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

廖振傑(JHEN-JIE LIAO)

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

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。

關鍵字

六位取代基

並列摘要

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.

並列關鍵字

Orotidine 5’-monophosphate decarboxylase ； 6-substituted 3-ribofuranosyluracil ； 6-chloro-3-(b-D-ribofuranosyl)uracil

參考文獻

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