Matos, A.M., Man, T., Idrissi, I. et al. (13 more authors) (2019) Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer’s disease : synthesis, binding affinity towards amyloid β oligomers (Aβo) and ability to disrupt Aβo-PrPC interactions. Pure and Applied Chemistry, 91 (7). pp. 1107-1136. ISSN 0033-4545
Abstract
With no currently available disease-modifying drugs, Alzheimer’s disease is the most common type of dementia affecting over 47 million people worldwide. In light of the most recent discoveries placing the cellular prion protein (PrPC) as a key player in amyloid β oligomer (Aβo)-induced neurodegeneration, we investigated whether the neuroprotective potential of nature-inspired flavonoids against Aβ-promoted toxicity would translate into the ability to disrupt PrPC-Aβo interactions. Hence, we synthesized a small library of flavones and studied their binding affinity towards Aβo by STD-NMR. C-glucosyl flavones exhibited improved binding affinity with morpholine, thiomorpholine or N-methylpiperazine rings attached to the flavone skeleton in ring B para position. Moreover, a N-methylpiperazinyl flavone displayed suitable physicochemical properties and optimal water solubility even without the sugar moiety, and a high interaction with Aβo involving the whole flavone core. Its C-glucosyl derivative, was, however, the best compound to inhibit PrPC-Aβo interactions in a dose-dependent manner, with 41 % of inhibition capacity at 10 μM. The potential of C-glucosyl flavones and their aglycones as protein-protein interaction inhibitors able to tackle PrPC-Aβo interactions is here presented for the first time, and supports this class of compounds as new prototypes for further development in the treatment of Alzheimer’s disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/. |
Keywords: | Aβo-PrPC interaction disruptors; Alzheimer’s disease; C-glucosylation; flavones; ICS-29 |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Department of Chemistry (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number ALZHEIMER'S SOCIETY 248 (AS-JF-14-001) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 Nov 2019 12:35 |
Last Modified: | 17 May 2024 15:31 |
Status: | Published |
Publisher: | De Gruyter |
Refereed: | Yes |
Identification Number: | 10.1515/pac-2019-0114 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:146983 |
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