6-(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 6-(1,2,4-Oxadiazol-3-yl)uridine Derivatives

吳元仁(Yuan-Rean Wu)

指導教授 ： 簡敦誠

國立臺灣師範大學/理學院/化學系/碩士(2009年)

摘要

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。

並列摘要

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.

並列關鍵字

uridine

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