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Title: | 類似物之合成、結構以及生物活性的研究 Studies on the Synthesis, Structural Analysis and Biological Activity of Destruxin B Aanalogs |
Authors: | AIH-JING CHIOU 邱愛菁 |
Publication Year : | 1993 |
Degree: | 碩士 |
Abstract: | 最初純化自昆蟲致病性真菌-Metarrhizium anisopliae的des-truxin B,其化學結構為 cyclo-(D-α-hydroxyl-γ-methylvaleryl-L-prolyl-L-isoleucyl-N-methyl-L-valyl-N-methyl-L-alanyl-β-alanyl) 。 根據結構-功能關係的研究報告,我們推測:結構中的酯鍵和N-甲基團,在其生物活性方面扮演很重要的角色。基於此,乃合成不同N-甲基化的destruxin B醯胺類似物,並嘗試以結構觀點來探討酯鍵與甲基團對生物活性的影響。
環狀勝?的合成,其產率主要決定於直鏈狀的胺基酸次序。而以Fmoc/NMP化學為主體的勝?固相自動合成儀,其所合成的直鏈狀醯胺類似物是將D-胺基酸(D-Leu)置淤N端,以期提高環化反應的產率而溫和的BOP/NaHCO3/DMF反應條件,最後的確得到高產率(86%)的環化結果,合成之醯胺類似物,包括dosmethyl-destruxin B-amide與protodestruxin-amide,均無天然野生種des-truxin B類似物的活性:抑制B型肝炎表面抗原基因的表現,顯然酯鍵和甲基團與生物活性有密切關聯。 架構醯胺類似物的構像時,NMR-ROESY光譜的資料是模擬程式-simulated annealing(SA)運算的距離限制。得到的十個初步SA構像,其部份勝?鍵的構型顯然與destruxin B晶體結構有明顯差異,至於它們與生物活性有無直接關聯,仍須進一步探討。 Destruxin B, first isolated from culture filtrates of the insect pathogenic fungus Metarrhizium anisopliae, is cyclo-(D-α-hydroxy-γ-methylvaleryl-L-prolyl-L-isoleucyl-N-methyl-L-valyl-N-methyl-L-alanyl- β-alanyl). According to the studies of structure-activity relationship, it was believed that the ester bond and N-methyl groups in the structure of destruxin B might play an important role in biological activity. Therefore, the analogs of destruxin B which had lactam structure and des-N-methylation were synthesized and their biological activities were also studied. In order to obtain a cyclic monomer in good yield at the cyclization step, the D-amino acid residue was placed at the N- terminus of linear precursors, which were synthesized by Fmoc/NMP chemistry of solid phase automated peptide synthesis. The yields of cyclization were very effective by BOP / NaHCO3 / DMF method. Unlike natural destruxin B and desmethyldestruxin B, these analogs including desmethyldestruxin B-amide and protodestruxinamide can’t suppress hepatitis B surface antigen gene expression in hepatoma 3B cell line. To build the tertiary structures of these analogs, NOE restraints from NMR-ROESY spectra were introduced to the simulation program---simulated annealing (SA) to calculate ten conformations. By comparison with the X-ray crystallography of destruxin B the conformation of the analogs obtained from preliminary studies show different configuration in the part of amide bonds and how the conspicuous difference in the structures correlating with their biological function remains to be investigated. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/75984 |
Fulltext Rights: | 未授權 |
Appears in Collections: | 生化科學研究所 |
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