臺灣博碩士論文加值系統

本論文主旨為設計與合成一系列1-芳香基取代吡咯[3,2-c]喹啉衍生物作為抗癌試劑，並對其做體外生物活性評估。Combretastatin A-4 (CA-4)為一有效的抗微管聚合抑制劑，CA-4結構特徵為在雙環上接有甲氧基之二芳香環順式乙烯結構。已有許多文獻報導指出喹啉衍生物在各方面皆擁有不錯的生物活性，因此本實驗室之前就曾以喹啉為骨架，設計1-芳香基取代吡咯[3,2-c]喹啉衍生物，迫使兩芳香環為順式結構，發現此系列化合物具有不錯的抗癌細胞活性。本論文進一步改變在喹啉環上的取代基，同樣以合成1-芳香基取代吡咯[3,2-c]喹啉衍生物為主，分別以4-Cl、4-Me及3,4,5-OMe取代之苯胺與2-acetylbutyrolactone進行縮合反應後，接著氯化得4-chloro-3-(2-chloroethyl)衍生物 2a-c，再與具不同取代基之苯胺進行取代及環化反應得到2,3-dihydropyrrolo[3,2-c]quinoline衍生物3及4，利用鈀金屬催化劑脫氫，分別得到5和6系列1-芳香基取代吡咯[3,2-c]喹啉衍生物。合成出之標的化合物均採SRB篩選方式，分別對胃癌細胞株AGS、肺癌細胞株A549和大腸直腸癌細胞株HT-29進行體外細胞毒性測試，發現未平面化之2,3-dihydropyrrolo[3,2-c]quinoline衍生物3a-c在苯胺之甲氧基在抑制活性上扮演著很重要的角色。更重要的，苯環上有甲氧基取代之5和6系列pyrrolo[3,2-c]quinoline衍生物，其抑制活性也明顯比未平面化前的3系列好，因此推測在結構活性關係(SAR)中，平面芳香結構為一必要的條件。

This thesis is aimed at design, synthesis, and evaluation of anticancer activity of 1-arylpyrrolo[3,2-c]quinoline derivatives. Combrestastatin A4 (CA-4) is a tubulin polymerization inhibitor, and its structural features possess two aryl rings containing methoxy groups in the cis form. Quinoline derivatives possess various biological activities in many aspects. It was used for the design of 1-arylpyrrolo[3,2-c]quinolines to force two aryl rings in cis form. In this study, we introduced substituents on the quinoline of 1-arylpyrrolo[3,2-c]quinoline derivatives. The synthesis was initiated from the condensation of aniline (4-Cl, 4-Me, and 3,4,5-OMe) and 2-acetylbutyrolactone. After chlorination, 4-chloro-3-(2-chloroethyl) derivatives 2a-c were substituted and cyclized by anilines to afford 2,3-dihydropyrrolo[3,2-c]quinolines 3 and 4. Aromatization of 3 and 4 was accomplished by dehydrogenation over palladium to afford target compounds 6 and 7. All synthesized compounds were subjected to SRB assay for the in vitro cytotoxicity against stomach cancer cell line AGS, lung cancer cell lines A549, and colon cancer cell line HT-293. The OMe on the 1-phenyl group played an important role in 3a-c. More importantly, pyrrolo[3,2-c]quinolines 5 and 6 conatining the methoxy substituent on the phenyl group possessed inhibitory activity much better than the corresponding 3 series. For the structure-activity relationship (SAR), the amomatic planar structure is assumed essential to the inhibitory activity.

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 標的化合物的合成 19
3.1.1 4-Chloro-3-(2-chloroethyl)-2-methylquinolines (2a-c) 19
3.1.2 1-Aryl-4-methyl-2,3-dihydropyrrolo[3,2-c]quinolines 3及4 20
3.1.3 1-Aryl-4-methyl-pyrrolo[3,2-c]quinoline衍生物5及6 24
3.1.4 8-Chloro-4-methyl-1-(pyridin-2-yl)-pyrrolo[3,2-c]quinoline (9) 25
3.2 體外生物活性測試 32
第四章 結論 37
第五章 實驗部分 38
5.1 檢驗方法與實驗儀器 38
5.2 試藥、溶劑 38
5.3 合成步驟 39
第六章 參考資料 68
第七章 圖譜資料 75
圖目錄
圖一、九十八年度台灣地區十大死亡原因比例 2
圖二、九十八年度台灣地區癌症死亡百分比 2
圖三、惡性腫瘤治療方法及化學治療之副作用 4
圖四、細胞週期 5
圖五、有絲分裂概況 7
圖六、微管結構及平衡狀態 8
圖七、微管聚合試劑 10
圖八、紫杉醇與β-tubulin鍵結情形 10
圖九、秋水仙素與α-tubulin鍵結情形 12
圖十、抗微管聚合試劑 13
圖十一、CA-4相關之前導藥物 14
圖十二、仿CA-4構型之雜環衍生物 15
圖十三、CA-4衍生物構型設計概念 17
圖十四、1-Arylpyrrolo[3,2-c]quinoline標的化合物設計概念 18
圖十五、化合物3f salt於CDCl3中的1H NMR圖譜 22
圖十六、D2O加入化合物3f salt於CDCl3中的1H NMR圖譜 23
圖十七、化合物7於DMSO-d6中的1H NMR圖譜 28
圖十八、化合物8於CDCl3中的1H NMR圖譜 29
圖十九、利用螢光光譜來鑑定化合物7、8及9螢光強度 30
表目錄
表一、化合物7與8物理、化學性質的不同 31
表二、1-Aryl-8-chloro-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline衍生物3a-j之體外生物活性 32
表三、1-Aryl-4-methylpyrrolo[3,2-c]quinoline衍生物5、6及9之體外生物活性 34
式目錄
式一、4-Chloro-3-(2-chloroethyl)-2-methylquinolines (2a-c)之合成 19
式二、1-Aryl-4-methyl-2,3-dihydropyrrolo[3,2-c]quinoline衍生物3及4之合成 20
式三、1-Aryl-4-methyl-pyrrolo[3,2-c]quinolines衍生物5及6之合成 24
式四、8-Chloro-4-methyl-1-(pyridin-2-yl)-pyrrolo[3,2-c]quinoline (9)之合成 25

Information received from the Internet Homepages of the Department of Health, Taiwan, R. O. C. (http://www.doh.gov.tw)
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