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系統識別號 U0007-2007201114312700
論文名稱(中文) 設計與合成N-芳香基-吲哚為抗癌試劑
論文名稱(英文) Design and synthesis of N-aryl-indole as anticancer agents
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 林子正
研究生(英文) Tzu-Cheng Lin
學號 M301098020
學位類別 碩士
語文別 中文
口試日期 2011-07-07
論文頁數 161頁
口試委員 委員-郭憲壽
委員-陳繼明
委員-林本元
指導教授-林美香
共同指導教授-劉景平
中文關鍵字 denbinobin, 吲   
英文關鍵字 indole, denbinobin, N-aryl-indole 
學科別分類
中文摘要 Denbinobin和calaquinone A皆屬於phenanthrenequinone結構的天然物,主要從蘭科植物當中分離而得;近期許多研究著重在抗癌活性性的探討上,研究結果顯示denbinobin對K-562細胞的IC50值為1.84μM,calaquinone A對於MCF-7細胞EC50值小於0.02μg/mL。截至目前為止,有許多全合成的方法被開發,但還沒有簡捷且可大量合成出denbinobin和calaquinone A的方法,本實驗室為有效地大量合成denbinobin和calaquinone A,以phenylacetic acid與benzaoldehyde進行Perkin condensation,再依序進行FeCl3氧化偶合反應、去羧基反應、AgO的對位甲氧基氧化反應…等,成功合出化合物7,再利用TMSI的選擇性去甲氧基反應可合成denbinobin,此一合成法將運用再calaquinone A的合成。

由於吲哚類化合物是一類重要的具有生物和藥物活性的分子,並被廣泛地應用在藥物合成上。因此,本篇利用吲哚為主要骨架,仿造現有的抗癌天然物的藥物活性結構,合成具強效抗癌活性的吲哚化合物。在現今常見的吲哚合成法中,本論文利用Hemetsberger-Knittel反應合成2-羧基-4,6,7-三甲氧基吲哚,再利用銅進行去羧基反應合成4,6,7-三甲氧基吲哚。將化合物51用碘化銅催化之Ullmann-type arylation成功將不同的芳香環接在吲哚的氮上,合成N-芳香基-4,6,7-三甲氧基吲哚類的化合物,最後使用氧化銀氧化合成N-芳香基-4,7-醌-6-甲氧基吲哚類化合物。仿造天然物所合成的 N-芳香基-4,6,7-三甲氧基吲哚或N-芳香基-4,7-醌-6-甲氧基吲哚的此類化合物(52-72、74-75),目前藥理活性測試尚在進行中。
英文摘要 Denbinobin and Calaquinone A are both phenanhrenequinone natural products and mainly separated from the Orchidaceae. Current studies focusing on the anticancer activity shows that denbinobin and calaquinone A exinhibited antiproliferative activity respectively against K-562 (the IC50 value of 1.84μM), and MCF-7 (the EC50 values < 0.02μg/mL) cancer cell lines. Up to date, there are many total synthetic methods have been developed, however, the concise total synthetic method is necessary to scale up denbinobin and calaquinone A. The synthetic methodology of this thesis starts from commercially available phenylacetic acids and benzaoldehydes and undergoes Perkin condensation, FeCl3 oxidation coupling reaction, decarboxylation, and quinone synthesis synthesize compound 7 subsequently reacting with TMSI to achieve demethylation to synthesize denbinobin. This synthetic approach is going to applied in the synthesis of calaquinone A as well.
