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Publication details

Document type
Journal articles

Document subtype
Full paper

Title
Glucosylpolyphenols as Inhibitors of A?-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

Participants in the publication
Ana M. de Matos (Author)
M. Teresa Blázquez-Sánchez (Author)
Andreia Bento-Oliveira (Author)
Rodrigo F. M. de Almeida (Author)
Dep. Química e Bioquímica
CQE-Ciências - Centro de Química Estrutural-Ciências
Rafael Nunes (Author)
Dep. Química e Bioquímica
BIOISI - Instituto de Biossistemas e Ciências Integrativas
Pedro E. M. Lopes (Author)
Miguel Machuqueiro (Author)
Dep. Química e Bioquímica
BIOISI - Instituto de Biossistemas e Ciências Integrativas
Joana S. Cristóvão (Author)
Cláudio M. Gomes (Author)
Dep. Química e Bioquímica
BIOISI - Instituto de Biossistemas e Ciências Integrativas
Cleide S. Souza (Author)
Imane G. El Idrissi (Author)
Nicola A. Colabufo (Author)
Ana Diniz (Author)
Filipa Marcelo (Author)
M. Conceição Oliveira (Author)
Óscar López (Author)
José G. Fernandez-Bolaños (Author)
Philipp Dätwyler (Author)
Beat Ernst (Author)
Ke Ning (Author)
Claire Garwood (Author)
Beining Chen (Author)
Amélia P. Rauter (Author)
Dep. Química e Bioquímica
CQE-Ciências - Centro de Química Estrutural-Ciências

Scope
International

Refereeing
Yes

Summary
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 that are 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 nontoxic 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.

Date of Publication
2020-09-22

Where published
Journal of Medicinal Chemistry

Publication Identifiers
ISSN - 0022-2623

Publisher
American Chemical Society (ACS)

Volume
63
Number
20

Number of pages
27
Starting page
11663
Last page
11690

Document Identifiers
DOI - https://doi.org/10.1021/acs.jmedchem.0c00841
URL - http://dx.doi.org/10.1021/acs.jmedchem.0c00841
DOI - https://doi.org/10.1021/acs.jmedchem.0c00841

Rankings
Web Of Science Q1 (2020) - 6.205 - Chemistry, Medicinal
SCIMAGO Q1 (2019) - 2.093 - Drug Discovery
SCIMAGO Q1 (2019) - 2.093 - Molecular Medicine
SCOPUS Q1 (2019) - 11.3 - Drug Discovery
SCOPUS Q1 (2019) - 11.3 - Molecular Medicine
Web Of Science 6.205 (2019) - Q1 - CHEMISTRY, MEDICINAL-SCIE

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APA
Ana M. de Matos, M. Teresa Blázquez-Sánchez, Andreia Bento-Oliveira, Rodrigo F. M. de Almeida, Rafael Nunes, Pedro E. M. Lopes, Miguel Machuqueiro, Joana S. Cristóvão, Cláudio M. Gomes, Cleide S. Souza, Imane G. El Idrissi, Nicola A. Colabufo, Ana Diniz, Filipa Marcelo, M. Conceição Oliveira, Óscar López, José G. Fernandez-Bolaños, Philipp Dätwyler, Beat Ernst, Ke Ning, Claire Garwood, Beining Chen, Amélia P. Rauter, (2020). Glucosylpolyphenols as Inhibitors of A?-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, 11663-11690. ISSN 0022-2623. eISSN . http://dx.doi.org/10.1021/acs.jmedchem.0c00841

IEEE
Ana M. de Matos, M. Teresa Blázquez-Sánchez, Andreia Bento-Oliveira, Rodrigo F. M. de Almeida, Rafael Nunes, Pedro E. M. Lopes, Miguel Machuqueiro, Joana S. Cristóvão, Cláudio M. Gomes, Cleide S. Souza, Imane G. El Idrissi, Nicola A. Colabufo, Ana Diniz, Filipa Marcelo, M. Conceição Oliveira, Óscar López, José G. Fernandez-Bolaños, Philipp Dätwyler, Beat Ernst, Ke Ning, Claire Garwood, Beining Chen, Amélia P. Rauter, "Glucosylpolyphenols as Inhibitors of A?-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" in Journal of Medicinal Chemistry, vol. 63, pp. 11663-11690, 2020. 10.1021/acs.jmedchem.0c00841

BIBTEX
@article{47120, author = {Ana M. de Matos and M. Teresa Blázquez-Sánchez and Andreia Bento-Oliveira and Rodrigo F. M. de Almeida and Rafael Nunes and Pedro E. M. Lopes and Miguel Machuqueiro and Joana S. Cristóvão and Cláudio M. Gomes and Cleide S. Souza and Imane G. El Idrissi and Nicola A. Colabufo and Ana Diniz and Filipa Marcelo and M. Conceição Oliveira and Óscar López and José G. Fernandez-Bolaños and Philipp Dätwyler and Beat Ernst and Ke Ning and Claire Garwood and Beining Chen and Amélia P. Rauter}, title = {Glucosylpolyphenols as Inhibitors of A?-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 = {Journal of Medicinal Chemistry}, year = 2020, pages = {11663-11690}, volume = 63 }