合成腺苷與含氮雜環之硫烷鍵共軛化合物作為抗病毒試劑

以作者查詢圖書館館藏

、以作者查詢臺灣博碩士

、以作者查詢全國書目

、勘誤回報

、線上人數：24

、訪客IP：3.144.29.148

姓名

謝秉勳(Bing-shiun Hsieh) 查詢紙本館藏

畢業系所

化學學系

論文名稱

合成腺苷與含氮雜環之硫烷鍵共軛化合物作為抗病毒試劑
(Syntheses of Adenosine Conjugated Nitrogen–Containing Heterocycles with a Thioalkyl Linker as Antiviral Agents)

相關論文

★ 合成醯胺鍵及胺鍵連結之鳥苷與香豆素共軛化合物並探討其構形	★ 合成含腺嘌呤核苷之新型奈米碳管
★ 合成具有抗病毒潛力的香豆素與腺嘌呤、腺苷、肌苷之胺鍵標靶共軛化合物	★ 腺苷與香豆素共軛連結化合物之合成與其構形之探討
★ 探討電子效應和立體障礙對於「胺基醇」轉換成烯類化合物之影響	★ 探討β胺醇之α碳上立體障礙與電子效應對苯炔誘導形成碳與碳雙鍵反應之影響
★ 研究「二苯並環庚烯」及「脂芳烴」之「阿昔洛韋」共軛化合物的結構與抗病毒活性的關係	★ 合成具有抗腸病毒活性「二苯」及「亞甲基二苯」與「阿昔洛韋」之共軛化合物
★ 合成脲鍵連結之「去甲替林」與「核苷」共軛化合物用作抗腸病毒藥劑	★ 合成「核苷」與「金剛胺」連結之脲鍵化合物作為抗病毒藥劑
★ 合成含胺基酸酯之「無環鳥苷」與「去甲替林」共軛化合物作為抗腸病毒藥劑	★ 探討合成含四級胺鹽之金奈米粒子之條件
★ 苯并咪唑與香豆素共軛連結化合物之合成與其構型之探討	★ 合成醯胺鍵結苯并咪唑與香豆素之化合物並探討其構形
★ 設計及合成含藥物之新穎鉑錯合物

檔案

[Endnote RIS 格式]

[Bibtex 格式]

[相關文章]

[文章引用]

[完整記錄]

[館藏目錄]

至系統瀏覽論文 ( 永不開放)

摘要(中)

目前病毒所造成的疾病和死亡是人類所面臨的重大問題之一，但由於病毒基因的快速變異，至今仍缺乏合適的藥物和疫苗。歐盟第七架構計畫中更將登革熱病毒、腸病毒和副黏液病毒列為優先針對目標，並對其對應藥物進行合成和優化，本實驗室參與了這項定名為SILVER之計畫，致力於新藥的開發。
由於含氮的雜環分子因為具有多種生物活性，已被廣泛應用於藥物開發上，且本實驗室以核苷鍵結香豆素，發現其對於C型肝炎病毒具有良好的抑制活性，因此為了拓展更多活性分子骨架，我們以合成硫烷鍵結腺苷與具抗病毒活性的含氮雜環分子為目標，分別為adenosine–TBBT 23、24與adenosine–HBB 28以及adenine–TBBT 25、26等共軛化合物。其合成方法為利用具有硫醇結構的腺苷與帶有離去基的含氮雜環分子在pH值為11.6的條件之下，進行親核性取代反應，並利用核磁共振光譜儀和高解析質譜儀鑑定結構，證實我們成功地合成目標分子。
此外本人對於benzotraiazole與醛類反應時所造成的一號與二號氮互變異構，以及化合物8-[(4’’,5’’,6’’,7’’-tetrabromobenzotriazol-1’’-yl)methylthio]- adenosine與8-[(benzimidazol-2-yl)(phenyl)methylthio]adenosine在核磁共振光譜中造成的化學偏移進行探討。最後，本人也針對在不同的pH值環境下，親核性取代反應的反應性進行討論。

摘要(英)

