因為 6-cyanouridine 5’-monophosphate (6-CN-UMP) 在 orotidine 5’-monophosphate decarboxlase (ODCase) 的催化下，轉換成 barbiturate 5’-monophosphate (BMP) 的反應啟發，我們設計以6-cyano-1,3-dimethyluracil 作為反應模型，希望藉此推導出 ODCase 催化 6-CN-UMP 轉換成 BMP的反應機制。而從6-cyano-1,3-dimethyluracil與各種的親核基試劑進行反應，例如：甲醇鈉、乙醇鈉、氫氧化鈉等，從實驗的結果發現，得到六位取代的產物，所以，推測 6-CN-UMP 轉換成 BMP 的反應機制是經由直接的取代反應而生成。另外，也試驗 5-bromo-1,3-dimethyluracil 與各式的親核基試劑進行反應，由實驗結果發現若加入的溶劑不同時，會有不同的產物生成，會分別得到六位取代或者五位取代的產物。
第二部分為針對 ODCase 的抑制劑的設計與合成，orotidine 5’-monophosphate (OMP) 與 ODCase 進行催化反應時，羧基會以 COO- 的形式與酵素活化位置結合，並和活化位置的 lysine 產生氫鍵；所以，設計一個可與酵素活化位置上的 lysine 產生氫鍵的化合物，就具有成為 ODCase 抑制劑的可能性。因此，我們設計在 uridine 的六位上合成一個 1,2,4-oxadiazole 環，首先以uridine 為起始物，先經由溴化再與與氰化鈉的反應，得到六位帶有腈基的化合物後，再加入 hydroxylamine 反應生成 oxime；接續再和benzoyl chloride、醋酸酐、p-nitrobenzoyl chloride等反應試劑進行 1,2,4-oxadiazole 合環反應，最後利用鹼性或酸性的條件將醣上的保護基去除，得到產物
6-(5-phenyl-1,2,4-oxadiazol-3-yl)urdine、6-(5-methyl-1,2,4-oxadiazol-3-yl)urdine、6-(5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl)urdine ，未來我們將利用相同的方式合成更多 1,2,4-oxadiazole 環的化合物，並會對它們進行ODCase 物活性篩選，希望可以從中找出 ODCase 的抑制劑。

Base on the catalytic reaction that orotidine 5’-monophosphate decarboxylase (ODCase) transformed 6-cyanourdine 5’-monophosphate (6-CN-UMP) into barbiturate nucleoside 5’-monophosphate (BMP), we have designed 6-cyano-1,3-dimethyluracil as a chemical model and analyzed these reactions toward various nucleophilc reagents. When 6-cyano-1,3-dimethyluracil reacted with some necleophiles, such as sodium methoxide, sodium hydroxide, and sodium ethoxide, 6-substituded products were obtained. These discoveries have led us to assume that ODCase transformed 6-CN-UMP into BMP through direct nucleophilic replacement. We also tested 5-bromo-1,3-dimethyluracil reacted with the above necleopiles in different solvents. It was found that both of 6-substituted and 5-substituted products were obtained.
In the second part, 6-(1,2,4-oxadiazol-3yl)uridine derivatives were designed as potential inhibitors of ODCase. Suger-protected uridine was treated with bromine and subsequently sodium cyanide to give 6-cyanouridine derivatives. Hydroxylamine was reacted with the cyano group to form oxime. The resulting 6-urdine carboxamidoxime derivatives were reacted benzoyl chloride, acetic anhydride and p-nitrobenzoyl chloride to give 1,2,4-oxadiazole derivatives. Their protecting groups were removed by base or acid to give the corresponding 6-(1,2,4-oxadiazol-3yl)uridine derivatives.

References
1. Christopherson, R. I.; Lyons, S. D.; Wilson, P. K. Acc. Chem. Res. 2002, 35, 961-971.
2. Donovan, W. P.; Kushner, S. R. J. Bacteriol. 1983, 156, 620-624.
3. Pragobpol, S.; Gero, A.; Lee, C.; O'Sullivan, W. Arch. Biochem. Biophys. 1984, 230, 285.
4. Gero, A.; O'sullivan, W.; Van Dyke, K. Blood Cells, 1990, 16, 467-498.
5. Krungkrai, J.; Krungkrai, S.; Phakanont, K. Biochem. Pharmacol. 1992, 43, 1295-301.
6. Scott, H.; Gero, A.; O'sullivan, W. Mol. Biochem. Parasitol. 1986, 18, 3-15.
7. Seymour, K. K.; Lyons, S. D.; Phillips, L.; Rieckmann, K. H.; Christopherson, R. I. Biochemistry, 1994, 33, 5268-5274.
