de Matos, A.M., Blázquez-Sánchez, M.T., Bento-Oliveira, A. et al. (20 more authors) (2020) Glucosylpolyphenols as inhibitors of Aβ-induced Fyn kinase activation and Tau phosphorylation: synthesis, membrane permeability, and exploratory target assessment within the scope of type 2 diabetes and Alzheimer’s disease. Journal of Medicinal Chemistry, 63 (20). pp. 11663-11690. ISSN 0022-2623
Abstract
Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer’s disease, and diabetes-induced dementia, there are no disease-modifying therapies able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer’s drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation, while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and β-glucosidase. Both compounds are non-toxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Chemical Society. This is an author-produced version of a paper subsequently published in Journal of Medicinal Chemistry. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 29 Sep 2020 09:18 |
Last Modified: | 25 Jan 2022 17:20 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Refereed: | Yes |
Identification Number: | 10.1021/acs.jmedchem.0c00841 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:166108 |