Many disease and death around the world caused by viruses are major problems of human being. However, because of fast mutation rate of the RNA viruses, there are lack of suitable drugs and vaccines to control them. To solve these problems, Seventh Framework Programme in European Union has proved a project that focus on drugs discovery towards dengue-, entero- and paramyxoviruses. We are participating in this program, so called SILVER, and devoting our efforts on drugs development in our laboratory.
In the research of drugs designing, scientists currently focus on the nitrogen–containing heterocycles, which contain various bioactivities. Moreover, our laboratory synthesized a series of nucleoside–coumarin conjugates, which exhibited potent activity on HCV. Therefore, I synthesized adenosine conjugated nitrogen–containing heterocycles, adenosine–TBBT 23, adenosine–TBBT 24, adenosine–HBB 28, adenine–TBBT 25 and adenine–TBBT 26, with thioalkyl linker as antiviral agent candidates. The synthetic method was a nucleophilic substitution in basic condition with 8-mercaptoadenosine as a nucleophile and heterocycles containing a leaving group as a electrophile. The target structures was checked by nuclear magnetic resonance and high resolution mass spectrometers.
On the other hand, I discussed the N-1 and N-2 tautomerization of benzotriazole when reacted with formaldehyde. I also discussed phenomena of the chemical shift of 8-[(4’’,5’’,6’’,7’’-tetrabromobenzotriazol-1’’-yl)methylthio]adenosine (23) and 8-[(benzimidazol- 2’’-yl)(phenyl)methylthio]adenosine (28) in nuclear magnetic resonance spectroscopy. Finally, the reactivity of nucleophilic substitution with 8-mercaptoadenosine (22) in different pH values is also discussed.

關鍵字(中)

★ 硫烷
★ 病毒
★ 腺苷

關鍵字(英)