8. Poduch, E.; Bello, A. M.; Tang, S.; Fujihashi, M.; Pai, E. F.; Kotra, L. P. J. Med. Chem. 2006, 49, 4937-4945.
9. 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.
10. Levine, H. L.; Brody, R. S.; Westheimer, F. H. Biochemistry, 1980, 19, 4993-4999.
11. David P. Ringer, B. A. H., Janet L. Etheredge, J. Biochem. Toxicol. 1991, 6, 19-27.
12. Cadman, E. C.; Dix, D. E.; Handschumacher, R. E. Cancer Res. 1978, 38, 682-688.
13. Houk, K. N.; Tantillo, D. J.; Stanton, C.; Hu, Y. Top. Curr. Chem. 2003, 238, 1-22.
14. Chan, K. K.; Wood, B. M.; Fedorov, A. A.; Fedorov, E. V.; Imker, H. J.; Amyes, T. L.; Richard, J. P.; Almo, S. C.; Gerlt, J. A. Biochemistry, 2009, 48, 5518-5531.
15. Wood, B. M.; Chan, K. K.; Amyes, T. L.; Richard, J. P.; Gerlt, J. A. Biochemistry, 2009, 48, 5510-5517.
16. Beak, P.; Siegel, B. J. Am. Chem. Soc. 1973, 95, 7919-7920.
17. Beak, P.; Siegel, B. J. Am. Chem. Soc. 1976, 98, 3601-3606.
18. Smiley, J. A.; Jones, M. E. Biochemistry, 1992, 31, 12162-12168.
19. Rishavy, M. A.; Cleland, W. W. Biochemistry, 2000, 39, 4569-4574.
20. Silverman, R. B.; Groziak, M. P. J. Am. Chem. Soc. 1982, 104, 6434-6439.
21. Shostak, K.; Jones, M. E. Biochemistry, 1992, 31, 12155-12161.
22. Wu, N.; Pai, E. J. Biol. Chem. 2002, 277, 28080-28087.
23. Houk, K.; Lee, J.; Tantillo, D.; Bahmanyar, S.; Hietbrink, B. ChemBioChem, 2001, 2, 113-118.
24. Miller, B. G.; Hassell, A. M.; Wolfenden, R.; Milburn, M. V.; Short, S. A. Proc. Natl. Acad. Sci. USA. 2000, 97, 2011-2016.
25. Harris, P.; Navarro Poulsen, J.-C.; Jensen, K. F.; Larsen, S. Biochemistry, 2000, 39, 4217-4224.
26. Pai, E. Orotidine Monophosphate Decarboxylase: A Mechanistic Dialogue, 2004, 10, b94537.
27. Lee, J. K.; Houk, K. N. Science, 1997, 276, 942-945.
28. Kurinovich, M.; Phillips, L.; Sharma, S.; Lee, J. Chem. Comm. 2002, 2002, 2354-2355.
29. Lee, T.-S.; Chong, L. T.; Chodera, J. D.; Kollman, P. A. J. Am. Chem. Soc. 2001, 123, 12837-12848.
30. Miller, B. G.; Butterfoss, G. L.; Short, S. A.; Wolfenden, R. Biochemistry, 2001, 40, 6227-6232.
31. Warshel, A.; Strajbl, M.; Villa, J.; Florian, J. Biochemistry, 2000, 39, 14728-14738.
32. Appleby, T. C.; Kinsland, C.; Begley, T. P.; Ealick, S. E. Proc. Natl. Acad. Sci. USA. 2000, 97, 2005-2010.
33. 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.
34. Callahan, B. P.; Bell, A. F.; Tonge, P. J.; Wolfenden, R. Bioorg. Chem. 2006, 34, 59-65.
35. Senda, S.; Hirota, K.; Asao, T. J. Org. Chem. 1979, 44, 970-973.
36. Senda, S.; Hirota, K.; Asao, T. J. Org. Chem. 1975, 40, 353-356.
37. Ohrui, H.; Fox, J. J. Tetrahedron Lett. 1973, 14, 1951-1954.
38. Senda, S.; Hirota, K.; Asao, T. Tetrahedron Lett. 1973, 14, 2647-2650.
39. Senda, S.; Hirota, K.; Asao, T. Chem. Pharm. Bull. 1975, 23, 1708-1713.
40. Bello, A. M.; Konforte, D.; Poduch, E.; Furlonger, C.; Wei, L.; Liu, Y.; Lewis, M.; Pai, E. F.; Paige, C. J.; Kotra, L. P. J. Med. Chem. 2009, 52, 1648-1658.
