設計及合成二聚體抑制劑並研究其抑制類澱粉蛋白之聚集作用

Design and Synthesis of Dimeric Inhibitors against β-Amyloid Aggregation

蔡雅如(Ya-Ju Tsai)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/碩士(2011年)

https://doi.org/10.6342/NTU.2011.01251

摘要

阿茲海默氏症是常見的神經退化疾病，與類澱粉蛋白(Aβ)的聚集有關。在生物體內或體外的環境中，類澱粉蛋白彼此間會隨著時間慢慢聚集。在人體的腦中聚集的類澱粉蛋白，會形成斑塊，一般認為是造成病人記憶喪失的原因。因此，設計合成能抑制類澱粉蛋白聚集的抑制劑，對阿茲海默氏症的治療，將是一種有潛力的策略。
在本篇研究中，我們合成一系列以不同種類長度連接兩個咖啡酸的二聚體化合物，迷迭香酸結構上以醯胺鍵取代酯基的類似物與苯磺酸EDANS 的衍生物。並以硫黃素T 的螢光放射實驗檢驗類澱粉蛋白的聚集程度。初步生物活性測試的結果顯示，咖啡酸二聚體化合物抑制類澱粉蛋白聚集的能力比咖啡酸好。迷迭香酸與其類似物具有相同程度的抑制效果。而經過苯環或萘環修飾的苯磺酸EDANS 化合物，其抑制類澱粉蛋白聚集的能力有所提升。初步的結果證實，設計的抑制劑具有抑制類澱粉蛋白聚集的能力。這類型化合物將會進行更進一步的生物活性測試與研究。我們相信這類型化合物，對於阿茲海默氏症和其他神經退化疾病的藥物設計與臨床治療上，具有一定的潛力。

關鍵字

神經退化性疾病 ； 類澱粉蛋白 ； 抑制劑

並列摘要

Alzheimer’s disease (AD) is a neurodegenerative disorder and it is associated with β-amyloid (Aβ) aggregation. Aβ peptides are prone to self-aggregation, in vivo and in vitro. Aggregation of Aβ in the brain is considered the primary influence on driving AD pathogenesis. Thus, design and synthesis of potent inhibitors against Aβ aggregation is a therapeutic strategy for AD.
In this study, homodimers of caffeic acid (CA) with different linkers, some rosmarinic acid (RA) analogues and 5-((2-aminoethyl)amino)naphthalene-1-sulfonic acid (EDANS) derivatives were synthesized. Inhibition of Aβ aggregation was evaluated by thioflavin T fluorescence assay. The results revealed that dimeric CA inhibitors are more efficient than CA molecule. The assay results also indicated that RA and its analogues have ability to inhibit Aβ aggregation. In addition, modified EDANS with benzyl and naphthylmethyl amines have better efficiency than EDANS. These findings suggest that the designed inhibitors could be used to inhibit Aβ aggregation. Further development of these compounds may promise a novel therapeutic intervention for AD and other neurodegeneration diseases.

並列關鍵字

nerodegenerative disease ； β-amyloid (Aβ) ； inhibitor

參考文獻

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