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研究生: 廖振傑
LIAO,JHEN-JIE
論文名稱: 設計及合成六位具有取代基 3-(β-D-Ribofuranosyl)uracil 的衍生物及其生物活性評估
Design, Synthesis and Biological Evaluation of 6-Substituted-3-(β-D-Ribofuranosyl)uracil Derivatives
指導教授: 簡敦誠
Chien, Tun-Cheng
學位類別: 碩士
Master
系所名稱: 化學系
Department of Chemistry
論文出版年: 2009
畢業學年度: 97
語文別: 中文
論文頁數: 89
中文關鍵詞: 六位取代基
英文關鍵詞: Orotidine 5’-monophosphate decarboxylase, 6-substituted 3-ribofuranosyluracil, 6-chloro-3-(b-D-ribofuranosyl)uracil
論文種類: 學術論文
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  • 中文摘要
    Orotidine 5’-monophosphate decarboxylase (ODCase) 抑制物的設計及合成為本論文的主要目的,主要分為: (a) 6-substituted uridine 和 (b) 6-substituted 3-ribofuranosyluracil 兩種類型,設計合成類似 ODCase 的受質或抑制劑結構以探討酵素作用機制與活性評估。
    首先以6-chloro-1,3-dimethyluracil 作為反應模型測試鹼基上數種的親核取代反應,評估反應性及可行性。6-Chloro-1,3-dimethyluracil 與親核性試劑進行取代反應,如 sodium azide、氰化鈉、正丁基胺、和 imidazole 可得到對應的 6-substituted 1,3-dimethyluracils. 然而,相同的反應應用在 6-iodouridine 時,卻無法合成預期的產物。
    此外, 以6-chlorouracil作為起始物, 與1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (TBAR) 在路易士酸下進行醣化反應 (glycosylation) 形成6-chloro-3-(2,3,5-tri-O-benzoyl--D-ribofuranosyl)uracil。利用親核性試劑無法直接對6-chloro-3-(-D-ribofuranosyl)uracil 衍生物做取代反應,因此我們推測 uracil N1上的氫會干擾取代反應。為了證明這個假設,我們在 N1 位置接上甲基或是 Benzyl 取代基,再由N1 有取代基的 6-chloro-3-(-D-ribofuranosyl)uracil 衍生物與親核性試劑(sodium azide、氰化鈉)反應,能得到相對應六位取代基的3-ribofuranosyluracils。這些 uridine 類似物是具有潛力的 ODCase 抑制劑,未來會更進一步研究其生物活性與評估。

    Abstract
    The main focus of this thesis is the design and synthesis of inhibitors for orotidine 5’-monophosphate decarboxylase (ODCase). The thesis includes two parts: (a) 6-substituted uridine and (b) 6-substituted 3-ribofuranosyluracil. These two types of structures were designed as the analogous structures of substrate / inhibitors for ODCase, in order to study the interactions between the enzyme and substrate / inhibitors.
    6-Chloro-1,3-dimethyluracil was chosen as the reaction model to investigate the synthesis of 6-substituted uridine. 6-Chloro-1,3-dimethyluracil underwent nucleophilic substitution reactions with nucleophilic reagents such as sodium azide, sodium cyanide, n-butylamine, and imidazole to afford the corresponding 6-substituted 1,3-dimethyluracils. However, the synthesis was unsuccessful when the same approach was applied to sugar-protected 6-iodouridine.
    Glycosylation of silylated 6-chlorouracil with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (TBAR) in the presence of Tin (IV) chloride (SnCl4) as a lewis acid afforded 6-chloro-3-(2,3,5-tri-O-benzoyl--D-ribofuranosyl)uracil. Direct nucleophilic substitution of this 6-chloro-3-(-D-ribofuranosyl)uracil derivative was unsuccessful. We rationalized that the unsubstituted nitrogen at 1-position of uracil interfered the reaction. To prove this hypothesis, methyl and benzyl substituents were introduced to the N1-position. The N1-substituted 6-chloro-3-(-D-ribofuranosyl)uracil derivatives underwent nucleophilic substitution with nucleophilic reagents such as sodium azide, or sodium cyanide to give the corresponding 6-substituted 3-ribofuranosyluracils. The synthesized uridine analogs are potential inhibitors of ODCase. Further biological evaluation will be investigated.

    目錄 Abstract 中文摘要 第一章 緒論 1-1. Orotidine 5’-monophosphate decarboxylase 的簡介 ……………………………1 1-2. ODCase 的反應機制 ……………………………………………………………3 1-3. ODCase的抑制劑與設計 ………………………………………………………9 1-4. 參考文獻 ………………………………………………………………………12 第二章 6-Chloro-1,3-dimethyluracil 與親核基的取代反應 2-1. 前言 …………………………………………………………………………13 2-2. 合成設計 ………………………………………………………………………13 2-3. 結果與討論 ……………………………………………………………………14 2-4. 總結 ……………………………………………………………………………19 2-5. 實驗步驟 ………………………………………………………………………19 2-6. 參考文獻 ………………………………………………………………………24 第三章 6-cyano-1,3-dimethyluracil 重排反應之探討 3-1. 前言 ……………………………………………………………………………25 3-2. 合成設計 ………………………………………………………………………28 3-3. 結果與討論 ……………………………………………………………………28 3-4. 總結 ……………………………………………………………………………31 3-5. 實驗步驟 ………………………………………………………………………31 3-6. 參考文獻 ………………………………………………………………………33 第四章 利用6-iodouridine 合成 uridine 六位取代衍生物 4-1. 前言 …………………………………………………………………………….34 4-2. 合成設計 ……………………………………………………………………….34 4-3. 結果與討論 ……………………………………………………………………35 4-4. 總結 …………………………………………………………………………….40 4-5. 實驗步驟 ……………………………………………………………………….40 4-5. 參考文獻 ……………………………………………………………………….44 第五章 6-substituted 3-ribofuranosyluracil 的合成 5-1. 前言 …………………………………………………………………………….45 5-2. 合成設計 ……………………………………………………………………….45 5-3. 結果與討論 …………………………………………………………………….48 5-4. 總結 …………………………………………………………………………….53 5-5. 實驗步驟 ……………………………………………………………………….54 5-5. 參考文獻 ……………………………………………………………………….58 第六章 儀器設備、光譜數據 6-1. 一般實驗處理 ………………………………………………………………….59 6-2. 儀器設備 ……………………………………………………………………….59 光譜資料 …………………………………………………………………………….61 Chien Lab Compound Characterization Checklist

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