系, 碩士論文, 2008.