臺灣博碩士論文加值系統

本研究利用天然生物鹼白鮮鹼(dictamine)三環呋喃喹啉 (furoquinoline)衍生物為骨架，在4-苯胺呋喃[2,3-b]喹啉(4-anilinofuro[2,3-b]quinoline) 4-C上進行修飾，數據指出，1-[4-(呋喃[2,3-b]喹啉-4-氨基)-苯基]乙酮(1-[4-(furo[2,3-b]quinoline- 4-ylamino)-phenyl]ethanone) (CIL-102, 1) (GI50 = 0.025 μM)及3-氯- 4-[(4-甲氧基苯基)氨基]呋喃[2,3-b]喹啉(3-chloro-4- [(4-methoxyphenyl)-amino]furo[2,3-b]quinoline) (CIL-378, 2) (GI50 = 0.025 μM)在抗腫瘤細胞增生表現出色且優於以上市藥物柔紅黴素(daunomycin)，但水溶解度低與其無選擇性的細胞毒性，是需克服的問題。本研究主要在4-苯胺呋喃[2,3-b]喹啉4-C上氮進行烷基化修飾，且進行其抑制腫瘤細胞增生活性的探討與評估，並提升在水中的溶解度及更好抑制癌細胞選擇性，進一步證明其為有效抗增生藥物。

The skeleton of natural dictamnine alkaloid belongs to a tricyclic furoquinoline derivative. Previous reports indicated that the introduction of a suitable substituent at the 4-position of furoquinoline ring afforded certain potential antiproliferative agents. For examples, 1-[4-(furo[2,3-b]quinoline-4-ylamino)phenyl]ethanone (1, GI50 = 0.025 μM) and 3-chloro-4-[(4-methoxyphenyl)amino]furo[2,3-b]quinoline (2, GI50 = 0.025 μM) exhibited more potent antiproliferative activities than the clinically used anticancer drug, daunomycin. However, poor water solubility and general cytotoxicities exhibited by both compounds 1 and 2 prompted extensive structural optimizations to overcome these problems. This thesis describes the synthesis and antiproliferative evaluation of certain N-alkyl 4-anilinofuro[2,3-b]quinoline derivatives with an aim to obtain novel furoquinoline derivatives with a high water solubility as well as a better selective anticancer activity. Certain N-alkyl 4-anilinofuro[2,3-b]quinoline derivatives were successfully synthesized and proved to be potential antiproliferative agents.

中文摘要 1
英文摘要 2
壹、緒論 3
貳、研究動機 7
參、合成方法結果與討論 15
肆、目標化合物活性結果與討論 28
伍、目標化合物水溶解度測試結果與討論 31
陸、結論 40
柒、合成實驗部分 41
一、溶劑及處理過程 41
二、儀器及試藥 41
三、各化合物的製備 45
捌、參考文獻 73
附錄 78

目錄
表一、呋喃喹啉衍生物體外癌細胞株之抑制活性(GI50, μM) 7
表二、化合物1與化合物2之藥物動力學測試 9
表三、以胺基烷氧基取代時水溶解性質 10
表四、含胺基長側鏈的修飾(7a與7b)，對抑制細胞增生的活性 11
表五、化合物1、2、7a、7b之藥物動力學測試 12
表六、蛋白酶活性測試之4-苯胺喹唑啉類SAR分析 13
表七、化合物9，以靜脈注射入老鼠體內AUC變化圖 14
表八、目標化合物之細胞毒性測試(以化合物1為主架構) 29
表九、目標化合物2，19，20之細胞毒性測試 30
表十、化合物2與烷基修飾之19、20、23水溶解度測試 31
表十一、化合物13a與13b之烷基化後之產物水溶解度測試 32
表十二、化合物17a與14b之烷基化後之產物水溶解度測試 33
表十三、以15a為領導化合物，接上側鏈後的水溶解度 38
表十四、以17a為領導化合物，接上側鏈後的水溶解度 39

目錄
圖一、細胞週期(Cell cycle) 1
圖二、具有顯著抗增生活性之化合物 8
圖三、4-苯胺呋喃[2,3-b]喹啉衍生物合成之目標產物 15
圖四、烷基化反應後得產物化合物19 24
圖五、化合物19 1H NMR (400 MHz, CDCl3)圖譜 25
圖六、化合物19 NOESY之2D-NOE圖譜 26
流程一、3,4-二氯呋喃[2,3-b]喹啉之反應機制 18
流程二、1-{4-[(Furo[2,3-b]quinolin-4-yl)methylamino]phenyl} ethanone合成路徑 20
Scheme 1. 17
Scheme 2. 21
Scheme 3. 22
Scheme 4. 27
Scheme 5. 36
Scheme 6. 37

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