★ Thioalkyl
★ Antiviral
★ Adenosine

論文目次

目錄
中文摘要 ............................................................................................................. i
英文摘要 ........................................................................................................... iii
謝誌 .................................................................................................................... v
目錄 ................................................................................................................... vi
圖目錄 ............................................................................................................... xi
縮寫對照表....................................................................................................... xiii
一、緒論 ........................................................................................................ 1
二、結果 ........................................................................................................ 7
2-1　合成新化合物1-(Hydroxymethyl)-4,5,6,7-tetrabromo-
benzotriazole(18a)與2-(Hydroxymethyl)-4,5,6,7-tetrabromo-
benzotriazole (18b) ......................................................................... 7
2-2　合成新化合物1-(Chloromethyl)-4,5,6,7-tetrabromo-
benzotriazole (19a)與2-(Chloromethyl)-4,5,6,7-tetrabromo-
benzotriazole (19b) ....................................................................... 10
2-3　合成新化合物8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)-
methylthio]adenosine (23) ............................................................. 12
2-4　利用NMR鑑定Adenosine–TBBT conjugate 23之化學位移...... 14
2-5　合成新化合物8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)
methylthio]adenosine (24) ............................................................. 16
2-6　利用NMR鑑定Adenosine–TBBT conjugate 24之化學位移 ..... 18
2-7　合成新化合物8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)
methylthio]adenine (25) ................................................................ 19
2-8　合成新化合物8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)
methylthio]adenine (26) ................................................................ 21
2-9　合成新化合物8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)
methylthio]adenosine (28) …......................................................... 22
三、討論 ...................................................................................................... 26
3-1　探討benzotriazole所產生的互變異構 ........................................ 26
3-2　結合核磁共振光譜與分子模擬探討共軛化合物23與28 .......... 28
3-2-1　探討共軛化合物23之S–CH2化學位移 ............................ 28
3-2-2　探討共軛化合物28之醣類一號氫化學位移 .................... 31
3-3　探討親核性取代反應之最佳條件 .............................................. 33
3-3-1　討論pH值對8-Mercaptoadenosine親核性影響 ................ 33
3-3-2　探討8-Mercaptoadenosine中硫原子之親核性質 .............. 34
四、結論 ...................................................................................................... 36
五、實驗部分 .......................................................................................... 38
1-(Hydroxymethyl)-4,5,6,7-tetrabromobenzotriazole (18b) ................... 39
1-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19a) ...................... 39
2-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19b) ...................... 40
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenosine (23) . 41
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenosine (24) . 41
8-[(Benzimidazol-2'-yl)(phenyl)methylthio]adenosine (28) ................... 42
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenine (25) ..... 42
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenine (26) ..... 43
六、參考文獻 .......................................................................................... 44
七、光譜 ...................................................................................................... 52
2-(Hydroxymethyl)-4,5,6,7-tetrabromobenzotriazole (18b)
1H核磁共振光譜圖 ............................................................................... 53
2-(Hydroxymethyl)-4,5,6,7-tetrabromobenzotriazole (18b)
13C核磁共振光譜圖 .............................................................................. 53
2-(Hydroxymethyl)-4,5,6,7-tetrabromobenzotriazole (18b)
紅外分光光譜圖 .................................................................................... 54
1-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19a)
1H核磁共振光譜圖 ............................................................................... 54
1-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19a)
13C核磁共振光譜圖 .............................................................................. 55
1-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19a)
紅外分光光譜圖 .................................................................................... 55
2-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19b)
1H核磁共振光譜圖 ............................................................................... 56
2-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19b)
13C核磁共振光譜圖 .............................................................................. 56
2-(Chloromethyl)-4,5,6,7-tetrabromobenzotriazole (19b)
紅外分光光譜圖 .................................................................................... 57
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenosine (23)
1H核磁共振光譜圖 ............................................................................... 57
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenosine (23)
13C 核磁共振光譜圖 ............................................................................. 58
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenosine (23)
紅外分光光譜 ........................................................................................ 58
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenosine (24)
1H核磁共振光譜圖 ............................................................................... 59
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenosine (24)
13C核磁共振光譜圖 .............................................................................. 59
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenosine (24)
紅外分光光譜 ........................................................................................ 60
8-[(benzimidazol-2-yl)(phenyl)methylthio]adenosine (28)
1H核磁共振光譜圖 ............................................................................... 60
8-[(benzimidazol-2-yl)(phenyl)methylthio]adenosine (28)
紅外分光光譜 ........................................................................................ 61
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenine (25)
1H核磁共振光譜圖 ............................................................................... 61
8-[(4',5',6',7'-Tetrabromobenzotriazol-1'-yl)methylthio]adenine (25)
紅外分光光譜 ........................................................................................ 62
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenine (26)
1H核磁共振光譜圖 ............................................................................... 62
8-[(4',5',6',7'-Tetrabromobenzotriazol-2'-yl)methylthio]adenine (26)
紅外分光光譜 ........................................................................................ 63

