https://scholars.lib.ntu.edu.tw/handle/123456789/179072
標題: | 尋找具生物活性的阿樸吩類化合物之有效合成策略 In Search of Effective Approaches towards the Synthesis ofioactive Aporphine Derivatives |
作者: | 黃禎嫻 Huang, Jen-Shian |
關鍵字: | 異喹啉生物鹼;5-HT7 受體;aporphine alkaloids;isoquinoline;5-HT7 | 公開日期: | 2009 | 摘要: | 阿樸吩類生物鹼(aporphine alkaloids)是一種異喹啉生物鹼(isoquinoline alkaloids),這類生物鹼是以四環結構為中心,並且在芳香環上具有不同程度的氧化。沙立樸吩(thaliporphine)是由樟科植物Lauraceae 分離出來的阿樸吩類生物鹼,其對人體內的5-HT7 受體有很高的親和力。本論文的研究目的,是以沙立樸吩為先導化合物,建立一條實用的合成路徑,得到一些不同取代基之阿樸吩類化合物,並測試其與5-HT7 受體之活性。在合成策略上,我們將此四環化合物分成上下兩環,首先透過Pictet-Spengler 反應將此兩塊結合成三環化合物,然後藉著預先置入的苯溴基,利用鈀金屬催化溴芳基,建立苯-苯鍵結,成功地架構阿樸吩四環。 另外,我們也嘗試利用Nef 反應修飾這條合成路徑,改善此路徑在合成上必須透過Wittig 反應合成偶合前驅物的缺點。以溴苯甲醛73與高藜蘆胺81為起始物算起,我們成功地利用四個步驟,合成總產率為89%的阿樸吩化合物。在我們的合成策略中,有許多反應不必經過純化步驟,就可得到產率與純度都很高產物,因此適合用來大量製備阿樸吩化合物。在生物活性方面,我們送測了三種具有不同取代基的阿樸吩化合物,得到它們與5-HT7 受體的抑制常數(Ki)。 The aporphine alkaloids, a family of isoquinoline alkaloids, is characterized by a tetracyclic motif and is oxidized on aromatic rings in different levels. Thaliporphine is an aporphine alkaloid that is separated from Lauraceae and has high affinity to the 5-HT7 receptor in human bodies. The goal of our research is to work out a practical route for the synthesis of different substituted-group aporphinoid alkaloids, using thaliporphine as a lead compound. In addition, the biological activities of our aporphine alkaloids as it binds to the 5-HT7 receptor are studied. Our synthetic strategy is to separate the tetracyclic motif into two parts. Starting from carbamate and phenylvinyl ether derivatives, Pictet-Spengler cyclization would give rise to a tricyclic structure. With the presence of a bromine handle, we successfully applied palladium-catalyzed direct arylation of aryl bromides to form the carbon-carbon linkage and construct the tetracyclic structure. In addition, we try to utilize Nef reaction to modify our synthetic strategy and improve the disadvantages of synthesizing the coupling precursors through Wittig reaction. Starting from benzyl aldehyde 73 and homoveratrylamine 81, we successfully synthesize the aporphine alkaloids via four steps and the total yield is9%. In our synthetic strategies, there are many reactions that do not need to go through purification steps and are able to obtain high-yield products with high purity.Therefore this synthetic strategy is suitable for great amount of aporphine derivatives production. As for the aspect of the biological activities, the ctivities of three compounds for the inhibitor constant to 5-HT7 receptor are examined. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/187573 |
顯示於: | 化學系 |
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ntu-98-R95223069-1.pdf | 23.32 kB | Adobe PDF | 檢視/開啟 |
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