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研究生:羅偉棻
研究生(外文):Wei Fen Lo
論文名稱:4-苯胺基&;#21579;喃[2,3-b]&;#21945;?縣?4-苯胺基&;#21579;喃[3,2-c]&;#21945;?翮l生物之合成與抗癌活性評估
論文名稱(外文):Synthesis and anticancer evaluation of 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives
指導教授:曾誠齊
指導教授(外文):cherng-chyi tzeng
學位類別:博士
校院名稱:高雄醫學大學
系所名稱:醫藥暨應用化學系博士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:128
中文關鍵詞:&;#21579喃&;#21945?縉傱
外文關鍵詞:furoquinolineanticancer
相關次數:
  • 被引用被引用:0
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實驗室過去合成了furo[2,3-b]quinoline及furo[3,2-c]quinoline衍生物,其中CIL-102被視為這系列衍生物中的指標藥物,作用機轉為微管抑制劑,但此類化合物共同的缺點有低水溶解度、選擇性不佳以及生物可利用率低的缺點,所以我們針對此類化合物進行結構的修飾,期望可以改善原有的缺點。
實驗數據顯示CIL-102會抑制PC-3、A549、MCF-7以及M-10細胞株,其IC50值分別為2.69, 0.61, 0.31 以及0.95 μM,這數據顯示此化合物對於癌細胞與正常細胞之間不具有選擇性。此實驗中以4-anilinofuro[2,3-b]quinoline作為主架構,在橋鏈的氮上置入烷基進行修飾,合成一系列的衍生物。將此系列衍生物進行體外抑制癌細胞增生的活性評估後,發現化合物N-(4-acetylphenyl)-N- (furo[2,3-b]quinolin-4-yl)methylamine (12a)具有很好的抑制活性及選擇性,針對PC-3 (前列腺癌細胞)其IC50值為0.22 μM。
第二部分實驗中,嘗試以4-anilinofuro[3,2-c]quinoline作為主架構,嘗試置入高親水性的aminoalkyl基團進行修飾,希望藉由提高水溶解度特性,進而提升其生物可利用率。


Certain furo[2,3-b]quinoline and furo[3,2-c]quinoline derivatives have been synthesized and evaluated for their antiproliferative activities. Among them, CIL-102 was found to be the most potent. However, it exhibited general cytotoxicity to most of cancers and normal cells. In addition, it displayed other drawbacks such as low oral availability and poor aqueous solubility. In order to improve these drawbacks, we optimized the chemical structure of CIL-102 to settle these problems.
CIL-102 is active against the growth of PC-3、A549, MCF-7 and M-10 cells with an IC50 value of 2.69, 0.61, 0.31 and 0.95 μM, respectively. Recent reports revealed that replacement of hydrogen on the linker nitrogen of N-(4-methoxyphenyl)-2-methylquinazolin-4-amine with a Me group enhanced over 2000-folds activity of antiproliferation. This dissertation describes synthesis and evaluation of N-alkylated 4-anilinofuro[2,3-b]quinoline derivatives such as CIL-102 with aims to improve anticancer activity and selectivity. Our results indicated that most of the newly synthesized compounds exhibited selective activity against prostate cancer cells. Among them, N-(4-acetylphenyl)- N-(furo[2,3-b]quinolin-4-yl)methylamine (12a) was one of the most potent antiproliferative agents with an IC50 value of 0.22 μM against PC-3 cell growth.
In the second part, we describe the preparation of furo[3,2-c]quinoline derivatives substituted with aminoalkyl hydrophilic groups and structural verification of these newly synthesized compounds.


中文摘要 1
英文摘要 2
壹、緒論 3
貳、4-苯胺&;#21579;喃[2,3-b]&;#21945;?翮l生物的合成 8
一、研究背景及目的 8
二、合成目標 14
三、合成方法、結果與討論15
(一)、逆合成分析15
(二)、實驗結果與討論16
四、目標化合物活性結果與討論 21
五、結論 30
&;#21444;、4-苯胺&;#21579;喃[3,2-c]&;#21945;?翮l生物的合成 32
一、研究背景及目的 32
二、合成目標 38
三、合成方法、結果與討論40
(一)、逆合成分析40
(二)、實驗結果與討論42

肆、合成實驗部分 47
一、溶劑處理過程 47
二、儀器 47
三、試藥 49
四、各化合物的製備 51
伍、參考文獻 51
陸、研究成果目錄 126


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