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研究生： 邱玉菁
Yu-Ching Chiou
論文名稱： 合成有潛力的抗癌化合物及利用人類穀氧還蛋白活化之抗癌化合物之前驅物
Synthesis of Potential Anticancer Agent and Pro-anticancer Agent Activited by Human Glutaredoxin
指導教授： 陳焜銘
Chen, Kwun-Min
學位類別： 碩士
Master
系所名稱： 化學系
Department of Chemistry
論文出版年： 2007
畢業學年度： 95
語文別： 中文
中文關鍵詞： 抗癌化合物 、人類穀氧還蛋白 、唾液酸轉移酶
英文關鍵詞： human glutaredoxin, sialyltransferase
論文種類： 學術論文
相關次數： 點閱：212  下載：1 
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    • 人類穀氧還蛋白（human glutaredoxin）為專門且有效地對麩胺基硫蛋白（protein-SSG）進行去麩胺基硫反應（deglutathionylation）的催化蛋白質。論文中主要是針對此還原機制設計藥物，以期釋放抗癌藥物於過度表現Glutaredoxin的癌細胞當中。本文所合成之藥物主要以石膽酸(Lithocholic acid)和鬼臼毒素(podophyllotoxin)為基底藥物進而修飾為人類穀氧還蛋白（human glutaredoxin）的受質，對含-SH基團中間產物測試α(2→3)唾液酸轉移酶之生物活性和乳癌細胞（MDA-MB-231 cell）的活性測試。在實驗室先前合成出具有活性的石膽酸（Lithocholic acid）衍生物中， 首先挑選以石膽酸為骨架所衍生具有Asparate amino acid基團者(Li-O-Asp)為主要發展目標，其對α(2→3)唾液酸轉移酶之IC50約為12 μM，而合成之化合物20中，發現多了-SH基團在尾端不僅可以增加抑制α(2→3)唾液酸轉移酶的活性(IC50約為7.5 μM)，在乳癌細胞（MDA-MB-231 cell）活性測試中亦可增加其殺死乳癌細胞（MDA-MB-231 cell）的能力(23% 抑制效果)，並發現在石膽酸(Lithocholic acid)尾端的羧基團對於增加殺死乳癌細胞之毒性是必須的，而含有酯基尾端會阻礙其對乳癌細胞毒殺能力。
    而利用人類穀氧還蛋白（human glutaredoxin）還原機制釋放抗癌藥物於細胞當中之生物實驗測試都陸續在進行中。

    Glutaredoxin, a member of the thiol-disulfide oxidoreductase (TDOR) enzyme family, catalyzes the reduction of protein-glutathionyl-mixed disulfides (protein-SSG). Based on the mechanistic pathway, the goal focuses on design and synthesis of inhibitor-glutathionyl-mixed disulfides (inhibitor-SSG), which might be effectively activated by glutaredoxin, overexpressed in several cancer cell lines. Synthesis of podophyllotoxin derivatives and lithocholic acid related compounds was achieved and several of them significantly displayed inhibitory property toward sialyltransferase and also notably inhibited the growth of breast cancer cell. For example, compound 20 is an inhibitor of sialyltransferase with an IC50 value of 7.5 M , meanwhile, it achieved 23% inhibition of MDA-MB-231 growth at the concentration of 20 µM. Furthermore, results demonstrate that the carboxylate group of lithocholic acid derivatives is essential for the inhibition of cancer cell growth and etherification of carboxylate group reduces the ability of cytotoxicity. Currently, study on activation of lithocholic acid-glutathionyl-mixed disulfide by glutaredoxin is still in progress.

    論文題目…………………………………………………………..1 中文摘要……………………………………………………….….2 Abstract…………………………………………………………...3 ㄧ、導論…………………………………………………………..4 二、研究背景與文獻論述…………………………………….….6 1. 唾液酸的結構與功能……………………………….……6 2. 唾液酸轉移酶在生物上的功能………………………….8 3. 唾液酸轉移酶抑制劑的設計……………………………12 3.1以donor結構為基礎所設計的抑制劑……………..12 3.2過渡狀態類似物的抑制劑…………………………..14 3.3醣受體類似物的抑制劑……………………………..15 4. 鬼臼毒素（podophyllotoxin）………………………….17 4.1鬼臼毒素衍生物於癌症之臨床應用…………………19 5. 人類穀氧還蛋白簡介……………………………………..20 6. 榖胱甘肽（Glutathione，簡稱GSH）簡介…………....24 三、結果與討論…………………………………………………...25 Part 1. 合成鬼臼毒素衍生物……………………….........25 Part 1.1 設計合成合成鬼臼毒素衍生物………..........25 Part 1.2生物活性……………………….......................32 Part 1.3 結論………………………..............................34 Part 2. 合成可由Glutaredoxin還原之石膽酸衍生物…………….……………………………………………………...35 Part 2.1石膽酸類似物合成………………………........35 Part 2.2 結論與未來展望………………………...........51 Part 2.3 生物活性測試………………………...............52 四、實驗方法與數據……………………………………………....53 1、實驗儀器………………………...........................................53 2、實驗藥品………………………...........................................55 3、實驗步驟與光譜數據……………………………………...58 五、參考文獻………………………………………………………90 六、光譜資料………………………………………………………96

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