Semi-synthetic isoflavones as BACE-1 inhibitors against Alzheimer's disease
| Autor: | Giovanni Ribaudo, Giuseppe Zagotto, Yu Han, Yuan Qing Qu, Alena Congling Qiu, Yuki Yu Jun Wu, Vincent Kam Wai Wong, Paolo Coghi, Betty Yuen Kwan Law, Enrico Zanforlin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
β-Secretase(BACE-1)
Cell Survival Pharmacology 01 natural sciences Biochemistry Alzheimer's disease In silico molecular docking Isoflavones P-gp Cell Line chemistry.chemical_compound Structure-Activity Relationship Prenylation Alzheimer Disease Drug Discovery Cytotoxic T cell Aspartic Acid Endopeptidases Humans Enzyme Inhibitors Molecular Biology biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry biology.organism_classification In vitro Recombinant Proteins 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Neuroprotective Agents chemistry Docking (molecular) Cancer cell Efflux Maclura pomifera Amyloid Precursor Protein Secretases |
| Popis: | BACE-1 is considered to be one of the targets for prevention and treatment of Alzheimer's disease (AD). We here report a novel class of semi-synthetic derivatives of prenylated isoflavones, obtained from the derivatization of natural flavonoids from Maclura pomifera. In vitro anti-AD effect of the synthesized compounds were evaluated via human recombinant BACE-1 inhibition assay. Compound 7, 8 and 13 were found to be the most active candidates which demonstrates good correlation between the computational docking and pharmacokinetic predictions. Moreover, cytotoxic studies demonstrated that the compounds are not toxic against normal and cancer cell lines. Among these three compounds, compound 7 enhance the activity of P-glycoprotein (P-gp) on A549 cancer cells and increases the activity of P-gp ATPase with a possible role on the efflux of amyloid-β across the blood- brain barrier. In conclusion, the present findings may pave the way for the discovery of a novel class of compounds to prevent and/or treat AD. |
| Databáze: | OpenAIRE |
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