41. Del'tsova, D. P.; Ananyan, E. S.; Gambaryan, N. P. Bull. Acad. Sci. USSR Div. Chem. Sci. 1971, 362-366.
42. Angehrn, P.; Buchmann, S.; Funk, C.; Goetschi, E.; Gmuender, H.; Hebeisen, P.; Kostrewa, D.; Link, H.; Luebbers, T.; Masciadri, R.; Nielsen, J.; Reindl, P.; Ricklin, F.; Schmitt-Hoffmann, A.; Theil, F.-P. J. Med. Chem. 2004, 47, 1487-1513.
43. Colandrea, V. J.; Legiec, I. E.; Huo, P.; Yan, L.; Hale, J. J.; Mills, S. G.; Bergstrom, J.; Card, D.; Chebret, G.; Hajdu, R.; Keohane, C. A.; Milligan, J. A.; Rosenbach, M. J.; Shei, G.-J.; Mandala, S. M. Bioorg. Med. Chem. Lett. 2006, 16, 2905-2908.
44. Al-Mousawi, S.; Moustafa, M.; Elnagdi, M. J. Chem. Res. 2007, 2007, 515-518.
45. Gallardo, H.; Cristiano, R.; Vieira, A. A.; Neves Filho, R. A. W.; Srivastava, R. M. Synthesis 2008, 2008, 605-609.
46. Tiwari, S.; Kohli, D. Med. Chem. Res. 2008, 17, 386-398.
47. Sureshbabu, V. V.; Hemantha, H. P.; Naik, S. A. Tetrahedron Lett. 2008, 49, 5133-5136.
48. Edmondson, S. D.; Wei, L.; Xu, J.; Shang, J.; Xu, S.; Pang, J.; Chaudhary, A.; Dean, D. C.; He, H.; Leiting, B.; Lyons, K. A.; Patel, R. A.; Patel, S. B.; Scapin, G.; Wu, J. K.; Beconi, M. G.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem. Lett. 2008, 18, 2409-2413.
49. Fouchet, M.-H.; Donche, F.; Martin, C.; Bouillot, A.; Junot, C.; Boullay, A.-B.; Potvain, F.; Magny, S. D.; Coste, H.; Walker, M.; Issandou, M.; Dodic, N. Bioorg. Med. Chem. 2008, 16, 6218-6232.
50. McBriar, M. D.; Clader, J. W.; Chu, I.; Del Vecchio, R. A.; Favreau, L.; Greenlee, W. J.; Hyde, L. A.; Nomeir, A. A.; Parker, E. M.; Pissarnitski, D. A.; Song, L.; Zhang, L.; Zhao, Z. Bioorg. Med. Chem. Lett. 2008, 18, 215-219.
51. Moloney, G. P.; Angus, J. A.; Robertson, A. D.; Stoermer, M. J.; Robinson, M.; Wright, C. E.; McRae, K.; Christopoulos, A. Eur. J. Med. Chem. 2008, 43, 513-539.
52. Ono, M.; Haratake, M.; Saji, H.; Nakayama, M. Bioorg. Med. Chem. 2008, 16, 6867-6872.
53. Palin, R.; Clark, J. K.; Evans, L.; Houghton, A. K.; Jones, P. S.; Prosser, A.; Wishart, G.; Yoshiizumi, K. Bioorg. Med. Chem. 2008, 16, 2829-2851.
54. Prystas, M. Collect. Czech. Chem. Commun. 1964, 29, 2956.
55. Asakura, J.; Robins, M. J. J. Org. Chem. 1990, 55, 4928-4933.
56. Kumar, R.; Wiebe, L.; Knaus, E. Can. J. Chem. 1994, 72, 2005-2010.
57. Tolstikov, G.; Mustafin, A.; Gataullin, R.; Spirikhin, L.; Sultanova, V.; Abdrakhmanov, I. Russ. Chem. Bull. 1993, 42, 1095-1099.
58. Ly, D.; Sanii, L.; Schuster, G. B. J. Am. Chem. Soc. 1999, 121, 9400-9410.
59. Zubin, E. M.; Stetsenko, D. A.; Zatsepin, T. S.; Gait, M. J.; Oretskaya, T. S. Bioorg. Med. Chem. 2005, 13, 4912-4920.
