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題 名 | Synthesis of Imidazo[4,5-b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides |
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作 者 | Zhu,Zhijian; Saluja,Sunita; Drach,John C.; Townsend,Leroy B.; | 書刊名 | Journal of the Chinese Chemical Society |
卷 期 | 45:4 1998.08[民87.08] |
頁 次 | 頁465-474 |
分類號 | 346.01 |
關鍵詞 | Herpes; Antivirals; Nucleosides; Benzimidazole; Imidazo[4,5-b]quinoxaline; Polyhalogenated; |
語 文 | 英文(English) |
英文摘要 | We have recently found 2, 5, 6 - trichloro- 1- (β-D-ribofuranosyl) benzimidazole (TCRB) and the corresponding 2-bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,5-b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole nucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2-subtituted 6, 7-dichloroimidazo[4, 5-b]quinoxalines involving a reaction of 2,3,6,7-tetrachloroquinoxaline with ammonia follwed by a ring annulation as the key step. This furnished the versatile heterocycle 6, 7-dichloroimidazo[4, 5-b]quinoxalin-2-one.Ribosylation of 2-subtituted imidazo[4,5-b]quinoxalines was influenced by the functional group at the 2-position and the 2-one compound was found to smoothly undergo ribosylation. The 2-one group of the nucleoside was converted into specifically selected 2-subsituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, that the binding pocket on the protein target of TCRB will tolerate some electronic and size changes. |
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