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研究生:孫揚盛
研究生(外文):YangSheng Sun
論文名稱:對羥苯丙酮酸雙氧酶與受質及抑制劑結合之分子模擬研究及潛在切斷DNA化合物2,6-雙甲氧基苯醌羧酸之合成嘗試
論文名稱(外文):Molecular Modeling of Substrate and Inhibitor Binding in 4-Hydroxyphenyl- pyruvate Dioxygenase and Synthesis of 2,6-Dimethoxybenzoquinone Carboxylic Acid as a Potential DNA Cleavage Agent
指導教授:楊定亞
指導教授(外文):DingYah Yang
學位類別:碩士
校院名稱:東海大學
系所名稱:化學系
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:98
中文關鍵詞:分子模擬自動嵌合26-雙甲氧基苯醌羧酸對羥苯丙酸雙氧
外文關鍵詞:molecular modelingAutoDock26-dimethoxybenzoquinone4-Hydroxyphenyl- pyruvate Dioxygenase
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本論文的第一部分為以對羥苯丙酮酸雙氧酶(4-hydroxyphenylpyruvate dioxygenase,4-HPPD)此一酵素之三度空間結構為研究主體,先以自動嵌合(Automated Docking,AutoDock)軟體尋找4-HPPD活化中心附近之受質對羥苯丙酮酸(4-hydroxyphenylpyruvate,4-HPP)及抑制劑(2-(2-nitro-4-trifloromethylbenzoyl)cyclohexa-1,3-dione,NTBC)之可能結合位置,再以InsightII軟體中的Discover及Docking模組建構出4-HPPD和4-HPP及NTBC之最佳結合位置,結果顯示4-HPP與4-HPPD之結合位置與文獻報導相符合,而NTBC與4-HPPD中的胺基酸殘基也有類似的結合作用力存在。
佘亮博士發現一些具有2,6-雙甲基苯醌的衍生物如2,6-雙甲基苯醌-3-硫醋酸(2,6-Dimethoxyhydroquinone- 3-mercaptoacetic acid, DMQ-MA),此類化合物在體外實驗(in vitro)對癌細胞有不錯的抑制效果,但因DMQ-MA此化合物具有硫原子易水解,若進行體內實驗(in vivo)藥物尚未到達目標區就水解而無作用,而本實驗室先前曾合成一化合物4-methoxy-3,6-dioxocyclohexa-1,4-dienyl acetic acid methyl ester具有類似苯醌的結構,經測試有不錯的抑制效果,但此化合物合成步驟過多,因此我們設計並嘗試以較少的合成步驟合成一新的類似衍生物2,6-雙甲氧基苯醌羧酸,期望此化合物具有更佳的抑制效果。

The thesis use the three-dimensional space of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) as the principal part of the research. The first, we use AutoDock (Automated Docking) software to find the probable binding site in the active site of 4-HPPD with substrate 4-hydroxyphenylpyruvate (4-HPP) and inhibitor 2-(2-nitro-4-trifloromethylbenzoyl)cyclohexa-1,3-dione (NTBC). Then we use Discover and Docking modules of Insight II software to model the best binding site of 4-HPPD with 4-HPP and NTBC. The result display the binding site of 4-HPPD with 4-HPP fit in with the paper, and there are the resembling binding force in the amino acid residues of 4-HPPD with NTBC.
Dr. Sheh discovered some derivatives of 2,6-dimethoxyhydroquinone-3-mercaptoacetic acid (DMQ-MA). The compounds have good inhibit effect with cancer cells (in vitro) but DMQ-MA hydrolysis easily because of sulfur atom. If we use DMQ-MA to proceed an in vivo experiment, the drug easily hydrolysis without affecting and does not reach the target. Our Lab synthesized the compound 4-methoxy-3,6-dioxocyclohexa-1,4-dienyl acetic acid methyl ester which has the similar structure of benzoquinone. After test, it was also a good inhibitor, but the steps of the copound was too much. So we design and test the less synthesis steps for a new likely compound 2,6-dimethoxybenzoquinone, we expect it is a better inhibitor.

第一部分、對羥苯丙酮酸雙氧酶與受質及抑制劑結合之分子模擬研究
壹、 緒論………………………………… ……………………………2
貳、 結果與討論……………………… …………………………..…20
參、 結論………………………………………………………….……29
肆、 實驗部份……..…………………………………………….……30
伍、 儀器及軟體……………………………………………………….33
陸、 參考文獻………………………………………………………….34
柒、 計算數據………………………………………………………….36
第二部分、潛在切斷DNA化合物2,6-雙甲氧基苯醌羧之合成嘗試
壹、 緒論………………………………………………………….74
貳、結果與討論…………………………………………………..……79
參、結論………………………………………………….……….……84
肆、實驗部分……………………………………………………………85
伍、參考文獻……………………………………………………………90
陸、光譜資料…………………………………………………………..92

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