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Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease

Natural polyphenol derivatives such as those found in green tea have been known for a long time for their useful therapeutic activity. Starting from EGCG, we have discovered a new fluorinated polyphenol derivative (1c) characterized by improved inhibitory activity against DYRK1A/B enzymes and by con...

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Autores principales: Araldi, Gian Luca, Hwang, Yu-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058583/
https://www.ncbi.nlm.nih.gov/pubmed/36986543
http://dx.doi.org/10.3390/ph16030443
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author Araldi, Gian Luca
Hwang, Yu-Wen
author_facet Araldi, Gian Luca
Hwang, Yu-Wen
author_sort Araldi, Gian Luca
collection PubMed
description Natural polyphenol derivatives such as those found in green tea have been known for a long time for their useful therapeutic activity. Starting from EGCG, we have discovered a new fluorinated polyphenol derivative (1c) characterized by improved inhibitory activity against DYRK1A/B enzymes and by considerably improved bioavailability and selectivity. DYRK1A is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome and Alzheimer’s disease), oncology, and type 2 diabetes (pancreatic β-cell expansion). Systematic structure–activity relationship (SAR) on trans-GCG led to the discovery that the introduction of a fluoro atom in the D ring and methylation of the hydroxy group from para to the fluoro atom provide a molecule (1c) with more desirable drug-like properties. Owing to its good ADMET properties, compound 1c showed excellent activity in two in vivo models, namely the lipopolysaccharide (LPS)-induced inflammation model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model for Parkinson’s disease.
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spelling pubmed-100585832023-03-30 Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease Araldi, Gian Luca Hwang, Yu-Wen Pharmaceuticals (Basel) Article Natural polyphenol derivatives such as those found in green tea have been known for a long time for their useful therapeutic activity. Starting from EGCG, we have discovered a new fluorinated polyphenol derivative (1c) characterized by improved inhibitory activity against DYRK1A/B enzymes and by considerably improved bioavailability and selectivity. DYRK1A is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome and Alzheimer’s disease), oncology, and type 2 diabetes (pancreatic β-cell expansion). Systematic structure–activity relationship (SAR) on trans-GCG led to the discovery that the introduction of a fluoro atom in the D ring and methylation of the hydroxy group from para to the fluoro atom provide a molecule (1c) with more desirable drug-like properties. Owing to its good ADMET properties, compound 1c showed excellent activity in two in vivo models, namely the lipopolysaccharide (LPS)-induced inflammation model and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model for Parkinson’s disease. MDPI 2023-03-15 /pmc/articles/PMC10058583/ /pubmed/36986543 http://dx.doi.org/10.3390/ph16030443 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Araldi, Gian Luca
Hwang, Yu-Wen
Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
title Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
title_full Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
title_fullStr Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
title_full_unstemmed Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
title_short Development of Novel Fluorinated Polyphenols as Selective Inhibitors of DYRK1A/B Kinase for Treatment of Neuroinflammatory Diseases including Parkinson’s Disease
title_sort development of novel fluorinated polyphenols as selective inhibitors of dyrk1a/b kinase for treatment of neuroinflammatory diseases including parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10058583/
https://www.ncbi.nlm.nih.gov/pubmed/36986543
http://dx.doi.org/10.3390/ph16030443
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