60. Procopio, A.; Gaspari, M.; Nardi, M.; Oliverio, M.; Romeo, R. Tetrahedron Lett. 2008, 49, 1961-1964.
61. Chang, Y.-C.; Herath, J.; Wang, T. H. H.; Chow, C. S. Bioorg. Med. Chem. 2008, 16, 2676-2686.
62. Kazanova, E.; Zubin, E.; Kachalova, V.; Stetsenko, D.; Gait, M.; Oretskaya, T. Russ. Chem. Bull. 2007, 56, 806-814.
63. Turner, J. J.; Meeuwenoord, N. J.; Rood, A.; Borst, P.; van der Marel, G. A.; van Boom, J. H. Eur. J. Org. Chem. 2003, 3832-3839.
64. Dini, C.; Drochon, N.; Guillot, J. C.; Mauvais, P.; Walter, P.; Aszodi, J. Bioorg. Med. Chem. Lett. 2001, 11, 533-536.
65. Ogilvie, K.; Nguyen-Ba, N.; Gillen, M.; Radatus, B.; Cheriyan, U.; Hanna, H.; Smith, K.; Galloway, K. Can. J. Chem. 1984, 62, 241-252.
66. Sekine, M.; Hata, T. J. Am. Chem. Soc. 1986, 108, 4581-4586.
67. Grotli, M.; Eritja, R.; Sproat, B. Tetrahedron, 1997, 53, 11317-11346.
68. Bridson, P. K.; Lin, X.; Melman, N.; Ji, X.-d.; Jacobson, K. A. Nucleosides, Nucleotides, Nucleic Acids, 1998, 17, 759 - 768.
69. de Kort, M.; Ebrahimi, E.; Wijsman, E. R.; van der Marel, G. A.; van Boom, J. H. Eur. J. Org. Chem. 1999, 2337-2344.
70. Sekine, M.; Hata, T. J. Am. Chem. Soc. 1986, 108, 4581-4586.
71. Qu, G.-R.; Ren, B.; Niu, H.-Y.; Mao, Z.-J.; Guo, H.-M. J. Org. Chem. 2008, 73, 2450-2453.
72. Jordăo, C. I. C.; Farinha, A. S. F.; Enes, R. F.; Tom? Augusto, C.; Silva, A. M. S.; Cavaleiro, J. A. S.; Ramos, C. I. V.; Santana-Marques, M. G.; Almeida Paz, F. A.; de la Torre Ramirez, J. M.; de la Torre, M. D. L.; Nogueras, M. Tetrahedron, 2008, 64, 4427-4437.
73. Gawley, R. E.; Zhang, Q. J. Am. Chem. Soc. 1993, 115, 7515-7516.
74. Yu, M.; Cheung, K.; Mayr, A. J. Chem. Soc., Dalton Trans. 1998, 1998, 2373-2378.
75. Yu, M.; Mayr, A.; Cheung, K. J. Chem. Soc., Dalton Trans. 1998, 1998, 475-482.
76. Mayr, A.; Pui Yin Yu, M. J. Organomet. Chem. 1999, 577, 223-227.
77. Doherty, J. B.; Ashe, B. M.; Barker, P. L.; Blacklock, T. J.; Butcher, J. W.; Chandler, G. O.; Dahlgren, M. E.; Davies, P.; Dorn, C. P. J. Med. Chem. 1990, 33, 2513-2521.
78. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925.
79. Kundu, N.; Sikdar, S.; Hertzberg, R.; Schmitz, S.; Khatri, S. J. Chem. Soc. Perkin Transactions 1, 1985, 1985, 1295-1300.
80. Hennig, L.; Alva-Astudillo, M.; Mann, G.; Kappe, T. Monatshefte für Chemie / Chemical Monthly 1992, 123, 571-579.
81. Fang, W.-P.; Cheng, Y.-T.; Cheng, Y.-R.; Cherng, Y.-J. Tetrahedron, 2005, 61, 3107-3113.
82. Saladino, R.; Bernini, R.; Crestini, C.; Mincione, E.; Bergamini, A.; Marini, S.; Teresa Palamara, A. Tetrahedron, 1995, 51, 7561-7578.
83. Vega, E.; Rood, G. A.; de Waard, E. R.; Pandit, U. K. Tetrahedron, 1991, 47, 4361-4368.
84. Prystas, M.; Sorm, F. Collect. Czech. Chem. Commun. 1964, 29, 2956-2970.
85. Asakura, J.-i.; Robins, M. J.; Asaka, Y.; Kim, T. H. J. Org. Chem. 1996, 61, 9026-9027.
86. Qu, G.-R.; Ren, B.; Niu, H.-Y.; Mao, Z.-J.; Guo, H.-M. J. Org. Chem. 2008, 73, 2450-2453.