Design, synthesis and biological evaluation of harmine derivatives as potent GSK-3β/DYRK1A dual inhibitors for the treatment of Alzheimer's disease.

European Journal of Medicinal Chemistry
Wenwu LiuQingchun Zhao

Abstract

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. ...Continue Reading

References

Apr 10, 1992·Science·J A Hardy, G A Higgins
Jul 30, 1982·Science·R T BartusA S Lippa
Mar 29, 2001·Physiological Reviews·D J Selkoe
Oct 9, 2001·Mechanisms of Ageing and Development·V N Talesa
Apr 2, 2003·European Journal of Medicinal Chemistry·Li DiGuy T Carter
Jan 29, 2010·The New England Journal of Medicine·Henry W Querfurth, Frank M LaFerla
Oct 29, 2010·Nature Communications·Yasushi OgawaMasatoshi Hagiwara
Jul 28, 2011·Medicinal Research Reviews·Rafael LeónJosé Marco-Contelles
Jan 12, 2013·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Anders WimoUNKNOWN Alzheimer Disease International
Apr 10, 2013·Asian Pacific Journal of Tropical Biomedicine·K PatelDinesh Kumar Patel
Mar 22, 2015·Pharmacology & Therapeutics·Ramzi AbbassiLenka Munoz
Sep 28, 2016·European Journal of Medicinal Chemistry·Christophe LabrièreCatherine Guillou
Dec 14, 2016·Future Medicinal Chemistry·Giulia Caron, Giuseppe Ermondi
Dec 24, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Kushal KumarRahul Deshmukh
Aug 21, 2018·European Journal of Medicinal Chemistry·Jiangkun DaiJunru Wang
Sep 23, 2018·European Journal of Medicinal Chemistry·Ankita PathakM Shahar Yar
Apr 29, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kunal KumarRobert J DeVita
May 26, 2020·European Journal of Medicinal Chemistry·Wenwu LiuQingchun Zhao
Dec 22, 2020·Journal of Medicinal Chemistry·Angela De SimoneAndrea Milelli
Jan 31, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tímea SzabóMátyás Milen
Feb 3, 2021·Journal of Medicinal Chemistry·Aurélien BeatoRomain Haudecoeur
Mar 9, 2021·Journal of Medicinal Chemistry·Kunal KumarRobert J DeVita

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