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研究生:賴雅韻
研究生(外文):Lai Ya Yun
論文名稱:一、3',6-Substituted2-Phenyl-4-quinolone-3-carboxylicacid衍生物之合成及其抗癌、抗血小板、抗過敏與抗發炎活性二、生薑成分Gingerdione及Ferulamide衍生物之抗癌活性與抗幽門桿菌活性
論文名稱(外文):Part I . Synthesis and Activities of Anticancer, Anti-platelet, Anti-allergy and Anti-inflammatory of 3',6-Substituted 2-Phenyl-4-quinolone-3-carboxylic acid derivatives Part II Activities of Anticancer and Anti-Helicobacter pylori of Gingerdione and
指導教授:郭盛助郭盛助引用關係黃麗嬌黃麗嬌引用關係
指導教授(外文):Kuo Sheng-ChuHuang Li-Jiau
學位類別:博士
校院名稱:中國醫藥學院
系所名稱:藥物化學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:195
中文關鍵詞:抗癌活性細胞致毒活性抗有絲分裂細胞週期薑酮
外文關鍵詞:2-phenyl-4-quinolone-3-carboxylic acidanticancercytotoxicityantimitoticcell cycle2-PQgingerdioneferulamide
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中 文 摘 要
本研究之目的旨在研發新型之抗有絲分裂劑;此論文分成二部分,其中第一部份,著者為了改善具強效抗有絲分裂之2-phenyl-4-quinolone類化合物的水溶性,成功地合成了2-phenyl-4-quinolone-3-carboxylic acid類標的化合物及其鹽類衍生物。將所合成的標的化合物初步測試了MCF、HOS、KB、KB-VIN、SK-ME-L、HCT-8、PC-3、IA9、 HT-29等細胞株,結果發現3’-fluoro-6-methoxy-2-phenyl-4-quinolone-3-carboxylic acid (57)對大部分細胞株均有顯著的抑制作用。因此將化合物57及其tromethamine鹽類(68)提供日本癌研究會癌化學療法中心以39種human cancer cell line進行體外試驗,評估結果發現此化合物對卵巢癌細胞之OVCAR-4具高度選擇性之抑制活性,另一方面由所得到的mean graph之表現,經比對後得知化合物57與已知之抗癌藥navelbine抑制癌細胞增殖的作用模式略為相近,唯相對係數不高(R = 0.512),故作用機轉仍不盡相同。另外化合物57的tromethamine鹽類(68)對OVCAR-4及HGC2998也具相當高之選擇性的抑制活性。再者分別試驗化合物57、68對PC-3、HL-60細胞週期的影響,所得的結果皆為G2/M phase arrest。就上述結果推測化合物57、68是作用機轉特異且具高度選擇性的新型抗有絲分裂劑,頗具開發的潛力。目前這兩個化合物均正在進行動物體內試驗、抗微管聚合活性及抗血小板活性測試。
另一方面,運用電腦分子模擬軟體來建構藥效集團(pharmacophore)的實驗中,利用ligand-based drug design的方式,著者初步建立了2-phenyl-4-quinolone類衍生物與微管蛋白作用之pharmacophore,此作用部分包括二個hydrogen bond acceptor及一個 hydrophobic group。此model與已知活性之化合物接合後,能夠準確地預測真正的微管聚合抑制活性值,且與化合物57接合的結果,亦預測出此化合物有相當強之抑制活性表現,故此由電腦分子模擬所得到的藥效集團具有相當之可信度,值得做更深入之探討。
第二部分,著者從事一系列gingerdione衍生物及其相關化合物ferulamides之合成,並將這類化合物送測篩選其細胞增殖抑制及抗幽門桿菌之活性。經活性篩選結果得知化合物45、48對HL-60細胞具有明顯的抑制活性,而化合物22、23、24對U937細胞具有中等之抑制活性。而在ferulamide類衍生物中,化合物75則對HL-60及U937細胞皆具有顯著的抑制活性。頗值得作為先導化合物。至於這兩類化合物抗幽門桿菌的活性目前仍在評估之中。

