異？？類生物鹼之新合成法開發及抗癌活性研究

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Title:	異？？類生物鹼之新合成法開發及抗癌活性研究
Authors:	莊大賢(Ta-Hsien Chuang)
Contributors:	藥學院藥學系
Date:	2012-07-31
Issue Date:	2012-06-15 11:45:11 (UTC+8)
Abstract:	酮基阿朴芬是一種???生物鹼。此含氮四環骨架的酮基阿朴芬化合物?僅廣泛分佈於許多植物，亦展現?相當多重要的生物活性，因此這種四環生物鹼一直受到許多有機合成學家的注意。本計畫將開發3-或4-羥基 ???的新合成法，並以已知具抗癌活性之天然物liriodenine 為設計起點，將此新合成法應用在4-或5-甲氧基-7-酮基阿朴芬生物鹼的合成並進?抗癌活性測試，以開發出?佳抗癌活性之藥物。本計畫將分以下三階段完成： (A) 4-羥基???之新合成法開發：我們設計?用瞬空熱解設備，將亞胺化合物加熱脫去乙醇產生乙烯酮，經電子環化重排反應，然後芳香化得到4-羥基???。此反應?僅為一種合成4-羥基???的新方法；另外，亦可進一步瞭解在無溶劑效應之影響下，苯環及C=N 雙鍵上取代基對電子環化反應的影響。 (B) 3-羥基???之新合成法開發：到目前為止，尚未有人探討有關苯炔與2-氮雜-1,3-丁二烯的[4+2]環化反應，?用此合成法?合成3-羥基???是一相當方?的合成方式。我們 ?用高反應活性之苯炔與含三烷基矽氧之二烯化合物，進?環合反應後水解合成3-羥基???，並藉由UV 光譜深入探討取代基與溶劑效應對內醯亞胺與內醯胺的互變?構轉換之影響。 (C) 酮基阿朴芬?生物鹼的合成及其抗癌活性研究：在藥?學方面，酮基阿朴芬?生物鹼展現?相當多重要的生物活性。我們將合成羥基???的方法應用到酮基阿朴芬的合成，除提供建?此? 特殊骨架的新合成法，並將所合成之生物鹼進?抗癌活性測試，進而探討此?型生物鹼結構與抗癌活性的關係，未?有希望開發出抗癌活性效果? 佳之7-酮基阿朴芬?藥物。 Oxoaporphine is one of a class of isoquinolines. The alkaloids, fused nitrogen-containing tetracyclic compounds, are found in a wide variety of plants and have received considerable synthetic attention due to their profound biological activities. The proposal, based on the well-known anticancer activities natural product, liriodenine, would focus on developing the novel syntheses of 3- and 4-hydroxylisoquinolines and applying the methods to the synthesis of 4- and 5-methoxy-7-oxoaporphines. These alkaloids would be conducted for the preliminary screening tests for their anticancer activities. It’s helpful to develop the novel anticancer drugs. The plan can be categorized in the following three directions: (A) Synthesis of 4-hydroxylisoquinolines: We propose using the technique of flash vacuum thermolysis to synthesize 4-hydroxylisoquinolines via the electrocyclic reaction of ketene generated by the loss of ethanol from imine, followed by the hydrogen rearrangement. It is not only a novel method to obtain 4-hydroxylisoquinolines, but it also helps us to realize the influence of substituents in the benzene ring or the C=N double bond on the electrocyclic reaction without solvent effects. (B) Synthesis of 3-hydroxylisoquinolines: To our knowledge, the reaction of benzyne with 2-aza-1,3-butadiene is seldom found in literature. We design a novel synthetic method to acquire 3-hydroxylisoquinolines via condensation of the active benzyne with 2-aza-1,3-bis(t-butyldimethylsilyloxy)-1,3-butadiene followed by hydrolysis. It is a convenient methodology for the synthesis of 3-hydroxylisoquinolines. In addition, we’ll also discuss the lactim-lactam tautomerism of the substituted 3-hydroxylisoquinolines on the basis of their UV spectra in various solvents. (C) Synthesis and anticancer activity test of oxoaporphine: Oxoaporphine is one of the important biologically active alkaloids in pharmaceutical studies. We apply the synthetic methods in hydroxylisoquinolines to the synthesis of oxoaporphine, and proceed with the preliminary screening tests of these alkaloids for their anticancer activities. We provide a new route approaching to the tetracyclic alkaloids, and discuss the structure-activity relations in the proposal. It would be helpful to develop better oxoaporphine drugs.
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