tamarixetin and syringetin

Alzheimer's disease (AD) is marked by the presence of amyloid plaques, neurofibrillary tangles, oxidatively damaged neuronal macromolecules and redox sensitive ions. Reduction of amyloid plaques and oxidative stress emerge as a convincing treatment strategy. Plaque reduction is achieved by inhibition of BACE1, the rate limiting enzyme generating the prime constituent of plaques, Aβ, through proteolysis of the amyloid precursor protein. Here, we report a QSAR model with five descriptors, developed to screen natural compounds as potent BACE1 inhibitors. Seven compounds out of which five flavonols namely isorhamnetin, syringetin, galangin, tamarixetin, rhamnetin and two flavanonols namely dihydromyricetin, taxifolin were screened. The ability of these compounds were validated using the BACE1 activity assay. The antioxidant property were estimated by the DPPH and ABTS assay. Although inhibition assay implied syringetin to be a promising BACE1 inhibitor, its poor antioxidant activity leaves it less effective as a multitarget ligand. Exhibiting moderate dual ability, isorhamnetin and taxifolin qualified as multi-target scaffolds for AD therapeutics. Our study reveals the importance of 4'-OH in the B ring of flavonols and the lack of any effect of 5'-OH in flavanonols for BACE1 inhibition. In case of antioxidant activity favourable association of 3'-O-methylation derivatives was observed in flavonols.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Disaccharides; Flavonoids; Flavonols; Humans; Molecular Docking Simulation; Neurons; Oxidative Stress; Plaque, Amyloid; Protein Conformation; Quantitative Structure-Activity Relationship; Quercetin

It has been reported that quercetin is an activator of rat vitamin D receptor (rVDR). However, the conclusion was based on experiments performed without all the appropriate control groups, raising the possibility of a false-positive finding. Furthermore, distinct differences exist in the chemical structures of quercetin and 1α,25-dihydroxyvitamin D3, which is a prototypic agonist of VDR. Therefore, we investigated systematically whether quercetin and other flavonols are agonists of rVDR, mouse VDR (mVDR), or human VDR (hVDR). Quercetin, 3-hydroxyflavone, galangin, datiscetin, kaempferol, morin, isorhamnetin, tamarixetin, myricetin, and syringetin did not activate rVDR, mVDR, or hVDR in HEK-293 and HepG2 cells transfected with the corresponding receptor expression plasmid and either the secreted phosphoprotein 1 (Spp1) or cytochrome P450 24A1 (CYP24A1) reporter plasmid, when compared to the respective empty vector control group transfected with one or the other reporter plasmid and treated with one of the flavonols. Control analysis indicated that lithocholic acid and 1α,25-dihydroxyvitamin D3, but not rifampicin, activated rVDR, mVDR, and hVDR. As shown in transfected HEK293 and HepG2 cells, the flavonols did not influence hVDR ligand binding domain transactivation, steroid receptor coactivator-1 recruitment, or hVDR target gene expression (transient receptor potential cation channel 6 and CYP24A1) in hVDR-expressing Caco-2 or LS180 cells. The cumulative data from the cell-based experiments were corroborated by results obtained from molecular docking analysis. In conclusion, quercetin, 3-hydroxyflavone, galangin, datiscetin, kaempferol, morin, isorhamnetin, tamarixetin, myricetin, and syringetin are not agonists of rVDR, mVDR, or hVDR, as judged by cell-based and in silico evidence.

Topics: Animals; Caco-2 Cells; Calcitriol; Disaccharides; Flavonoids; Gene Expression Regulation; HEK293 Cells; Hep G2 Cells; Humans; Kaempferols; Mice; Molecular Docking Simulation; Osteopontin; Quercetin; Receptors, Calcitriol; Structure-Activity Relationship; Transgenes; Vitamin D3 24-Hydroxylase