4-苯胺基呋喃[2,3-b]喹啉及4-苯胺基呋喃[3,2-c]喹啉衍生物之合成與抗癌活性評估

Synthesis and anticancer evaluation of 4-anilinofuro[2,3-b]quinoline and 4-anilinofuro[3,2-c]quinoline derivatives

羅偉棻(Wei Fen Lo)

指導教授 ： 曾誠齊

高雄醫學大學/生命科學院/醫藥暨應用化學系博士班/博士(2015年)

摘要

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。

關鍵字

呋喃喹 ； ?縉傱

並列摘要

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.

並列關鍵字

furoquinoline ； anticancer

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