臺灣博碩士論文加值系統

本研究已合成一系列三環平面吡啶[3,2-g]喹啉(pyrido-[3,2-g]-
quinoline)類的衍生物，並進行九大癌細胞六十類癌細胞株之細胞毒性評估；其中化合物9a (diethyl 4,6-diamino-10-methyl-
pyrido-[3,2-g]quinoline-3,7-dicarboxylate) 及9d (diethyl- 4,6-bis-(3-dimethylaminopropylamino)-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxylate)對乳癌(MCF-7)、肺癌(NCI-H460)、神經癌(SF-268)及兩種攝護腺癌(LNCaP、PC-3)細胞具有良好的細胞毒活性；進一步評估9a，9b，9c，及9d等化合物對抗乳癌(MCF-7)及兩種攝護腺癌(LNCaP、PC-3)細胞成長的活性，結果顯示降低細胞毒活性的排序為9d > 9a > > 9b及9c；而9d對兩種攝護腺癌細胞(LNCaP、PC-3)及乳癌細胞(MCF-7)之IC50分別為5.63、6.42及3.96 ?戥M；本研究將9d進行細胞週期分析，其結果顯示對9d 抑制LNCaP、MCF-7細胞生長乃由於G1 arrest，隨後並誘發細胞凋亡(apoptosis)；本研究進一步透過Annexin V-FITC及PARP 之裂解模式，確認9d可對LNCaP細胞誘發凋亡。
為了探討9d引發細胞凋亡之機制，本研究進行一些與細胞週期調節有關的蛋白質，包括p53和其下游因子p21及與細胞週期進行有關的cyclin D1、cyclin E、 retinoblastoma (Rb)、phoso-retinoblastoma (pRb)及 c-Myc之研究；結果顯示p53有些微增加，但p21並無變化，此結果表示p21可能不是造成G1 arrest的因子；另外，cyclin D1及cyclin E僅在9d 濃度80 ?戥M時才會減少；相反地，c-Myc、Rb及pRb則隨時間及藥物濃度增加而明顯減少。因此，本研究進一步檢測與c-Myc有關之上游調節因子：Erk1/2和phospho-Erk1/2(p-Erk1/2)，結果發現9d對Erk1/2並無影響，但當9d 濃度5 ?戥M 24小時p- Erk1/2即有增加的現象，顯示9d對LNCaP細胞週期之作用可能是經由p-Erk1/2 路徑影響c-Myc之減少而造成G1 arrest。

The present report describes the synthesis and evaluation of tricyclic pyrido[3,2-g]quinoline derivatives in which an additional pyridine ring is linearly fused on the antibacterial quinoline-3-carboxylic acid. Among them, only both diethyl 4, 6- diamino -10- methylpyrido-
[3,2-g]quinoline-3,7-dicarboxylate (9a) and diethyl 4,6-bis-(3-dimethyl-
aminopropylamino) -10- methylpyrido[3,2-g]quinoline-3,7-dicarboxylate
(9d) were able to inhibit cell proliferation of MCF-7 (Breast), NCI-H460 (Lung), and SF-268 (CNS) implying either amino or dimethylaminopropyl moiety at C-4 and C-6 positions is crucial for the antiproliferative activity of pyrido[3,2-g]quinoline derivatives. Compounds 9a – 9d were further evaluated for their activity against the growth of MCF-7 and two prostate cancer cell lines, LNCaP and PC-3. Results indicated the antiproliferative activity decreased in an order 9d > 9a >> 9b and 9c. Compound 9d was the most cytotoxic with an IC50 value of 5.63 and 3.96 ?戥M, respectively, against LNCaP and MCF-7. Flow cytometric analyses revealed that growth inhibition of LNCaP by 9d was due to cell cycle arrest in G1 phase, and followed by apoptosis. We further confirmed this 9d-induced apoptosis by Annexin V-FITC and cleavage pattern of PARP in LNCaP cells.
To delineate the molecular mechanism of 9d-induced apoptosis, we examined the protein level of several cell cycle regulators including p53 and its downstream target(p21), cyclin D1, cyclin E, Rb, pRb and c-Myc. The results demonstrated that p53 was slightly increased but its target, p21, was not changed by treatment of 9d, suggesting p21 might not be a factor responsible for G1 arrest. Moreover, both cyclin D1 and cyclin E were decreased only in the presence of 80 ?戥M of 9d. In constrast, c-Myc, Rb and pRb were significantly reduced by 9d. Thus, we further examined the upstream regulators, Erk1/2 and p-Erk1/2 related to c-Myc. We found that 9d did not have the influence on Erk1/2, but it made p-Erk1/2 increase under the 5 ?戥M at 24 h. It indicated that the function of 9d to LNCaP cell cycle was probable by the effect of p-Erk1/2 on the decrease of c-Myc and then G1 arrest showed.

