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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

  • Ana M. de Matos
    Ana M. de Matos
    Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • M. Teresa Blázquez-Sánchez
    M. Teresa Blázquez-Sánchez
    Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Andreia Bento-Oliveira
    Andreia Bento-Oliveira
    Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Rodrigo F. M. de Almeida
    Rodrigo F. M. de Almeida
    Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Rafael Nunes
    Rafael Nunes
    Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
    Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
    More by Rafael Nunes
  • Pedro E. M. Lopes
    Pedro E. M. Lopes
    Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Miguel Machuqueiro
    Miguel Machuqueiro
    Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Joana S. Cristóvão
    Joana S. Cristóvão
    Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Cláudio M. Gomes
    Cláudio M. Gomes
    Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
  • Cleide S. Souza
    Cleide S. Souza
    Department of Chemistry, The University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF, United Kingdom
  • Imane G. El Idrissi
    Imane G. El Idrissi
    Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, Via Orabona, 4, 70125 Bari, Italy
  • Nicola A. Colabufo
    Nicola A. Colabufo
    Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “A. Moro”, Via Orabona, 4, 70125 Bari, Italy
  • Ana Diniz
    Ana Diniz
    UCIBIO, REQUIMTE, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica 2829-516, Portugal
    More by Ana Diniz
  • Filipa Marcelo
    Filipa Marcelo
    UCIBIO, REQUIMTE, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica 2829-516, Portugal
  • M. Conceição Oliveira
    M. Conceição Oliveira
    Mass Spectrometry Facility at CQE, Insituto Superior Técnico, Av. Rovisco Pais, Lisboa 1049-001, Portugal
  • Óscar López
    Óscar López
    Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, Sevilla E-41071, Spain
  • José G. Fernandez-Bolaños
    José G. Fernandez-Bolaños
    Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, Sevilla E-41071, Spain
  • Philipp Dätwyler
    Philipp Dätwyler
    Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland
  • Beat Ernst
    Beat Ernst
    Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, Basel CH-4056, Switzerland
    More by Beat Ernst
  • Ke Ning
    Ke Ning
    Department of Neuroscience, Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, United Kingdom
    More by Ke Ning
  • Claire Garwood
    Claire Garwood
    Department of Neuroscience, Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield S10 2HQ, United Kingdom
  • Beining Chen*
    Beining Chen
    Department of Chemistry, The University of Sheffield, Dainton Building, Brook Hill, Sheffield S3 7HF, United Kingdom
    *Email: [email protected]. Tel.: +447710075082.
    More by Beining Chen
  • , and 
  • Amélia P. Rauter*
    Amélia P. Rauter
    Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa 1749-016, Portugal
    *Email: [email protected]. Tel.: +351968810971.
Cite this: J. Med. Chem. 2020, 63, 20, 11663–11690
Publication Date (Web):September 22, 2020
https://doi.org/10.1021/acs.jmedchem.0c00841
Copyright © 2020 American Chemical Society

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    Abstract

    Abstract Image

    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.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00841.

    • DFT calculations, STD-NMR experiments, ThT fluorescence assays, membrane PAINS calculations, aggregation studies, 1H NMR and 13C NMR spectra of novel final compounds and key intermediates, analysis of the purity of tested compounds by HPLC-DAD-ESI(−)MS, and analysis of the purity of tested compounds by HPLC-DAD (PDF)

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