設計合成石膽酸衍生物應用於癌症之合併治療

Design and Synthesis of Lithocholic Acid Derivatives for Combination Treatment in Cancer

柳公政(Kung-Cheng Liu)

指導教授 ： 李文山

國立臺灣師範大學/理學院/化學系/碩士(2006年)

摘要

本論文分為兩個部份探討:

第一部分：
唾液酸轉移?的表現量和許多癌症有關，且和癌症轉移息息相關，所以本實驗室嘗試去改善由石膽酸為骨架，所衍生的唾液酸轉移?抑制劑，找到一系列效果更好的抑制劑。其中，首度合成出石膽酸結合鉑金屬或NBD (7-Nitro-2,1,3-benzoxadiazole)的新型複合物，找到化合物針對酵素抑制其IC50已經達到nM的等級；在乳癌癌細胞實驗中，以20μM的濃度也達到了35%的毒殺效果，而且更進一步證明可以有效抑制癌細胞的轉移，將來在癌症治療中可以與化療藥物合併或單獨使用。

第二部分：
人類癌細胞中的穀胱甘?-S-轉移酵素 (Human glutathione-S-transferases ; hGSTs)，其過度表現對於化療的藥物會產生抗藥性，GSH的類似物通常可以當作hGSTs很好的抑制劑，但是卻很容易被γ-麩醯基轉胺? (γ-GT)辨認而切斷。我們以石膽酸的骨架作衍生，找到一個結構穩定而且效果很好的抑制劑，在乳癌癌細胞中，這個藥物成功控制了hGSTs所造成的抗藥性，將設計的化合物與抗癌藥物合併使用，在抗癌藥物原本三分之一的濃度之下，就可以達到原本的毒殺效果。

並列摘要

Part I：
It has been reported that the expression of sialic acid is directly correlated with metastatic potential of cancer cells. In patients’ tumor cells, there is great increase in activities of sialytransferases (ST). We tried to design and synthesize the more potent ST inhibitors by modifying the substructure of lithocholic acid (LA) and evaluating their structure-activity relationship. We had successfully discovered LA- cis-Diamminedichloroplatinum or LA-7-Nitro-2,1,3-benzoxadiazole (NBD) complexes were with enhancement of inhibitory property and cytotoxicity. The latter the most active compounds toward ST with their IC50 value of at nM range. In MDA-MA-231 cell line, LA-NBD complexes 20μM display 35% inhibition of cell growth. Furthermore, the data indicated that both ST inhibitors significantly decreased the migration ability of MDA-MA-231 cells. The results are promising for coming testing in animal study and the inhibitors might be the potential drug candidates in the future.

Part II：
Overexpression of human gutathione S-transferases (hGSTs) causes tumor cells resistance to chemotherapeutic drugs. Therefore, finding a potential hGSTs inhibitor, GSH conjugate analogues which are resistant toγ-gutamyltranspeptidases (γ-GT)-mediated breakdown, can enhance the cytotoxicity of the anticancer drugs. We design a new type of hGSTs inhibitor with lithocholic acid moiety which is stable toward γ-GT and highly selective to GSTA2. Furthermore, the co-use of inhibitor increases the property of cytotoxicity of low dosage anti-cancer agents against MDA-MA-231 cell line.