臺灣博碩士論文加值系統

雖然具有喹啉環(quinoline)的化合物已被發現有廣泛的生物活性，但是目前對於合成茚喹啉類化合物及其藥理活性所知仍然有限。
藉由對茚[ 1 , 2 - c ] 喹啉類化合物結構修飾合成出一系列衍生物(如結構式I 所示)；其中R1 表示為氫或鹵素；R2 表示為氫、鹵素、羥基、烷取代胺基、芳香取代胺基或環狀取代之二級胺基如piperazine, morpholine及其取代衍生物；R3 表示為氫、羥基或烷取代胺基；而R4 表示為氫、烷取代胺基或芳香取代胺基。這些化合物如結構I 所示以Hela 子宮頸癌細胞、SAS 口腔癌細胞、SKHep 肝癌細胞、AGS 胃癌細胞、RCC 786-O 腎癌細胞、PC-3 前列腺癌細胞、A549 肺癌細胞等七種台灣本土常見人類癌細胞株進行
抗增生活性篩選，其結果證實具有廣泛及強效的抗腫瘤活性。
(E)-9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-3-(dimethylamino)propyl oxime 化合物15b 會造成Hela 子宮頸癌細胞其型態會呈現萎縮、產生空泡之現象。以流式細胞儀分析細胞週期結果發現，化合物15b 也會造成Hela 子宮頸癌細胞之細胞週期停滯在S 期，並且造成多倍體(> 4n)染色質的細胞出現，進而引起細胞凋亡。由DNA 嵌入活性實驗中，化合物21a 與21b 具有嵌入DNA 的作用，而此作用似乎與其生物活性有關。

Although the quinoline ring is found in a wide variety of biologically active compounds and is frequently condensed with various heterocycles, synthesis and biological evaluation of the indenoquinoline skeleton attracts only very limited attention.
Synthesis of certain indeno[1,2-c]quinoline derivatives (formula I) wherein R1 represents hydrogen and halide; R2 represents hydrogen, halide, hydroxy, alkylamino, arylamino, cyclic alkylamino such as piperazine, morpholine and their substituted derivatives; R3 represents hydrogen, hydroxy, and alkylamino.
R4 represents hydrogen, alkylamino, and arylamino. The antiproliferative activities of compounds represented by formula I against human cervical epithelioid carcinoma (HeLa), oral squamous cell carcinoma (SAS),
hepatocelluar carcinoma (SKHep), human stomach adenocarcinoma (AGS),renal cancer (RCC 786-O), prostate cancer (PC-3), and non-small cell lung cancer (A549) were also evaluated since these cancers are commonly seen in
Asian countries including Taiwan. The results have shown broad and potent antiproliferactivity.
(E)-9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-3-(dimethylamino)propyl oxime, compound 15b induced the morphological changes of Hela cell including cells shrunken and membrane blebbing phenomenon. Flowcytometric analysis also indicated 15b can induce cell cycle arrest in S phase, and DNA polyploidy (> 4n) followed by apoptosis. The unwinding experiments show that compound 21a and 21b do intercalate into double-stranded DNA to get effective biological activities.

正文目錄------------------------------------------------------------------ I
表目錄--------------------------------------------------------------------- II
圖目錄--------------------------------------------------------------------- III
正文目錄
中文摘要------------------------------------------------------------------ 1
英文摘要------------------------------------------------------------------ 2
壹、緒論-------------------------------------------------------------------- 3
貳、研究背景及目的----------------------------------------------------- 11
參、合成方法、結果與討論------------------------------------------- 18
一、茚[1,2-c]喹啉類衍生物之逆合成分析---------------------- 18
二、茚[1,2-c]喹啉類衍生物之實驗結果與討論-------------- 21
肆、藥理活性結果與討論----------------------------------------------- 32
一、體外抗癌活性--------------------------------------------------- 32
二、細胞型態分析--------------------------------------------------- 48
三、細胞週期之分析------------------------------------------------ 50
四、DNA嵌入活性(DNA unwinding)分析----------------------- 52
伍、結論-------------------------------------------------------------------- 55
陸、合成實驗部份------------------------------------- 58
一、溶劑及處理過程------------------------------------------------ 58
二、儀器及試藥------------------------------------------------------ 58
三、各化合物之製備------------------------------------------------ 63
柒、藥理活性實驗方法-------------------------------------------------- 172
一、體外抗癌活性測試--------------------------------------------- 172
二、細胞型態分析--------------------------------------------------- 173
三、細胞週期之分析------------------------------------------------ 173
四、DNA嵌入活性(DNA unwinding)分析----------------------- 173
捌、參考文獻-------------------------------------------------------------- 174
玖、研究成果目錄-------------------------------------------------------- 184
一、投稿論文--------------------------------------------------------- 184
二、學會口頭論文發表--------------------------------------------- 184
三、學會壁報論文發表--------------------------------------------- 185
表目錄
表一、Camptothecin 衍生物體外肺癌細胞株之抑制活性-------- 16
表二、三環喹啉類衍生物體外癌細胞之抑制活性----------------- 17
表三、茚[1,2-c]喹啉類衍生物系列-1 體外癌細胞株之IC50 (μM) 35
表四、茚[1,2-c]喹啉類衍生物系列-2 體外癌細胞株之IC50 (μM) 38
表五、茚[1,2-c]喹啉類衍生物系列-3 體外癌細胞株之IC50 (μM) 40
表六、茚[1,2-c]喹啉類衍生物系列-4 體外癌細胞株之IC50 (μM) 42
表七、茚[1,2-c]喹啉類衍生物系列-5 體外癌細胞株之IC50 (μM) 44
表八、茚[1,2-c]喹啉類衍生物系列-6 體外癌細胞株之IC50 (μM) 45
表九、茚[1,2-c]喹啉類衍生物系列-7 體外癌細胞株之IC50(μM) 47
表十、化合物15b 對子宮頸癌細胞(Hela cell)之細胞週期分佈 51
圖目錄
圖一、細胞週期(cell cycle) --------------------------------------------- 4
圖二、DNA 嵌入藥物-------------------------------------------------- 7
圖三、拓樸異構酶抑制劑----------------------------------------------- 8
圖四、DNA 嵌入劑------------------------------------------------------- 11
圖五、DNA-Dactinomycin 結合之複合物---------------------------- 13
圖六、吲哚[3,2-c]喹啉類衍生物--------------------------------------- 14
圖七、茚[1,2-c]異喹啉類衍生物--------------------------------------- 14
圖八、茚[1,2-c]異喹啉與茚[1,2-c]喹啉電子雲密度分析---------- 15
圖九、Mechanism of 2-hydroxy-3-phenylquinoline-4-carboxylic
acid----------------------------------------------------------------
19
圖十、Mechanism of indeno[1,2-c]quinoline------------------------- 20
圖十一、Retrosynthesis of indeno[1,2-c]quinoline----------------- 20
圖十二、化合物29b之X-Ray 單晶繞射光譜------------------------ 30
圖十三、利用倒立式顯微鏡觀察細胞型態之變化----------------- 48
圖十四、利用倒立螢光顯微鏡觀察細胞型態之變化-------------- 49
圖十五、利用流式細胞儀分析細胞週期----------------------------- 50
圖十六、化合物21a 與21b 電泳分析圖------------------------------ 53
圖十七、benzimidazo[1,2-c]quinazoline 與化合物21a 結構堆疊
分析圖----------------------------------------------------------- 54

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