中文摘要 ……………………………………… 1
英文摘要 ……………………………………… 3
第一章 緒論 ……………………………… 5
第二章 研究背景與動機 ………………………………… 30
第三章 合成方法 …………………………………… 41
第四章 結果與討論 ……………………….……..……..…… 49
第一節 細胞毒活性評估 .………………….……...………… 49
第二節 細胞毒活性結果與討論 ………………….…...…….… 52
第五章 結論 …………………………………………………. 68
第六章 實驗部分 …………………………...……………..… 69
第一節 儀器、試藥與抗體 ………………………………… 69
第二節 實驗材料與方法 …………………...……………… 75
第三節 各化合物的製備 ……………...…………………… 85
(一) Diethyl 4,6-dihydroxy-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxylate衍生物的製備 (2-3)….…..….. 86
(二) Diethyl 4,6-dimethoxy-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxylate衍生物的製備 (4a-5b) ………. 88
(三) 4,6-Dihydroxy-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxamide衍生物的製備 (6a-6c) ………………… 92
(四) Diethyl 4,6-dichloro-10-methylpyrido[3,2-g]quinoline-3,7-dicarboxylate的製備 (7) ……………… 95
(五) Diethyl 10-methyl-4,6-bisphenylaminopyrido[3,2-g]-
quinoline-3,7-dicarboxylate衍生物的製備 (8a-8c) …96
(六) Diethyl 4,6-diamino-10-methylpyrido[3,2-g]quinoline-
3,7-dicarboxylate衍生物的製備 (9a-9d) .……………… 99
(七) Diethyl 2-{[3-(carbonylvinylamino)-2-methylphenyl-
amino]- methylene}malonate的製備 (10a) …………… 103
(八) Diethyl 2-{[3-(2,2-bisacetylcarbonylvinylamino)-2-methylphenylamino]- methylene}malonate的製備 (10b)
……………………………………………………………. 104
(九) 4,6-Dihydroxy-10-methylpyrido[3,2-g]quinoline的製備
(11a) ………………..………………………….….….….. 105
(十) 3,7-Diacetyl-4,6-dihydroxy-10-methylpyrido[3,2-g]-
quinoline的製備 (11b) …………………….…....……... 106
(十一) 4,6-Dichloro-10-methylpyrido[3,2-g]quinoline 的製備 (12a) ……..……………………………………………… 107
(十二) 4,6-Bismethylamino-10-methylpyrido[3,2-g]quinoline
的製備 (13) ……………..……..…………….…….…… 108
(十三) 4,6-Bisphenylamino-10-methylpyrido[3,2-g]quinoline
衍生物的製備 (14a-14c) …………………..….......……. 109
(十四) 2,6-Bis(2’,2’-dicarboethoxyvinylamino)-4-methylphenol的製備 (15a) …………………..……...….….. 112
(十五) 2,6-Bis(2’,2’-dicarboethoxyvinylamino)-4-methylbenzoic acid 的製備 (15b) ………….… 113
第六章 參考文獻 ………………..…………..…..…. 114
第七章 研究成果目錄 …………………………… 129

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