Abstract
The purpose of this study was to search novel antimitotic agents. There were two parts in the thesis. Firstly, the target compounds, 3',6 substituted 2-phenyl-4- quinolone-3-carboxylic acids and their salts were successfully prepared to improve the solubility of 2-phenyl-4-quinolones, of which many compounds were potent antimitotic agents. They were preliminary offered to evaluate the activities of cell proliferation, including MCF, HOS, KB, KB-VIN, SK-ME-L, HCT-8, PC-3, IA9, HT-29 cell lines. Among them, 3'-fluoro-6-methoxy-2-phenyl-4-quinolone-3- carboxylic acid (57) was the most potent. Compound 57 and its tromethamine salt (68) proceeded to screen 39 human cancer cell lines in vitro in the Japan Cancer Chemotherapy Institute. Compound 57 demonstrated the promising and selective effect on ovarian cancer cell line (OVCAR-4), and compound 68 also showed the most active inhibitory activity against OVCAR-4 and HGC2998. After compared their mean graphs with known potent antimitotic agents by COMPARE program, the pattern of compound 57 was similar to navelbine, but not exactly the same. On the other hand, compound 57 and compound 68 were also screened cell cycle assay of PC-3 and HL-60 cancer cell lines, and both showed G2/M phase arrest. Above the results, compound 57 demonstrated a potent novel and selective antimitotic agent. Both of the two compounds have been selected for further in vivo animal assay and merit as new lead compounds of anticancer agents.
The inhibition activities of tubulin polymerization and antiplatelet activity of the target compounds are being screened.
On the other hand, we generated hypothetical pharmacophore of 2-phenyl-4- quinolone analogues for tubulin with CATALYST program. The produced pharmacophore included two hydrogen bond acceptors and one hydrophobic group. In order to demonstrate its validation, we estimated the compounds of test set. Not only the activities were precisely evaluated, but also it could forecast that compound 57 would have a promising inhibitory activity of tubulin polymerization.
Secondly, gingerdione and ferulamide derivatives were synthesized to evaluate cell proliferation activity and inhibition activity against Helicobacter pylori. Among gingerdione derivatives, 1-(3,4-dimethoxyphenyl)-3,5-dodecenedione (45) and 1-(3, 4-dimethoxylphenyl)-3,5-tetradecenedione (48) showed potent inhibition against HL-60 cell, and 1-(4-hydroxy-3-methoxyphenyl)-3,5-dodecanedione (22), 1-(4- hydroxy-3-methoxyphenyl)-3,5-tridecanedione (23) and 1-(4-hydroxy-3-methoxy phenyl)-3,5-tetradecanedione (24) have the moderate cell proliferational inhibition against U937 cell. Among the synthesized ferulamid derivatives, N,N-dimethyl- ferulamide (75) was the most potent compound in the inhibition cell proliferation activity of both HL-60 cell and U937 cell.
The assay of inhibitory activity against Helicobacter pylori has been undergone screening.

Part I 目 錄
第一章  緒論
第一節 2-phenyl-4-quinolone類緣化合物之研究概況
壹、天然植物中2-phenyl-4-quinolone類生物鹼成分的研究
貳、天然2-phenyl-4-quinolone類生物鹼之生物活性
參、合成2-phenyl-4-quinolone類化合物之生物活性
肆、2-phenyl-4-quinolone類緣化合物相關之電腦分子模擬
第二節 2-phenyl-4-quinolone-3-carboxylic acid ethyl ester衍生
物之化學合成
第三節 微管蛋白聚合抑制劑之概述
第四節 細胞週期(cell cycle)
第五節 腫瘤壞死因子(Tumor necrosis factor; TNF)
第六節 肥胖細胞與嗜中性白血球之生理功能
第七節 小神經膠質細胞之生理
第八節 抗血小板藥物之概述
第九節 研究動機與目的
第二章 研究經過
第一節 化學合成
壹、3, 4'-Substituted N-phenylbenzamides之合成
貳、3',6-Substitued 2-phenyl-4-quinolone-3-carboxylic acid
ethyl esters之合成
參、3',6-Substitued 2-phenyl-4-quinolone-3-carboxylic acids之
合成
肆、3',6-Substitued 2-phenyl-4-quinolone-3-carboxylic acid
tromethamine salts之合成
各類代表化合物之圖譜
第二節 2-Phenyl-4-quinolones類衍生物之藥效基團的建構
第三節 藥理活性試驗結果
壹、細胞致毒活性
(一)人類腫瘤細胞株之複製抑制活性(HTCL replication, human
tumor cell lines replication)
(二)利用人類癌細胞(human cancer cell line panel)評估化合
物57之抗癌活性
(三)利用人類癌細胞(human cancer cell line panel)評估化合
物68之抗癌活性
(四)與化合物57或68抗癌活性較為相近之五種抗癌藥物的概述
貳、對PC-3、HL60細胞週期的影響
參、嗜中性白血球過氧化物形成之抑制活性
肆、嗜中性白血球脫顆粒反應之抑制活性
伍、肥胖細胞脫顆粒反應之抑制活性
陸、一氧化氮蓄積之抑制活性
柒、TNF-α形成之抑制活性
第三章 結論
第四章 實驗部分
第一節 試藥、溶媒及材料第二節 重要儀器
第三節 化合物之製備
第四節 藥理實驗簡介
參考文獻
化合物之物理化學性質及光譜數據表
Part II 目 錄
第一章 緒論
第一節 薑科植物薑之研究概況及藥理活性
壹、中藥薑的化學成分
貳、薑中化學成分之合成
參、薑主成分之生理作用
肆、Gingerol衍生物之生理活性
第二節 幽門桿菌
第三節 研究動機與目的
第二章 研究經過
第一節 Gingerdione類緣化合物(16-24)之合成
第二節 1-(3,4-Substituted phenyl-3,5-alkanediones (34-39)之合

第三節 1-(3,4-Substituted phenyl-3,5-alkenediones (43-48)之合

第四節 Mono-substituted ferulamides (55-66)之合成
第五節 Di-substituted ferulamides (75-80)之合成
第三節 藥理活性試驗結果
壹、細胞致毒活性
第四章 結論
第五章 實驗部分
第一節 試藥、溶媒及材料
第二節 重要儀器
第三節 化合物之製備
第四節 藥理實驗模式
參考文獻
化合物之物理化學性質及光譜數據表

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