設計與合成N-芳香基-吲哚為抗癌試劑

Design and synthesis of N-aryl-indole as anticancer agents

林子正(Tzu-Cheng Lin)

指導教授 ： 林美香

共同指導教授 ： 劉景平

臺北醫學大學/藥學院/藥學研究所/碩士(2011年)

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。

關鍵字

denbinobin, 吲哚

並列摘要

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.

並列關鍵字

indole, denbinobin, N-aryl-indole

參考文獻

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