二甲苯胺基-二噻吩乙烯衍生物之複合式分子開關以及具光活化性質之氮芥類抗癌前驅藥物的開發與研究

Development of Multi-Addressable Molecular Switches Based on Ditolylamino Dithienylethene Derivatives and Photoacvtivated Nitrogen Mustard-Based Anticancer Prodrugs

楊旻哲(Min-Che Yang)

指導教授 ： 陳昭岑

國立臺灣大學/理學院/化學研究所/碩士(2015年)

https://doi.org/10.6342/NTU.2015.11266

摘要

論文第一部分針對修飾上二甲苯胺基的F6DTE-DTA與H6DTE-DTA兩個二噻吩乙烯衍生物進行研究，利用價格便宜且較為溫和的Cu(ClO4)2作為氧化劑，使苯胺基氧化產生穩定自由基陽離子，再以紫外-可見光吸收光譜、循環伏安法、核磁共振光譜等實驗，來探討分子在接受光與電兩種不同訊號來源時，所進行各種組態之間的轉換。除此之外也探討具有不同架橋的F6DTE-DTA與H6DTE-DTA，對於分子在光與電場作用下組態的轉換有何不同。
論文第二部分則是研究關於具光活化性質抗癌前驅藥物的開發。氮芥類衍生物是已經用於臨床癌症治療的DNA烷化劑，將芳香氮芥基團修飾上二噻吩乙烯，並於另一端修飾上甲基化吡啶，合成出Close*分子。經由水解速率測試以及凝膠電泳實驗證實，Close*分子確實能夠經由近紅外光的激發而進行開環反應，形成具有與DNA進行烷基化活性的Open*。照光前後活性的巨大差異，使Close*有成為光活化化學治療之藥物的潛力。

關鍵字

分子開關 ； 光活化抗癌藥物

並列摘要

In the first part of the thesis, two ditolylamino dithienylethene derivatives, namely F6DTE-DTA and H6DTE-DTA, were designed and synthesized. Cu(ClO4)2, an inexpensive and mild chemical oxidant, was used to oxidize the ditolylamino groups and multistates with stable radical cations were thus formed correspondingly. The transformation of each state under electrochemical or light stimuli was confirmed by UV-vis absorption spectra, cyclic voltammograms, and nuclear magnetic resonance spectroscopy. Furthermore, the electronic nature of DTE core was also assessed how it would affect the multistate transformation of F6DTE-DTA and H6DTE-DTA.The second part of the thesis is to develop the photoactivated anticancer prodrug. Incorporation of the aniline mustard, a therapeutic DNA alkylating warhead, as well as methylpyridinium to the dithienylethene core was achieved by multistep synthesis to afford Close*. Close* could undergo ring-opening reaction to form Open* under near-infrared light stimulus accompanied by the activation of DNA-alkylating activity of aniline mustard based on the hydrolysis rate and DNA-PAGE results. The distinct DNA-alkylating property after light stimulus indicates Close* has great potential to be developed into a photoactivated chemotherapy prodrug with good tissue penetration as well as minimal adverse effects on the normal cells.

並列關鍵字

Molecular Switches ； Photoacvtivated Anticancer Prodrugs

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