參考文獻

六、參考文獻 (References)
1. Neyts, J.; Leyssen, P.; De Clercq, E. Antiviral drugs in current clinical use. Antiviral Res. 2008, 78, 9–25.
2. Seventh Framework Programme home page. http://cordis.europa.eu/fp7/home_en.html
3. Maryanoff, B. E. Inhibitors of serine proteases as potential therapeutic agents: the road from thrombin to tryptase to cathepsin G. J. Med. Chem. 2004, 47, 669–787.
4. Mileni, M.; Garfunkle, J.; Ezzili, C.; Scott Kimball, F.; Cravatt, B. F.; Stevens, R. C.; Boger, D. L. X-ray crystallographic analysis of ?-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase. J. Med. Chem. 2010, 53, 230–240.
5. Jonathan Fray, M.; Bull, D. J.; Carr, C. L.; Gautier, E. C. L.; Mowbray, C. E.; Stobie, A. Structure–activity relationships of 1,4-dihydro-(1H,4H)-quinoxaline-2,3-diones as N-methyl-D-aspartate (glycine site) receptor antagonists. 1. heterocyclic substituted 5-alkyl derivatives. J. Med. Chem. 2001, 44, 1951–1962.
6. Graneto, M. J.; Kurumbail, R. G.; Vazquez, M. L.; Shieh, H. -S.; Pawlitz, J. L.; Williams, J. M.; Stallings, W. C.; Geng, L.; Naraian, A. S.; Koszyk, F. J.; Stealey, M. A.; Xu, X. D.; Weier, R. M.; Hanson, G. J.; Mourey, R. J.; Compton, R. P.; Mnich, S. J.; Anderson, G. D.; Monahan, J. B.; Devraj, R. Synthesis, crystal structure, and activity of pyrazole–based inhibitors of p38 kinase. J. Med. Chem. 2007, 50, 5712–5719.
7. Kim, Y. S. and Milner, J. A. Targets for indole-3-carbinol in cancer prevention. J. Nutr. Biochem. 2005, 16, 65–73.
8. Takeuchi, T.; Oishi, S.; Watanabe, T.; Ohno, H.; Sawada, J.; Matsuno, K.; Asai, A.; Asada, N.; Kitaura, K.; Fujii, N. Structure–activity relationships of carboline and carbazole derivatives as a novel class of ATP–competitive kinesin spindle protein inhibitors. J. Med. Chem. 2011, 54, 4839–4846.
9. Beghyn, T. B.; Charton, J.; Leroux, F.; Laconde, G.; Bourin, A.; Cos, P.; Maes, L.; Deprez, B. Drug to genome to drug: discovery of new antiplasmodial compounds. J. Med. Chem. 2011, 54, 3222–3240.
10. Li, Y.-F.; Wang, G.-F.; He, P,-L.; Huang, W.-G.; Zhu, F.-H.; Gao, H.-Y.; Tang, W.; Luo, Y.; Feng, C.-L.; Shi, L.-P.; Ren, Y.-D.; Lu, W.; Zuo, J.-P. Synthesis and anti-hepatitis B virus activity of novel benzimidazole derivatives. J. Med. Chem. 2006, 49, 4790–4794.
11. Ndakala, A. J.; Gessner, R. K.; Gitari, P. W.; October, N.; White, K. L.; Hudson, A.; Fakorede, F.; Shackleford, D. M.; Kaiser, M.; Yeates, C.; Charman, S. A.; Chibale, K. Antimalarial pyrido[1,2-а]benzimidazoles. J. Med. Chem. 2011, 54, 4581–4589.
12. Kazmierski, W. M.; Anderson, D. L.; Aquino, C.; Chauder, B. A.; Duan, M.; Ferris, R.; Kenakin, T.; Koble, C. S.; Lang, D. G.; Mcintyre, M. S.; Peckham, J.; Watson, C.; Wheelan, P.; Spaltenstein, A.; Wire, M. B.; Svolto, A.; Youngman, M. Novel 4,4-disubstituted piperidine–based C–C chemokine receptor-5 inhibitors with high potency against human immunodeficiency virus-1 and an improved human ether-a-go-go related gene (hERG) profile. J. Med. Chem. 2011, 54, 3756–3767.
13. Wu, C.-Y.; King, K.-Y.; Kuo, C.-J.; Fang, J.-M.; Wu, Y.-T.; Ho, M.-Y; Liao, C.-L, Shie, J.-J.; Liang, P.-H.; Wong, C.-H. Stable benzotriazole esters as mechanism–based inactivators of the severe acute respiratory syndrome 3CL protease. Chem. Biol. 2006, 13, 261–268.
