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Publication details

Document type
Journal articles

Document subtype
Full paper

Title
Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer’s disease: synthesis, binding affinity towards amyloid ? oligomers (A?o) and ability to disrupt A?o-PrPC interactions

Participants in the publication
Ana M. Matos (Author)
CQB - Centro de Química e Bioquímica 
Teresa Man (Author)
Imane Idrissi (Author)
Cleide C. Souza (Author)
Emma Mead (Author)
Charlotte Dunbar (Author)
Joanna Wolak (Author)
Maria C. Oliveira (Author)
David Evans (Author)
James Grayson (Author)
Benjamin Partridge (Author)
Claire Garwood (Author)
Ke Ning (Author)
Gary Sharman (Author)
Beining Chen (Author)
Amélia P. Rauter (Author)
Dep. Química e Bioquímica
CQB - Centro de Química e Bioquímica 

Scope
International

Refereeing
Yes

Summary
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.

Date of Publication
2019-07-26

Institution
FACULDADE DE CIÊNCIAS DA UNIVERSIDADE DE LISBOA

Where published
Pure and Applied Chemistry

Publication Identifiers
ISSN - 1365-3075
eISSN - 0033-4545

Publisher
Walter de Gruyter GmbH

Volume
91
Number
7

Number of pages
29
Starting page
1107
Last page
1136

Document Identifiers
URL - http://dx.doi.org/10.1515/pac-2019-0114
DOI - https://doi.org/10.1515/pac-2019-0114

Rankings
SCIMAGO Q1 (2018) - 1,24 - Chemistry (miscellaneous)

Keywords
Alzheimer’s disease C-Glucosylation Aβo-PrPC interaction disruptors Flavones ICS29

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APA
Ana M. Matos, Teresa Man, Imane Idrissi, Cleide C. Souza, Emma Mead, Charlotte Dunbar, Joanna Wolak, Maria C. Oliveira, David Evans, James Grayson, Benjamin Partridge, Claire Garwood, Ke Ning, Gary Sharman, Beining Chen, Amélia P. Rauter, (2019). Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer’s disease: synthesis, binding affinity towards amyloid ? oligomers (A?o) and ability to disrupt A?o-PrPC interactions. Pure and Applied Chemistry, 91, 1107-1136. ISSN 1365-3075. eISSN 0033-4545. http://dx.doi.org/10.1515/pac-2019-0114

IEEE
Ana M. Matos, Teresa Man, Imane Idrissi, Cleide C. Souza, Emma Mead, Charlotte Dunbar, Joanna Wolak, Maria C. Oliveira, David Evans, James Grayson, Benjamin Partridge, Claire Garwood, Ke Ning, Gary Sharman, Beining Chen, Amélia P. Rauter, "Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer’s disease: synthesis, binding affinity towards amyloid ? oligomers (A?o) and ability to disrupt A?o-PrPC interactions" in Pure and Applied Chemistry, vol. 91, pp. 1107-1136, 2019. 10.1515/pac-2019-0114

BIBTEX
@article{39348, author = {Ana M. Matos and Teresa Man and Imane Idrissi and Cleide C. Souza and Emma Mead and Charlotte Dunbar and Joanna Wolak and Maria C. Oliveira and David Evans and James Grayson and Benjamin Partridge and Claire Garwood and Ke Ning and Gary Sharman and Beining Chen and Amélia P. Rauter}, title = {Discovery of N-methylpiperazinyl flavones as a novel class of compounds with therapeutic potential against Alzheimer’s disease: synthesis, binding affinity towards amyloid ? oligomers (A?o) and ability to disrupt A?o-PrPC interactions}, journal = {Pure and Applied Chemistry}, year = 2019, pages = {1107-1136}, volume = 91 }