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
| Autor: | Claire J. Garwood, M Teresa Blázquez-Sánchez, Andreia Bento-Oliveira, Filipa Marcelo, Amélia P. Rauter, Joana S. Cristóvão, Pedro Lopes, José G. Fernández-Bolaños, Nicola Antonio Colabufo, Ke Ning, Ana Diniz, Cláudio M. Gomes, Ana M. Matos, Rafael Nunes, M Conceição Oliveira, Imane Ghafir El Idrissi, Beat Ernst, Cleide dos Santos Souza, Beining Chen, Rodrigo F.M. de Almeida, Philipp Dätwyler, Miguel Machuqueiro, Óscar López |
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| Rok vydání: | 2020 |
| Předmět: |
Cell Membrane Permeability
Amyloid Membrane permeability Glycoside Hydrolases Induced Pluripotent Stem Cells Context (language use) tau Proteins Pharmacology Proto-Oncogene Proteins c-fyn 01 natural sciences 03 medical and health sciences FYN Glucosides Alzheimer Disease Drug Discovery medicine Dementia Cholinesterases Humans Phosphorylation Butyrylcholinesterase 030304 developmental biology 0303 health sciences Amyloid beta-Peptides Molecular Structure Drug discovery Chemistry Polyphenols medicine.disease 0104 chemical sciences 010404 medicinal & biomolecular chemistry HEK293 Cells Diabetes Mellitus Type 2 Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 63(20) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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