- Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer's disease
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Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss and behavioral disturbances, ultimately leading to death. Glycogen synthase kinase 3β (GSK-3β) and dual-specificity tyrosine phosphorylation regulated kinase1A (DYRK1A) have gained a lot of attention for its role in tau pathology. To search for potential dual GSK-3β/DYRK1A inhibitors, we focused on harmine, a natural β-carboline alkaloid, which has been extensively studied for its various biological effects on the prevention of AD. In this study, a new series of harmine derivatives were designed, synthesized and evaluated as dual GSK-3β/DYRK1A inhibitors for their multiple biological activities. The in vitro results indicated that most of them displayed promising activity against GSK-3β and DYRK1A. Among them, compound ZDWX-25 showed potent inhibitory effects on GSK-3β and DYRK1A with IC50 values of 71 and 103 nM, respectively. Molecular modelling and kinetic studies verified that ZDWX-25 could interact with the ATP binding pocket of GSK-3β and DYRK1A. Western blot analysis revealed that ZDWX-25 inhibited hyperphosphorylation of tau protein in okadaic acid (OKA)-induced SH-SY5Y cells. In addition, ZDWX-25 showed good blood-brain barrier penetrability in vitro. More importantly, ZDWX-25 could ameliorate the impaired learning and memory in APP/PS1/Tau transgenic mice. These results indicated that the harmine-based compounds could be served as promising dual-targeted candidates for AD.
- Liu, Wenwu,Liu, Xin,Tian, Liting,Gao, Yaping,Liu, Wenjie,Chen, Huanhua,Jiang, Xiaowen,Xu, Zihua,Ding, Huaiwei,Zhao, Qingchun
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- Beta-carboboline GSK3beta/DYRK1A dual inhibitor and preparation method thereof and application of beta-carboboline GSK3beta/DYRK1A dual inhibitor in resisting Alzheimer's disease
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The invention discloses a beta-carboline GSK3beta/DYRK1A dual inhibitor as shown in a general formula I, a preparation method of the beta-carboline GSK3beta/DYRK1A dual inhibitor and application of the beta-carboline GSK3beta/DYRK1A dual inhibitor in resi
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- Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroaryl bromides
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A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer.
- Cant, Alastair A.,Bhalla, Rajiv,Pimlott, Sally L.,Sutherland, Andrew
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supporting information; experimental part
p. 3993 - 3995
(2012/06/05)
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