臺灣博碩士論文加值系統

第一部分:新類型的6-(或6,7-)取代的2-(羥基取代苯基)喹啉-4-酮衍生物被合成出，並篩選其抑制腫瘤細胞增殖的活性以建立結構與活性的關係，其中最有潛力的化合物為2-(3-羥基-5-甲氧基苯基)-6-(1-吡咯烷基)喹啉-4-酮 (8)，此化合物對多株腫瘤細胞株表現出強烈的抑制活性，尤其是NCI H522非小細胞肺癌細胞株。深入研究後證實其作用機轉類似抗有絲分裂劑長春花新鹼。化合物8結構C環上的羥基提供了一個使化合物較容易形成較佳水溶性及物理化學上較安定的親水性前驅藥的基團。化合物8足以獲選作為新型抗癌藥物發展的先導化合物。
研究化合物5在人類血癌HL-60細胞株誘導細胞凋亡之機轉。化合物5造成HL-60細胞毒殺效果、細胞型態改變、降低細胞數、增加ROS生成和降低粒線體膜電位。利用末端去氧核苷酸轉移酶dUTP末端缺痕標記染色(TUNEL)證實化合物5誘導細胞凋亡。比色法與西方點墨法之結果顯示化合物5誘導增加HL-60的caspase-7/-3、caspase-8和caspase-9之活化。西方點墨法結果顯示給予化合物5會增加HL-60的外因性細胞凋亡蛋白(Fas/CD95、FasL、FADD)、內因性細胞凋亡蛋白(cytochrome c、Apaf-1、AIF和Endo G)、Bax/Bcl-2之比例和磷酸化p37 MAPK。細胞凋亡會受到N‐acetylcysteine (NAC; a ROS 清除劑)或diphenyleneiodonium chloride (DPI; a NADPH oxidase inhibitor)抑制，而細胞凋亡顯著減少。用SB202190可阻斷化合物5調控HL-60的Fas/CD95增加與細胞凋亡。綜合上述結果，化合物5可透過ROS調控p38 MAPK訊息活化而誘導外因性與內因性之HL-60的細胞凋亡。
第二部分: 作為我們持續尋找具潛力抗癌候選藥物2-苯基喹啉-4-酮的羥基衍生物的一部分，合成一系列的6-烷胺基取代2-(2或3-氟-5羥基取代苯基)喹啉-4-酮衍生物並評估其對腫瘤細胞株增殖的抑制活性。
這些化合物大多數呈現出顯著的抗癌活性。其中2-(3-氟-5-羥基取代苯基)-6-(1-吡咯烷基)喹啉-4-酮(83)是最有發展希望的。化合物83展出對多種腫瘤細胞株的抑制活性，尤其是對血癌細胞株(HL-60, Molt-4, and CCRF-CEM)的強烈抑制活性。化合物83其結構C環上的羥基提供了一個使化合物較容易衍生為較佳水溶性及物理化學性質上較安定的親水性前驅藥。化合物83足以獲選作為新型抗血癌藥物發展的先導化合物。
第三部分:2-(3-hydroxy-5-methoxyphenyl)-6,7-methylenedioxy-1H-quinolin-4-one(1) 磷酸化反應後，生成diphosphate (2). 本研究發現在溫和和反應條件下與甲醇反應，diphosphate (2)可透過簡易且高位向選擇性脫去phosphate基團，生成一磷酸酯取代於苯環上之monophosphate (3)。本實驗利用LC-MS與HPLC分析研究dephosphorylation之詳細機轉。

