簡便的合成4-疊氮-1-丁基胺並用以建構篩選芬布芬及利尿酸之分子庫

A facilitate synthesis of 4-azido-1-butanamine and its use for construction and the screening of the library of Fenbufen and Ethacrynic acid

蘇元孝(Yuan-Siao Su)

指導教授 ： 俞鐘山

國立清華大學/原子科學院/生醫工程與環境科學系/碩士(2009年)

https://doi.org/10.6843/NTHU.2009.00358

摘要

本研究在探討將核心胺基化合物與羧酸化合物以組合化學的方法在不分離純化的狀態於液相建立起醯胺化分子庫並進行細胞毒性分析。
在合成核心化合物的路徑上，先以一步驟的合成方法合成出4-azidobutan-1-amine做為供我們實驗室液相合成使用的連接體(Linker)，再將此連接體以醯胺化反應(amide formation)修飾原本就擁有抗癌潛力的化合物(Fenbufen以及Ethacrynic acid)，並且使連接體末端裸露出的Azido group(N3)還原成Amino group(NH2)藉此建立醯胺化分子庫以達到快速篩選的效果。
分子庫建立過程中使用肺癌A549細胞株以及乳癌MCF7細胞株還有人類直腸癌C26細胞株，以及老鼠胰臟癌Tramp細胞株來做為分子庫的毒殺試驗平台。使用多種細胞株的原因也是希望可以發現具有選擇性的毒殺化合物。
依據實驗結果發現了一些具有毒殺效果的化合物，其中包括了N-(4-(4-(biphenyl-4-yl)-4-oxobutanamido)butyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide、N-(4-(4-(biphenyl-4-yl)-4-oxobutanamido)
butyl)-2-ethylhexanamide以及4-(biphenyl-4-yl)-N-(4-(2-(2,3-
dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)butyl)-4-oxobutanamide。並且嘗試單獨製備純化並做進一步的生物分析。也代表了此一步驟合成連接體之方法可以用在修飾潛力藥物，並且用於我們實驗室所構築之醯胺化分子庫系統上。另外我們初步篩選到的潛力化合物針對不同的細胞具有不同的毒殺性，不過整體上來說此次分子庫建立以Fenbufen為主體修飾之核心化合物似乎毒殺效果上比Ethacrynic acid為主體之修飾物好些。

關鍵字

分子庫

並列摘要

Aim of this research is to construct a library via amide formation under solution-phase condition.
To synthesize the core compound：a linker with amino and azido groups at the terminal end of butane, 4-azidobutan-1-amine), was prepared。After coupling with the activated acid derivatives of fenbufen and ethacrynic acid, the azido group was reduced to deliver the primary amines which could serve as a new core amine compound for construction of the library.
The cell lines used in our library included A549、MCF7、C26、and Tramp, which were derivated from lung cancer, breast cancer, colon cancer and pancreas cancer, respectively. Through the screening on the basis of the four different types of cancers, potential compound with selectivity may be easily discovered.
Indeed, after the first round of screening, three compound with improved cytotoxicity were found, e.g. N-(4-(4-(biphenyl-4-yl)-4-
oxobutanamido)butyl)-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide、N-(4-(4-(biphenyl-4-yl)-4-oxobutanamido)
butyl)-2-ethylhexanamide and 4-(biphenyl-4-yl)-N-(4-(2-(2,3-
dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)butyl)-4-oxobutanamide. Further prepare of these compound and purification to determinate the IC50 value were performed. We can see that one-step synthesis linker to modify potential compound is succeed in our library system. In addition, we primary screening some potential anti-cancer compound seems that may have cytotoxic selectivity. Overall, we find that modified Fenbufen core amine is more cytotoxic than modified EA core amine.

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