| Summary: | 博士 === 中國醫藥學院 === 藥物化學研究所 === 90 === 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.
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