Inhibition of amyloid fibril formation and cytotoxicity by caffeic acid-conjugated amyloid-β C-terminal peptides

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• 作者：Takuya Arai^a ; ^b ; Akiko Ohno^c ; Kazunori Mori^b ; Hiroshi Kuwata^b ; Mirei Mizuno^b ; Kohei Imai^b ; Shuntaro Hara^b ; Motoko Shibanuma^b ; Masaaki Kurihara^c ; Naoki Miyata^a ; Hidehiko Nakagawa^a ; Kiyoshi Fukuhara^b ; ^{fukuhara@pharm.showa-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Aβ ; amyloid-β ; AD ; Alzheimer&rsquo ; s disease ; CA ; caffeic acid ; DCFH-DA ; 2&prime ; 7&prime ; -dichlorodihydrofluorescein diacetate ; DHCA ; dihydrocaffeic acid ; DIPEA ; N ; N-diisopropylethylamine ; DMF ; N ; N-dimethylformamide ; DMSO ; dimethyl sulfoxide ; Gly ; glycine ; HBTU ; O-(benzotriazol-1-yl)- N ; N ; N&prime ; N&prime ; -tetramethyluronium hexafluorophosphate ; HFIP ; 1 ; 1 ; 1 ; 3 ; 3 ; 3-hexafluoro-2-propanol ; HOBt ; 1-hydroxybenzotriazole ; HRMS ; high resolution mass spectrometry ; PI ; propidium iodide ; ROS ; reactive oxy
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：26
• 期：22
• 页码：5468-5471
• 全文大小：555 K

文摘

Amyloid-β (Aβ) deposition and oxidative stress observed in the brains of patients with Alzheimer’s disease (AD) are important targets for therapeutic intervention. In this study, we conjugated the antioxidants caffeic acid (CA) and dihydrocaffeic acid (DHCA) to Aβ_1–42 C-terminal motifs (Aβ_x–42: x = 38, 40) to synthesize CA-Aβ_x–42 and DHCA-Aβ_x–42, respectively. Among the compounds, CA-Aβ_38–42 exhibited potent inhibitory activity against Aβ_1–42 aggregation and scavenged Aβ_1–42-induced intracellular oxidative stress. Moreover, CA-Aβ_38–42 significantly protected human neuroblastoma SH-SY5Y cells against Aβ_1–42-induced cytotoxicity, with an IC₅₀ of 4 μM. These results suggest that CA-Aβ_38–42 might be a potential lead for the treatment of AD.