Part I:New 6- (or 6,7-) substituted 2-(hydroxyl substituted henyl)quinolin-4-one derivatives were synthesized and screened for antiproliferative effects against cancer cell lines. Structure-activity relationship correlations were established and the most promising compound 2-(3-hydroxy-5-methoxyphenyl)-6-pyrrolidin-1-ylquinolin-4- one (8) exhibited strong inhibitory activity against various human cancer cell lines, particularly non-small cell lung cancer NCI-H522. Additional studies suggested a mechanism of action resembling that of the antimitotic drug vincristine. The presence of a C-ring OH group in 8 will allow this compound to be converted readily to a water soluble and physiochemically stable hydrophilic prodrug. Compound 6h is proposed as a new anticancer lead compound.
To discover the signaling pathways associated with compound 5‐induced apoptosis in human leukemia HL‐60 cells. Compound 5‐induced cytotoxic effect, cell morphological changes, decreased the cell number and increased reactive oxygen species (ROS) production and loss of mitochondrial membrane potential (ΔΨm) in HL‐60 cells. Compound 5‐induced apoptosis was confirmed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Results from colorimetric assays and Western blot indicated that activities of caspase‐7/‐3, caspase‐8 and caspase‐9 were increased in compound 5‐treated HL‐60 cells. Western blot analysis showed that the protein levels of extrinsic apoptotic proteins (Fas/CD95, FasL and FADD), intrinsic related proteins (cytochrome c, Apaf‐1, AIF and Endo G), the ratio of Bax/Bcl‐2 and phosphorylated p38 MAPK were increased in HL‐60 cells after compound 5 treatment. Cell apoptosis significantly reduced after pre‐treatment with N‐acetylcysteine (NAC; a ROS scavenger) or diphenyleneiodonium chloride (DPI; a NADPH oxidase inhibitor). Blockage of p38 MAPK signaling by SB202190 abolished compound 5‐induced Fas/CD95 up‐regulation and apoptosis in HL‐60 cells. Taken together, we concluded that compound 5 induces both of extrinsic and intrinsic apoptotic pathways via ROS‐mediated activation of p38 MAPK signaling in HL‐60 human leukemia cells in vitro.
Part II:As part of our continuing search for potenticial anticancer drug candidates in hydroy derivatives of 2-phenylquinolin-4-ones, a serious of 6-alkylamino 2-(2 or 3-fluoro-5-hydroxyphenyl)quinolin-4-one derivatives was synthesized and evaluated for their antiproliferation against cancer cell lines.
Most of these compounds showed significant anticancer activity. Among them, 2-(3-fluoro-5-hydroxyphenyl)-6-pyrrolidin-1-yl- quinolin-4-one (83) was the most promising. Compound 83 exhibited strong inhibitory activity against a variety of human cancer cell lines, particularly against leukemia cell line (HL-60, Molt-4, and CCRF-CEM). Compound 83 contains a hydroxyl group at C-ring which allows it to be derived readily into water soluble and physicochemistry stable hydrophilic prodrug. Compound 83 in identified as a new lead compound for development of new anti-leukemia drug candidate.
Part III:Phosphorylation of 2-(3-hydroxy-5-methoxyphenyl)-6,7- methylenedioxy-1H-quinolin-4-one (1) afforded diphosphate 2. We found that, upon treatment with methanol under mild conditions, 1 can undergo facile and highly regioselective dephosphorylation to give the monophosphate 3, with a phosphate group remaining on the phenyl ring. The details of the dephosphorylation process were postulated and then probed by LC-MS and HPLC analyses.

第一部分
目錄...............i
圖目錄.................iii
表目錄........x
縮寫表.....................xxix
中文摘要.................xxx
英文摘要..............xxxii
第一章 緒論...........................1
第一節 癌症流行病學....1
第二節 抗癌藥之簡述................5
第三節 2-Phenyl-4-quinolone衍生物之研究概況......20
第二章 研究動機與目的.........................32
第三章 結果與討論..............38
第一節 化學合成.........38
第二節 藥理活性試驗結果.....................56
第四章 結論..............................................88
第五章 實驗方法........................89
第一節 試藥與溶媒......89
第二節 重要儀器與實驗材料...............92
第三節 化合物之製備.................................94
第四節 藥理實驗方法.................135
第六章 參考文獻.....................145
圖譜..........................................158
第二部分
目錄....... xi
圖目錄.....xiii
表目錄........xxii
中文摘要.......174
英文摘要.......176
第一章 緒論.....178
第二章 研究動機與目的....183
第三章 結果與討論.....186
第一節 化學合成......186
第二節 藥理活性試驗結果.....205
第四章 結論.......215
第五章 實驗方法....216
第一節 試藥與溶媒......216
第二節 重要儀器與實驗材料.....218
第三節 化合物之製備.......220
第四節 藥理實驗方法.......253
第六章 參考文獻......256
圖譜.......257
第三部分
目錄...............xxiii
圖目錄................xxiv
表目錄.................xxviii
中文摘要......................321
英文摘要......................323
第一章 研究動機與目的...................325
第二章 結果與討論...................327
第一節 化合物合成…………………………………...….…327
第二節Regioselective phosphorylation機轉之研究......329
第三章 結論................353
第四章 實驗方法..............354
第一節 試藥與溶媒...............354
第二節 重要儀器與實驗材料..............356
第三節 反應產物分析實驗方法...............359
第四節 化合物之光譜資料................361
第五章 參考文獻.....................369
圖........................370

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