發展具光活化性質之氮芥類抗癌前驅藥物應用於選擇性烷化去氧核醣核酸

Abstract

發展對癌細胞具高度選擇性的抗癌藥物，解決化療藥物具嚴重副作用的問題，為許多研究團隊努力的目標。本論文發展具光活化性質的抗癌前驅藥物，選用高熱穩定度且吸收波長較長的二噻吩乙烯作為光調控開關，修飾上臨床癌症治療使用的氮芥類DNA烷化劑與具拉電性的吡啶鎓離子，合成出Py-F6DTE-Mus-c與NAEPy-F6DTE-Mus-c兩個分子。 由水解速率測試證實，Py-c與NAEc皆可經由近紅外光的激發開環形成活性較高的Py-o與NAE-o。透過圓二色光譜法，探討Py-o、Py-c、NAE-o與NAE-c對DNA二級結構造成的影響，結果顯示合環狀態的Py-c與 NAE-c會對DNA的二級結構有較明顯的影響。此外利用凝膠電泳實驗進一步比較分子在照射近紅外光前後對DNA進行烷基化的能力差異，實驗結果顯示Py-c與 NAE-c在經過近紅外光活化後將有較高的活性對DNA進行烷化。以上研究結果顯示Py-c與NAE-c有成為光活化藥物的潛力，。然而，從細胞毒性實驗結果來看，NAE-o、NAE-c與經近紅外光活化之NAE-c對MCF-7的毒性差異不大，而細胞屬於相對複雜的系統，因此，未來研究方向應更進一步解析NAE-c、NAE-o與細胞作用時的相關機制。

Development of highly selective anticancer drugs toward tumor cells in order to resolve the severe side effects caused by chemotherapeutic drugs is a primary goal for many research groups. The thesis is aimed to develop a photoactived anticancer prodrug. Incorporation of the aniline mustard, a clinical DNA alkylator, as well as electrophilic pyridinium to the dithienylethene (DTE) core was achieved by multistep synthesis to afford Py-F6DTE-Mus-c and NAEPy-F6DTE-Mus-c. Development of highly selective anticancer drugs toward tumor cells in order to resolve the severe side effects caused by chemotherapeutic drugs is a primary goal for many research groups. The thesis is aimed to develop a photoactived anticancer prodrug. Incorporation of the aniline mustard, a clinical DNA alkylator, as well as electrophilic pyridinium to the dithienylethene (DTE) core was achieved by multistep synthesis to afford Py-F6DTE-Mus-c and NAEPy-F6DTE-Mus-c.