臺灣博碩士論文加值系統

本論文設計與合成一系列第2、4、6、7位置不同取代基喹唑啉衍生物，並測試其對胃癌細胞株AGS、肺癌細胞株A549、肝癌細胞株HepG2、大腸直腸癌細胞株HT-29和前列腺癌細胞株PC-3的抑制生長活性。喹唑啉第4位置接上cyclohexylamino或cyclohexanemethylamino兩種基團、第2位置接上不同取代基的苯胺基得到標的化合物4a,b和6a,b，其中4b和6a對於HT-29與HepG2有活性。當在喹唑啉的第6、7位置導入甲氧基，10a-e與12a-e兩系列衍生物抑制HepG2的GI50值分別為2.7-3.35M及0.12-2.78M，其中2-苯胺基上有鹵素取代對HepG2有選擇性，GI50值為0.05-0.59 M，證明在喹唑啉的第6、7位置導入甲氧基增強抑制癌細胞生長活性。結果也顯示喹唑啉第4位置cyclohexanemethylamino取代基對於抑制癌細胞活性相當重要。將第2位置苯胺置換成對位吡啶後的化合物17b對所有測試癌細胞株均增強抑制活性，但若為鄰位吡啶取代則完全失去抑制活性。

In this thesis, a series of 2-, 4-, 6, and 7-substituted quinazoline derivatives were designed and synthesized as well as their cytotoxicities againststomach cancer cell line AGS, lung cancer cell lines A549, hepatocellular liver carcinoma cell line HepG2, colon cancer cell line HT-29 andprostate cancer cell line PC-3 were evaluated. Target compounds 4a,b and 6a,b are 4-cyclohexylamino/cyclohexanemethylamino and 2-(substituted anilino) substituted quinazoline. Among them, 4b and 6a possess moderate inhibitory activity against HT-29. Introducing methoxy groups onto the 6- and 7-position of quinazoline, two series of com-pounds 10a-e and 12a-e exhibit cytotoxicity against HepG2 with GI50 values ranging at 2.7-3.35 M and 0.12-2.78 M, respectively, and 2-(halogen substituted anilino) compounds possess high cytotoxicity against HepG2 with GI50 values of 0.05 - 0.59 M. These results demonsatrate that introduction of methoxy group onto the 6 and 7 positions of quinazoline enhances the cancer cell inhibitory activity. Our results further showed the significant role to inhibitory activity of the 4-cyclohexanemethylamino substituent. Replacement of the 2-anilino group to 2-(pyridin-4-yl) group enhance the inhibitory activities against all tested cancer cell lines. Nevertheless, 2-(pyridin-2-yl) substituted compound showed no inhibitory activity.

表目錄 v
圖目錄 vi
式目錄 viii
第一章 緒論 1
第二章 實驗設計 29
2.1 喹唑啉衍生物6, 7位置導入-OCH3基團之探討(targetIII和IV) 35
2.2 喹唑啉衍生物第4位置疏水基團探討(targetV-VI) 36
2.3 喹唑啉衍生物第2位置雜環取代之探討(targetVII) 37
第三章 結果與討論 38
3.1 標的化合物的合成 38
3.1.1 2,4-Quinazolinedione (1)的合成 38
3.1.2 2,4-Dichloroquinazoline (2)的合成 38
3.1.3 2-Chloro-4-cyclohexylaminoquinazoline (3)的合成 39
3.1.4 2-Anilino-4-cyclohexylaminoquinazoline衍生物4a-b的合成(target I) 40
3.1.5 2-Chloro-4-cyclohexanemethylaminoquinazoline (5)的合成 41
3.1.6 2-Anilino-4-cyclohexanemethylaminoquinazoline衍生物6a-b的合成(targetII) 42
3.1.7 6,7-Dimethoxyquinazoline-2,4-dione (7)的合成 42
3.1.8 2,4-Dichloro-6,7-methoxyquinazoline (8)的合成 43
3.1.9 2-Chloro-4-cyclohexylamino-6,7-methoxyquinazoline (9)的合成 43
3.1.10 2-Anilino-4-cyclohexylamino-6,7-dimethoxyquinazoline衍生物10a-e的合成(targetIII) 44
3.1.11 2-Chloro-4-cyclohexanemethylamino-6,7-dimethoxyquinazoline (11)的合成 45
3.1.12 2-Anilino-4-cyclohexanemethylamino-6,7-dimethoxyquinazoline衍生物12a-e的合成(targetIV) 46
3.1.13 2-Chloro-4-cyclohexylmethoxyquinazoline (13)的合成 46
3.1.14 2-Anilino-4-cyclohexylmethoxyquinazoline衍生物14a-g的合成(targetV) 47
3.1.15 2-Chloro-4-cyclopropanemethylquinazoline (15)的合成 48
3.1.16 2-Ailino-4-cyclopropanemethylaminoquinazoline衍生物16a-b的合成(targetVI) 48
3.1.17 2-Pyridinylamino-4-cyclohexanemethylaminoquinazoline衍生物17a與17b的合成(targetVII) 49
3.1.18 4-Cyclohexanemethylamino-2-(thioph-2-ylmethylamino)quinazoline17c的合成(targetVII) 50
3.1.19 2-(3-Chlorobenzylamino)-4-cyclohexanemethylaminoquinazoline (17d)的合成(targetVII) 51
3.2 抗癌活性測試 52
3.2.1 TargetI和targetII抗癌活性測試 52
3.2.2 TargetIII和targetIV抗癌活性測試 53
3.2.3 TargetV和targetVI抗癌活性測試 55
3.2.4 TargetVII抗癌活性測試 58
第四章 結論 61
第五章 實驗部分 63
5.1 檢驗方法與實驗儀器 63
5.2 試藥與溶劑 63
5.3 合成步驟 64
第六章 參考文獻 99

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