Design, Synthesis, and Evaluation of Multitarget-Directed Resveratrol Derivatives for the Treatment of Alzheimer鈥檚 Disease

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• 作者：Chuanjun Lu ; Yueyan Guo ; Jun Yan ; Zonghua Luo ; Hai-Bin Luo ; Ming Yan ; Ling Huang ; Xingshu Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5843-5859
• 全文大小：906K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer鈥檚 disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced 尾-amyloid (A尾) aggregation and Cu(II)-induced A尾_1鈥?2 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC₅₀ = 7.56 渭M and 10d, IC₅₀ = 6.51 渭M for self-induced A尾 aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured A尾 fibrils generated by self- and Cu(II)-induced A尾 aggregation. Furthermore, 5d crossed the blood鈥揵rain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD.