3,3鈥?4鈥?5,5鈥?Pentahydroxyflavone is a potent inhibitor of amyloid 尾 fibril formation

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• 作者：Hiroko Ushikubo^a ; Sayaka Watanabe^a ; Yui Tanimoto^a ; Kazuho Abe^a ; Aiki Hiza^b ; Takahiro Ogawa^b ; Tomohiro Asakawa^b ; Toshiyuki Kan^b ; Tatsuhiro Akaishi^a ; ^{tatuaka@musashino-u.ac.jp}
• 关键词：Alzheimer's disease ; Amyloid 尾 protein ; Fisetin ; Flavonoids ; 3 ; 3&prime ; 4&prime ; 5 ; 5&prime ; -Pentahydroxyflavone
• 刊名：Neuroscience Letters
• 出版年：2012
• 期刊代码：52_03043940
• 类别：neu
• 出版时间：28 March, 2012
• 卷：513
• 期：1
• 页码：51-56
• 文件大小：822 K

摘要

The natural flavonoid fisetin (3,3鈥?4鈥?7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid 尾 protein (A尾). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease. To find even more effective drugs based on the structure of fisetin, we synthesized a series of fisetin analogues lacking the 7-hydroxyl group and compared their effects on A尾 fibril formation determined by the thioflavin T fluorescence assay. 3,3鈥?4鈥?Trihydroxyflavone and 3鈥?4鈥?dihydroxyflavone inhibited A尾 fibril formation more potently than fisetin or 3鈥?4鈥?7-trihydroxyflavone, suggesting that the 7-hydroxy group is not necessary for anti-amyloidogenic activity. 3,3鈥?4鈥?5鈥?Tetrahydroxyflavone and 3鈥?4鈥?5鈥?trihydroxyflavone inhibited A尾 fibril formation far more potently than 3,3鈥?4鈥?trihydroxyflavone and 3鈥?4鈥?dihydroxyflavone, suggesting that 3鈥?4鈥?5鈥?trihydroxyl group of the B ring is crucial for the anti-amyloidogenic activity of flavonoids. Based on the structure-activity relationship, we synthesized 3,3鈥?4鈥?5,5鈥?pentahydroxyflavone, and confirmed that this compound is the most potent inhibitor of A尾 fibril formation among fisetin analogues that have been tested. Cytotoxicity assay using rat hippocampal neuron cultures demonstrated that A尾 preincubated with 3,3鈥?4鈥?5,5鈥?pentahydroxyflavone was significantly less toxic than A尾 preincubated with vehicle. 3,3鈥?4鈥?5,5鈥?Pentahydroxyflavone could be a new therapeutic drug candidate for the treatment of Alzheimer's disease.