Indole derivatives possess biological and therapeutic activity and are widely used in the medicinal chemistry. In an attempt to develop effective anticancer agents, therefore, this thesis utilizes the indole as the main skeleton to mimic the structure of natural product exhibiting potent anticancer activity. Hemetsberger-Knittel indole synthesis is selected among various indole synthetic approaches to synthesize 2-carboxy-4,6,7-trimethoxyindole followed by the usage of copper for decarboxylation to afford 4,6,7- trimethoxyindole (51). CuI-catalytic Ullmann-type arylation successfully introduces various aromatic rings on the nitrogen of compound 51 to furnish N-aryl-4,6,7-trimethoxyindoles. Finally, AgO oxidation is utilized to yield N-aryl-4,7-quinone-6-methoxyindoles. The pharmacological assay of the synthetic N-aryl-4,6,7-trimethoxyindoles or N-aryl-4,7-quinone-6-methoxyindoles (52-72, 74-75) is in progress.
論文目次 目錄
目錄-------------------------------------------------------I
表目錄---------------- -----------------------------------IV
圖目錄-----------------------------------------------------V
流程目錄------------------------------------------------VIII
附錄目錄--------------------------------------------------IX
中文摘要---------------------------------------------------X
英文摘要--------------------------------------------------XI

壹、 緒論
1.1 前言---------------------------------------------------1
1.2 抗癌藥物的天然物---------------------------------------3
1.3 研發中的抗癌天然物-------------------------------------9
貳、 Denbinobin & Calaquinone A
2.1 Denbinobin & Calanquinone A介紹-----------------------13
2.2 Denbinobin & Calanquinone A全合成回顧-----------------19
2.3 Denbinobin和calanquinone A逆合成設計------------------25
2.4 Denbinobin和calanquinone A的全合成--------------------29
2.5結果與討論---------------------------------------------41
參、 Denbinobin與Calaquinone A的Indole衍生物
3.1 Indole(吲哚)簡介--------------------------------------42
3.2吲哚類衍生物的研究構想與設計---------------------------43
3.3吲哚類衍生物的合成-------------------------------------47
3.4 結果與討論--------------------------------------------54
肆、 結果與貢獻討論-----------------------------------55
伍、 實驗部分
5.1實驗儀器與溶劑-----------------------------------------57
5.2化合物實驗方法與光譜資料
化合物28合成方法--------------------------------------59
化合物30合成方法--------------------------------------60
化合物32合成方法--------------------------------------61
化合物33合成方法--------------------------------------62
化合物35合成方法--------------------------------------63
化合物36合成方法--------------------------------------64
化合物37合成方----------------------------------------65
化合物39合成方法--------------------------------------66
化合物40合成方法--------------------------------------67
化合物41合成方法--------------------------------------68
化合物42合成方法--------------------------------------69
化合物43合成方法--------------------------------------70
化合物44合成方法--------------------------------------71
化合物45合成方法--------------------------------------72
化合物46合成方法--------------------------------------73
化合物7合成方法---------------------------------------74
化合物47合成方法--------------------------------------75
化合物48合成方法--------------------------------------76
化合物49合成方法--------------------------------------77
化合物50合成方法--------------------------------------78
化合物51合成方法--------------------------------------79
化合物52合成方法--------------------------------------80
化合物53合成方法--------------------------------------81
化合物54合成方法--------------------------------------82
化合物55合成方法--------------------------------------83
化合物56合成方法--------------------------------------84
化合物57合成方法--------------------------------------85
化合物58合成方法--------------------------------------86
化合物59合成方法--------------------------------------87
化合物60合成方法--------------------------------------88
化合物61合成方法--------------------------------------89
化合物62合成方法--------------------------------------90
化合物63合成方法--------------------------------------91
化合物64合成方法--------------------------------------92
化合物65合成方法--------------------------------------93
化合物66合成方法--------------------------------------94
化合物67合成方法--------------------------------------95
化合物68合成方法--------------------------------------96
化合物69合成方法--------------------------------------97
化合物70合成方法--------------------------------------98
化合物71合成方法--------------------------------------99
化合物72合成方法-------------------------------------100
化合物73合成方法-------------------------------------101
化合物74-B合成方法-----------------------------------102
化合物74合成方法-------------------------------------103
化合物75合成方法-------------------------------------104
陸、 參考文獻----------------------------------------105
附錄-----------------------------------------------------110
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