14. Lilienkampf, A.; Mao, J.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozikowski, A. P. Structure–activity relationships for a series of quinoline–based compounds active against replicating and nonreplicating mycobacterium tuberculosis J. Med. Chem. 2009, 52, 2109–2118.
15. Tseng, C.-H.; Lin, R.-W.; Chen, Y.-L.; Wang, G.-J.; Ho, M.-L.; Tzeng, C.-C. Discovery of indeno[1,2-c]quinoline derivatives as inhibitors of osteoclastogenesis induced by receptor activator of NF-?B ligand (RANKL). J. Med. Chem. 2011, 54, 3103–3107.
16. Chen, Y.-W.; Chen, Y.-L.; Tseng, C-H.; Liang, C.-C.; Yang, C.-N.; Yao, Y.-C.; Lu, P.-J.; Tzeng, C.-C. Discovery of 4-anilinofuro[2,3-b]quinoline derivatives as selective and orally active compounds against non–small–cell lung cancers. J. Med. Chem. 2011, 54, 4446–4461.
17. Singh, P.; Kaur, J.; Kaur, P.; Kaur, S. Search for MDR modulators: design, syntheses and evaluations of N-substituted acridones for interactions with p-glycoprotein and Mg2+. Bioorg. Med. Chem. 2009, 17, 2423–2427.
18. Manfroni, G.; Paeshuyse, J.; Massari, S.; Zanoli, S.; Gatto, B.; Maga, G.; Tabarrini, O.; Cecchetti, V.; Fravolini, A.; Neyts, J. Inhibition of subgenomic hepatitis C virus RNA replication by acridone derivatives: identiﬁcation of an NS3 helicase inhibitor. J. Med. Chem. 2009, 52, 3354–3365.
19. Tabarrini, O.; Manfroni, G.; Fravolini, A.; Cecchetti, V.; Sabatini, S.; De Clercq, E.; Rozenski, J.; Canard, B.; Dutartre, H.; Paeshuyse, J.; Neyts, J. Synthesis and anti-BVDV activity of acridones as new potential antiviral agents. J. Med. Chem. 2006, 49, 2621–2627.
20. Chen, J. J.; Wei, Y.; Drach, J. C.; Townsend, L. B. Synthesis and antiviral evaluation of trisubstituted indole N-nucleosides as analogues of 2,5,6-trichloro-1-(?-D-ribofuranosyl) benzimidazole (TCRB). J. Med. Chem. 2000, 43, 2449–2456.
21. Harper, S.; Avolio, S.; Pacini, B.; Filippo, M. D.; Altamura, S.; Tomei, L.; Paonessa, G.; Marco, S. D; Carfi, A.; Giuliano, C.; Padron, J.; Bonelli, F.; Migliaccio, G.; Francesco, R. L.; Rowley, M.; Narjes, F. Potent inhibitors of subgenomic hepatitis C virus RNA replication through optimization of indole-N-acetamide allosteric inhibitors of the viral NS5B polymerase. J. Med. Chem. 2005, 48, 4547–4557.
22. Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J. C.; Townsend, L. B. Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-2-substituted-5,6- dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6-trichloro-1-(?-D- ribofuranosyl)benzimidazole. J. Med. Chem. 1998, 41, 1252–1262.
23. Keller, L.; Beaumont, S.; Liu, J. -M.; Thoret, S.; Bignon, J. S.; Wdzieczak–Bakala, J.; Dauban, P.; Dodd, R. H. New C5–alkylated indolobenzazepinones acting as inhibitors of tubulin polymerization: cytotoxic and antitumor activities. J. Med. Chem. 2008, 51, 3414–3421.
24. Nien, C.-Y.; Chen, Y.-C.; Kuo, C.-C.; Hsieh, H.-P.; Chang, C.-Y.; Wu, J.-S.; Wu, S.-Y.; Liou, J.-P.; Chang, J.-Y. 5-Amino-2-aroylquinolines as highly potent tubulin polymerization inhibitors. J. Med. Chem. 2010, 53, 2309–2313.
25. Manohar, S.; Khan, S. I.; Rawat, D. S. Synthesis, antimalarial activity and cytotoxicity of 4-aminoquinoline-triazine conjugates. Bioorg. Med. Chem. Lett. 2010, 20, 322–325.
