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研究生:吳元仁
研究生(外文):Yuan-Rean Wu
論文名稱:6-(1,2,4-Oxadiazol-3-yl)uridine衍生物的設計、合成及其生物活性評估
論文名稱(外文):Design, Synthesis and Biological Evaluation of 6-(1,2,4-Oxadiazol-3-yl)uridine Derivatives
指導教授:簡敦誠
指導教授(外文):Tun-Cheng Chien
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
畢業學年度:97
語文別:中文
論文頁數:114
外文關鍵詞:uridine
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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.
目錄 i
縮寫對照表 iii
英文摘要 iv
中文摘要 v
Chapter I Introduction 1
Chapter II The Reaction of 5-Br-1,3-DMU and 6-CN-1,3-DMU with Nucleophiles: as a Model Reaction for the Hydrolysis of 6-CN-UMP under ODCase Catalysis
2-1 前言 15
2-2 實驗概念與合成設計 21
2-3 結果與討論 23
2-4 總結 31
Chapter III Design and Synthesis of 6-(1,2,4-Oxadiazol-3-yl)uridine Derivatives
3-1 前言 33
3-2 實驗概念與合成設計 35
3-3 結果與討論 36
3-3-1合成 6-(1,2,4-oxadiazol-3-yl)-1,3-dimethyluracil 衍生物作為 uridine 的反應模型 36
3-3-2 起始物的製備 41
3-3-3 合成 6-(5-phenyl-1,2,4-oxadiazol-3-yl)uridine 42
3-3-4 合成 6-(5-methyl-1,2,4-oxadiazol-3-yl)uridine 43
3-3-5合成 6-(5-tichloromethyl-1,2,4-oxadiazol-3-yl)uridine 48
3-3-6合成 6-(5-(p-nitrophenyl)-1,2,4-oxadiazol-3-yl)uridine 53
3-3-7合成其他的 6-(1,2,4-oxadiazol-3-yl)uridine 衍生物 55
3-4 總結 58
Chapter IV Conclusion 59
Chapter V Experimental section 61
5-1 一般實驗處理 61
5-2 儀器設備 61
5-3 實驗步驟 62
Reference 100
Checklist 104
光譜資料 114
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