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研究生(外文):Jian, Zhenxing
論文名稱(外文):1-Aryltriazolo[4,5-c]quinoline Derivatives As Potential Anticancer Agents
指導教授(外文):Chen, Shiahuy
口試委員(外文):Chang, ChihshiangChiang, Chaoyi
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本論文主旨是設計與合成1-芳香基三氮肼[4,5-c]喹啉衍生物作為潛能抗癌試劑。Combretastatin A-4 (CA-4)為抗微管聚合抑制劑,而喹啉衍生物在各方面皆擁有不錯的生物活性,因此以喹啉為骨架,設計1-芳香基三氮肼[3,2-c]喹啉衍生物,迫使兩芳香環像CA-4中的順式結構。首先anthranilic acids和2-nitroacetaldehyde oxime進行反應形成2-(2-nitroethylideneamino)benzoic acid (2),經環化及脫水反應得4-hydroxy-3-nitroquinoline (3),化合物3經氯化反應後得4-chloro-3-nitroquinoline,再與不同取代基之苯胺進行取代反應得到4-arylanilino-3-nitroquinoline (4),還原成氨基後再進行diazotization和cyclization得到一系列1-aryltriazolo[4,5-c]quinoline (6)衍生物。針對肺癌細胞株A549、大腸直腸癌細胞株HCT、肝癌細胞株HepG2、和胰腺癌細胞株PANC1作體外細胞毒性測試,以4-OMe取代之5b及3-OH-4-OMe取代之6g活性最佳,GI50值5b為0.088 μM (A549)、0.086 μM (HCT)、0.10 μM (HepG2)及5.93 μM (PANC1),而6g之IC50值為0.70 μM (A549)、0.06 μM (HCT)、0.24 μM (HepG2)及0.45 μM (PANC1)。
This thesis is aimed at design and synthesis of 1-aryltriazolo[4,5-c]quinoline derivatives as potential anticancer agents. Combrestastatin A4 (CA-4) is a tubulin polymerization inhibitor, and quinoline derivatives are known to possess biological activities in many aspects. Thus, quinoline skeleton was chosen for the design of 1-aryltriazolo[3,2-c]quinoline derivatives to force the two aromatic rings in cis conformations as those in CA-4. Condensation of anthranilic acids with 2-nitroacetaldehyde oxime resulted in 2-(2-nitroethylideneamino)benzoic acid (2), which was cyclized and dehydrated to give 4-hydroxy-3-nitroquinoline (3). Compound 3 was chlorinated to afford 4-chloro-3-nitroquinoline, which was substituted by anilines to give 4-arylanilino-3-nitroquinolines (4). After reduction, diazotization, and cyclization, a series of 1-aryltriazolo[4,5-c] quinoline derivatives (6) were obtained. Target compounds were evaluated for their cytotoxicities against lung cancer (A549), colon cancer (HCT), liver hepatocellular carcinoma (hepG2), and pancreatic carcinoma carcinoma (PANC1) cell lines. Compound 5b with 4-OMe and 6g with 3-OH-4-OMe exhibited high potency. The values of IC50 were 0.088 μM (A549), 0.086 μM (HCT), 0.10 μM (HepG2), and 5.93 μM (PANC1) for 5b and 0.70 μM (A549), 0.06 μM (HCT), 0.24 μM (HepG2), and 0.45 μM (PANC1) for 6g.
第一章 緒論 1
第二章 實驗設計 17
第三章 結果與討論 19
3.1.1 2-Amino-4,5-dimethoxybenzoic acid (1b) 23
3.1.2 2-β-Nitroethylidenaminobenzoic acid (2) 23
3.1.3 4-Hydroxy-3-nitroquinoline (3) 24
3.1.4 4-Anilino-3-nitroquinoline衍生物 (4) 26
3.1.5 1-Arylimidazo[4,5-c]quinoline衍生物(5) 27
3.1.6 1-Aryltriazolo[4,5-c]quinoline衍生物 (6) 28
第四章 結論 34
第五章 實驗部分 37
5.1 實驗方法與實驗儀器 37
5.2 試藥、溶劑 37
5.3 合成步驟 38
第六章 參考資料 55
Information received from the Internet Homepages of the Department of Health, Taiwan, R. O. C. (http://www.doh.gov.tw)
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黃皓倫,碩士論文,靜宜大學應用化學研究所 (2008)。
蒲家弘,碩士論文,靜宜大學應用化學研究所 (2010)。
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