5-(1,2,4-Oxadiazol-3-yl)uridine 衍生物的設計、合成及其生物活性評估 Design, Synthesis and Biological Evaluation of 5-(1,2,4-Oxadiazol-3-yl)uridine Derivatives

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TMPKmt 酵素催化thymidine 磷酸化形成 TMP (thymidine monophosphate),進一步成為 DNA 合成的單元。從 TMPKmt 酵素與 TMP 類似物的活性關係,可以推論 uridine 五位取代基將有尺寸效應,此類衍生物可能對細菌、病毒或癌細胞有抑制效果。因此我們希望能合成一系列於 uridine 五位具有 oxadiazole 取代基的衍生物,以評估其生物活性。 我們參考文獻方法製備了 5-cyanouridine 衍生物。將 5-cyano基團與 hydroxylamine 反應形成對應的 uridine-5-carboxzmidoxime。 Oxime 與數種不同的 benzoyl chloride 經脫水反應後形成一系列 5-(5-phenyl-1,2,4-oxadiazol-3-yl)uridine 衍生物。 我們將 uridine-5-carboxamidoxime 衍生物與醋酸酐反應,則可得到 5-(5-methyl-1,2,4-oxadiazol-3-yl)uridine。同時,我們嘗試利用 click 反應將 5-cyanouridine 與 sodium azide 進行 [3 + 2] 合環反應,但未能得到預期的 5-(tetrazol-5-yl)uridine 產物。 這些五位具有取代基的 uridine 衍生物,有潛力成為細菌、病毒或癌細胞的抑制劑,未來將會進一步進行生物活性評估。
TMPKmt (thymidine monophosphate kinase of Mycobacterium tuberculosis) catalyzes the conversion of thymidine to TMP (thymidine monophosphate). TMP is an important component for DNA replication. According to the affinity between TMPKmt for the TMP analogues, we interpreted that there could be a binding pocket in TMPKmt around the 5-substituent on thymidine. Therefore, 5-substituted uridine derivatives could be potential agents possessing antiviral and anticancer activities. Synthesis of 5-(5-substituted-1,2,4-oxadiazole)uridine was accomplished starting from 5-cyanouridine derivatives. The uridine 5-carboxamidoxime was obtained from the reaction of 5-cyanouridine derivatives with hydroxylamine. The oxime was subjected to several benzoyl chlorides to afford the corresponding 5-(5-phenyl-1,2,4-oxadiazol-3-yl)uridine derivatives. Alternatively, 5-(5-methyl-1,2,4-oxadiazol-3-yl)uridine was obtained from the reaction of the oxime with acetic anhydride. It is noteworthy that our attempt to synthesize 5-(tetrazol-5-yl)uridine from 5-cyanouridine via click chemistry was unsuccessful. These 5-substituted-uridine analogs are potential chemotherapeutical agents for bacteria, virus or cancer cells. Biological evaluation of the synthesized compounds will be investigated in the future.