26. Delmas, F.; Avellaneda, A.; Di Giorgio, C.; Robin, M.; De Clercq, E.; Timon–David, P.; Galy, J.-P. Synthesis and antileishmanial activity of (1,3-benzothiazol-2-yl)- amino-9-(10H)-acridinone derivatives. Eur. J. Med. Chem. 2004, 39, 685–690.
27. Ghosh, B.; Antonio, T.; Zhen, J.; Kharkar, P.; Reith, Maarten E. A.; Dutta, A. K. Development of (S)-N6-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-N6-propyl-4,5,6,7- tetrahydrobenzo[d]-thiazole-2,6-diamine and Its analogue as a D3 receptor preferring agonist: potent in vivo activity in parkinson’s disease animal models. J. Med. Chem. 2010, 53, 1023–1037.
28. Wikel, J. H.; Paget, C. J.; Delong, D. C.; Nelson, J. D.; Wu, C. Y. E.; Paschal, J. W.; Dinner, A.; Templeton. R. J.; Chaney, M. O.; Jones, N. D.; Chamberlin J. W. Synthesis of syn and anti isomers of 6-[[(hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]- 1H-benzimidazol-2-amine. Inhibitors of rhinovirus multiplication J. Med. Chem. 1980, 23, 368–372.
29. Langford, M. P.; Ball, W. A.; Ganley. J. P. Inhibition of the enteroviruses that cause acute hemorrhagic conjunctivitis (AHC) by benzimidazoles; Enviroxime (LY 122772) and Enviradone (LY 127123). Antiviral Res. 1995, 27, 355–365.
30. De Palma, A. M.; Heggermont, W.; Leyssen, P.; Pürstinger, G.; Wimmer, E.; De Clercq, E.; Rao, A.; Monforte, A.-M.; Chimirri, A.; Neyts, J. Anti–enterovirus activity and structure–activity relationship of a series of 2,6-dihalophenyl-substituted- 1H,3H-thiazolo[3,4-a]benzimidazoles. Biochem. Biophys. Res. Commun. 2007, 353, 628–632.
31. Tamm, I.; Bablanian, R.; Nemes, M. M.; Shunk, C. H.; Robinson, F. M.; Folkers, K. Relationship between structure of benzimidazole derivatives and selective virus inhibitory activity. J. Exp. Med. 1961, 113, 625–656.
32. Borowski, P.; Deinert, J.; Schalinski, S.; Bretner, M.; Ginalski, K.; Kulikowski, T.; Shugar, D. Halogenated benzimidazoles and benzotriazoles as inhibitors of the NTPase/helicase activities of hepatitis C and related viruses. Eur. J. Biochem. 2003, 270, 1645–1653.
33. Neyts, J.; De Clercq, E.; Singha, R.; Chang, Y. H.; Das, A. R.; Chakraborty, S. K.; Hong, S. C.; Tsay, S.-C.; Hsu, M.-H.; Hwu, J. R. Structure–activity relationship of new anti-hepatitis C virus agents: heterobicycle coumarin conjugates. J. Med. Chem. 2009, 52, 1486–1490.
34. De Clercq, E. The design of drugs for HIV and HCV. Nature 2007, 6, 1001–1018.
35. Shugar, D.; Zien, P.; Bretner, M.; Zastazpiło, K.; Szyszka, R. Selectivity of 4,5,6,7-tetrabromobenzimidazole as an ATP–competitive potent inhibitor of protein kinase CK2 from various sources. Biochem. Biophys. Res. Commun. 2003, 306, 129–133.
36. Schnopp, M. and Haberhauer, G. Highly selective recognition of ?-chiral primary organoammonium ions by C3–symmetric peptide receptors. Eur. J. Org. Chem. 2009, 26, 4458–4467.
37. Katritzky, A. R.; Oniciu, D. C.; Serdyuk, L.; Ghiviriga, I. Study of the orientation of lithiation of 1- and 2-alkylbenzotriazoles. J. Org. Chem. 1995, 60, 1244–1249.
38. Holmes, R. E. and Robins, R. K. Purine nucleosides. VII. Direct bromination of adenosine, deoxyadenosine, guanosine, and related purine nucleosides. J. Am. Chem. Soc. 1964, 86, 1242–1245.
39. Hwu, J. R.; Lin, S.-Y.; Tsay, S.-C.; De Clercq, E.; Leyssen, P.; Neyts, J. Coumarin–purine ribofuranoside conjugates as new agents against hepatitis C virus. J. Med. Chem. 2011, 54, 2114–2126.
