設計與合成 1-Deazauridine 的衍生物作為研究 OMP Decarboxylase 機制的探針

Abstract

本論文第一部分主要是根據 6-cyanouridine 5’-monophosphate (6-CN-UMP) 在 orotidine 5’-monophosphate decarboxylase (ODCase) 催化下轉換成 barbiturate nucleoside 5’- monophosphate (BMP) 的反應，設計以 6-cyano-1,3-dimethyluracil 作為模型反應的起始物，希望藉由其與各種親核試劑反應結果，推測出 ODCase 催化 6-CN-UMP 轉換成 BMP 的可能機制。當 6-cyano-1,3-dimethyluracil 與多種親核試劑反應時，例如 NaOMe, n-BuNH2 等，實驗結果發現會得到六位取代的產物，所以推測 ODCase 催化 6-CN-UMP 轉換成 BMP 的反應也是經由直接取代而產生。

第二部份則是酵素受質及產物類似物的合成，希望建立系統化的方法合成出 1-deazauridine 的 C-nucleoside 衍生物。我們以 3,5 -dibromo-2,6-dimethoxypyridine 作為起始物，在 n-BuLi 作用下與 ribonolactone 衍生物進行加成反應得到 hemiacetal 衍生物，再利用 Et3SiH 和 BF3 . Et2O 將其去羥基還原得到 ribonucleoside 衍生物， α/β 比例為 1.25/1 ， β isomer 以管柱層析分離純化出。將 β form 產物醣上的保護基移除後得到產物 1-(5-bromo-2,6-dimethoxypyridine- 3-yl)-β-D-ribofuranose。後續的去甲基保護，由於產物的不穩定以及純化的困難，未能得到預期的產物。未來希望可以利用合成1-deazauridine 相同的方法合成出更多 1-deazauridine 衍生物。

Based on the catalytic reaction that orotidine 5’-monophosphate decarboxylase (ODCase) transformed 6-cyanouridine 5’-monophosphate (6-CN-UMP) into barbiturate nucleoside 5’-monophosphate (BMP), we designed 6-cyano-1,3-dimethyluracil as a chemical model and analyzed its reactions toward various nucleophilic conditions. When 6-cyano-1,3- dimethyluracil reacted with some nucleophiles, such as sodium methoxide or n-butylamine, 6-substituded products were obtained, which allowed us to assume that ODCase transformed 6-CN-UMP into BMP through nucleophilic hydrolysis pathway.

In the second part, we hope to establish a feasible pathway for the synthesis of 1-deazauridine derivatives. 3,5-Dibromo-2,6-dimethoxy- pyridine was treated with n-butyllithium and then reacted with ribonolactone derivative to give the corresponding hemiacetal. The hemiacetal was reductively dehydroxylated with triethylsilane and borontrifluoride ethyletherate to give the ribonucleoside derivative with an α/β ratio of 1.25/1. The β isomer was purified by flash column chromatography. The removal of protecting groups on the sugar afforded 1-(5-bromo-2,6-dimethoxypyridin-3-yl)-β-D-ribofuranose. Attempts for demethylation were unsuccessful possibly due to the instability of 1-deazauridine. In summary, we have established a feasible pathway for the synthesis of 1-deazauridine derivatives.