2-苯基喹啉與2-呋喃喹?@衍生物之合成及細胞毒活性評估

Synthesis and Cytotoxic Evaluation of 2-Phenylquinoline and 2-Furanylquinoline Derivatives

趙越玲(Yue-Ling Zhao)

指導教授 ： 曾誠齊

高雄醫學大學/藥學院/藥學研究所/博士(2005年)

摘要

中文摘要

本論文合成了一系列2-苯基喹?C和2-?@喃喹?C的衍生物，並針對九類癌細胞(包括白血病、非小細胞肺癌、結腸癌、中樞神經癌、黑色素皮膚癌、卵巢癌、腎癌、前列腺癌、及乳癌)共六十株人類癌細胞進行細胞毒活性評估。在2-苯基喹?C的C(4)有4-乙醯苯胺取代的化合物1-[4-(6-Methoxy-2-phenylquinoline-4-ylamino)phenyl]- ethanone (7) (GI50 = 3.89 μM)和它的oxime (9a) (GI50 = 3.02 μM)及O-methyloxime (9b) (GI50 = 3.89 μM)衍生物，對六十種癌細胞株具有有效的細胞毒活性，且其細胞毒活性優於3-乙醯苯胺取代的類似物 (8, 9.12 μM; 10a, 8.51 μM; 10b, 8.32 μM) 。 而在C(3)位置有?A酸基取代的2-苯基喹?C類似物 (14, 16a, 16b, 17a, 17b) 呈現完全沒有細胞毒活性， 顯示在2-苯基喹?C環上，C(3)位置有?A酸基的取代是不適當的，因為它會妨礙2-苯基和喹?C環共平面的形成 。 化合物7對數種腫瘤細胞例如NCI-H226 (非小細胞肺癌) (GI50 = 0.94 μM)、MDA-MB-231/ATCC (乳癌) (GI50 = 0.04 μM)和SF-295 (中樞神經癌) (GI50＜0.01 μM)的細胞毒活性特別好，具有選擇性的細胞毒活性。
在2-?@喃喹?C的C(4)有3-甲氧基苯胺取代的化合物4-(3- Methoxyphenylamino)-2-furan-2-ylquinoline Hydrochloride (24e) (GI50 = 3.05 μM)和C(4)有4-乙醯苯胺取代的化合物1-[4-(2- Furan-2-ylquinoline-4-ylamino)phenyl]ethanone Hydrochloride (24a) (GI50 = 4.36 μM)， 對六十種癌細胞株具有有效的細胞毒活性 。 C(4)有4-乙醯苯胺取代的化合物 24a 和它的oxime (25a) (GI50 = 5.54 μM)及O-methyloxime (25b) (GI50 = 5.99 μM)衍生物的細胞毒活性，優於3-乙醯苯胺取代的類似物 (24b, 10.50 μM; 26a, 6.85 μM ; 26b, 20.60 μM)。在C(4)的苯胺環上有甲氧基取代的2-?@喃喹?C衍生物的細胞毒活性以間位取代的化合物 (24e) (GI50 = 3.05 μM)優於對位 (24d) (GI50 = 5.98 μM)和鄰位 (24f) (GI50 = 7.45 μM)取代的化合物。
在C(3)有酯基或?A酸基取代的化合物中，只有化合物37a對NCI-H460 (lung cancer)有抑制生長的活性， 其它在C(3)有酯基或?A酸基取代的化合物 37b、38a和38b無法將癌細胞株的成長控制在32%以下，皆呈現沒有抗癌活性，顯示C(3)的?A酸基在此類化合物的結構上是不適當的。

關鍵字

2-苯基?? ； 2-?喃??

並列摘要

Abstract

The present report describes the synthesis and anticancer evaluation of certain 4-anilino-2-phenylquinoline and 4-anilino-2- furanylquinoline derivatives. In the 4-anilino-2-phenylquinoline derivatives, 1-[4-(6-Methoxy-2-phenylquinoline-4-ylamino)phenyl]ethanone (7), its oxime (9a), and its methyloxime (9b), exhibited significant cytotoxicity against all 60 cancer cells with a mean GI50 value of 3.89, 3.02, and 3.89 μM respectively while 4-(4-Acetylphenylamino)-6-methoxy- 2-phenylquinoline-3-carboxylic acid (14) and its 3-carboxylic acid congeners 16a, 16b, 17a, and 17b were inactive, indicated free carboxylic acid at C(3) position is unfavorable. Among these compounds, 7 is especially active against the growth of certain solid cancer cells such as NCI-H226 (non-small cell lung cancer), MDA-MB-231/ATCC (breast cancer), and SF-295 (CNS cancer) with GI50 values of 0.94, 0.04, and ＜0.01 μM respectively.
In the 4-anilino-2-furanylquinoline derivatives, 4-(3-Methoxy- phenylamino)-2-furan-2-ylquinoline Hydrochloride (24e) and 1-[4-(2- Furan-2-ylquinoline-4-ylamino)phenyl]ethanone Hydrochloride (24a) exhibited significant cytotoxicity against all 60 cancer cells with a mean GI50 value of 3.05 and 4.36 μM respectively, all the 3-carboxylic acid derivatives 37b, 38a, and 38b are inactive with exception of 37a which exhibits marginal inhibitory activity against NCI-H460.

並列關鍵字

2-Phenylquinoline ； 2-Furanylquinoline

參考文獻

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