40. Gualtieri, F.; Brody, G.; Fieldsteel, A. H.; Skinner, W. A. Antiviral agents. 2. Analogs of 2-(?-hydroxybenzyl)benzimidazole. J. Med. Chem. 1972, 15, 420–422.
41. Katritzky, A. R.; Rachwal, S.; Rachwal, B. The chemistry of N–substituted benzotriazoles. Part 2. Reactions of benzotriazole with aldehydes and aldehyde derivatives. 1-(?-hydroxyalkyl)-, 1-(?-alkoxyaIkyl)-, and 1-(?-acyloxyalkyl)- benzotriazoles. J. Chem. Soc. Perkin Trans. 1 1987, 791–797.
42. Katritzky, A. R.; Perumal, S.; Savage, P. An NMR study of the equilibria involved with benzotriazole, carbonyl compounds, and their adducts. J. Chem. Soc. Perkin Trans. 2 1990, 921–924.
43. Attardo, G. and Tripathy, S. Eur. Patent WO 2010132999, 2010.
44. Giessner–Prettre, C. and Pullman, B. Ring–current effects in the nmr of nucleic acids: a graphical approach. Biopolymers 1976, 15, 2277–2286.
45. Brooks, B. R.; Brooks, C. L.; Mackerell, A. D.; Nillson, L.; Petrelia, R. J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A. R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M.; Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R. W.; Post, C. B.; Pu, J. Z.; Schaefer, M.; Tidor, B.; Venable, R. M.; Woodcock, H. L.; Wu, X.; Yang, W.; York, D. M.; Karplus, M. CHARMM: the biomolecular simulation program. J. Comput. Chem. 2009, 30, 1545–1614.
46. Janiak, C. Dalton Trans. 2000, 3885–3896.
47. Åström, H.; Limén, E.; Strömberg, R. Acidity of secondary hydroxyls in ATP and adenosine analogues and the question of a 2',3'-hydrogen bond in ribonucleosides. J. Am. Chem. Soc. 2004, 126, 14710–14711.
48. Refaey, S. A. M.; Taha, F.; Abd El–Malak A. M. Corrosion and inhibition of 316L stainless steel in neutral medium by 2-mercaptobenzimidazole. Int. J. Electrochem. Sci. 2006, 80–91.
49. Šponer, J. E.; Leszczynski, J.; Glahé, F.; Lippert, B.; Šponer, J. Protonation of platinated adenine nucleobases. Gas phase vs condensed phase picture. Inorg. Chem. 2001, 40, 3269–3278.
50. Sanina, N.; Roudneva, T.; Shilov, G.; Morgunov, R.; Ovanesyan, N.; Aldoshin, S. Structure and properties of binuclear nitrosyl iron complex with benzimidazole-2-thiolyl. Dalton Trans. 2009, 1703–1706.
51. Folchetti, N; Challice, J.; Mullaney, R. Organic Chemistry, 6th ed.; Pearson Prentice Hall, London, 2006; pp 451–452.
52. Kaiya, T; Tanaka, H.; Kohda, K. Formation of 2'-deoxy-2-nitroadenosines by reaction of 2'-deoxyadenosines with copper(II) nitrate/acetic anhydride. Nucleosides, Nucleotides & Nucleic Acids 2002, 21, 427–433.
53. Pinna, L. A.; Pagano, M. A.; Andrzejewska, M. A.; Ruzzene, M.; Sarno, S.; Cesaro, L.; Bain, J.; Elliott, M.; Meggio, F.; Kazimierczuk, Z. Optimization of protein kinase CK2 inhibitors derived from 4,5,6,7-tetrabromobenzimidazole. J. Med. Chem. 2004, 47, 6239–6247.
54. Katritzky, A. R.; Lan, X.; Yang, L. Z.; Denisko, O. V. Properties and synthetic utility of N-substituted benzotriazoles. Chem. Rev. 1998, 98, 409−548.
55. Meyer, R. B. and Skibo, B. O. Inhibition of inosinic acid dehydrogenase by 8-substituted purine nucleotides. J. Med. Chem. 1981, 24, 1155–1161.
56. Markland, W.; McQuaid, T. J.; Jain, J.; Kwong, A. D. AAC, Antimicrob Agents 2000, 44, 859–866.

指導教授

胡紀如(Jih Ru Hwu)

審核日期

2011-8-31

推文