| 摘要: | 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, |
