morin and galangin

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

Even hydroxyflavones show diverse biological functions, they have two common features such as showing antioxidative effects and containing hydroxyl groups. The authors tested the antioxidative effects of thirty hydroxyflavones using 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. While the scavenging activity of galangin, 3,5,7-trihydroxyflavone was 52.5%, fisetin, 3,7,3',4'-tetrahydroxyflavone showed 85.2%. To investigate the relationships between the structures of hydroxyflavones and their antioxidative effects, the three-dimensional quantitative structure-activity relationships were examined.

Topics: Antioxidants; Flavones; Flavonoids; Flavonols; Free Radical Scavengers; Models, Molecular; Quantitative Structure-Activity Relationship

Mushroom tyrosinase (EC 1.14.18.1) is a copper containing oxidase that catalyzes both the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones, and then forms brown or black pigments. In the present study, the effects of some flavonoids on the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) have been studied. The results show that flavonoids can lead to reversible inhibition of the enzyme. A kinetic analysis showed that the flavonols are competitive inhibitors, whereas luteolin is an uncompetitive inhibitor. The rank order of inhibition was: quercetin > galangin > morin; fisetin > 3,7,4;-trihydroxyflavone; luteolin > apigenin > chrysin.

Topics: Agaricales; Apigenin; Binding, Competitive; Catalysis; Copper; Dose-Response Relationship, Drug; Enzyme Inhibitors; Flavonoids; Flavonols; Kinetics; Luteolin; Models, Chemical; Molecular Structure; Monophenol Monooxygenase; Quercetin; Rutin; Structure-Activity Relationship

The protective effect of flavonoids against linoleic acid hydroperoxide (LOOH)-induced cytotoxicity was examined by using cultured endothelial cells. When the cells were incubated with both LOOH and flavonoids, most flavonols protected the cells from injury by LOOH. Flavones bearing an ortho-dihydroxy structure also showed a protective effect against the cytotoxicity of LOOH. However, flavanones had no effect. The structure-activity relationship revealed the presence of either the ortho-di-hydroxy structure in the B ring of the flavonoids or 3-hydroxyl and 4-oxo groups in the C ring to be important for the protective activities. The interaction between flavonoids and a-tocopherol was also examined in this system. Flavonoids that were protective against LOOH-induced cytotoxicity had at least an additive effect on the action of alpha-tocopherol against LOOH-induced damage.

Topics: Antioxidants; Cell Survival; Cells, Cultured; Chromones; Endothelium, Vascular; Enzyme Inhibitors; Flavones; Flavonoids; Flavonols; Humans; Kaempferols; Linoleic Acids; Lipid Peroxides; Luteolin; Mutagens; Quercetin; Structure-Activity Relationship; Umbilical Veins; Vitamin E

A broad screening of phytochemicals has demonstrated that certain flavone and flavonol derivatives have a relatively high affinity at A3 adenosine receptors, with Ki values of > or = 1 microM (Ji et al. J. Med. Chem. 1996, 39, 781-788). We have further modified the flavone structure to achieve a degree of selectivity for cloned human brain A3 receptors, determined in competitive binding assays versus [125I]AB-MECA[N6-(4-amino-3-iodobenzyl)adenosine-5'-(N-methylur onamide)]. Affinity was determined in radioligand binding assays at rat brain A1 and A2a receptors using [3H]-N6-PIA ([3H]-(R)-N6-phenylisopropyladenosine) and [3H]CGS21680 [[3H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]-5'-(N-ethylcarbamoyl++ +)adenosine], respectively. The triethyl and tripropyl ether derivatives of the flavonol galangin, 4, had Ki values of 0.3 - 0.4 microM at human A3 receptors. The presence of a 5-hydroxyl group increased selectivity of flavonols for human A3 receptors. The 2',3,4',7-tetraethyl ether derivative of the flavonol morin, 7, displayed a Ki value of 4.8 microM at human A3 receptors and was inactive at rat A1/A2a receptors. 3,6-Dichloro-2'-(isopropyloxy)-4'-methylflavone, 11e, was both potent and highly selective (approximately 200-fold) for human A3 receptors (Ki = 0.56 microM). Among dihydroflavonol analogues, the 2-styryl instead of the 2-aryl substituent, in 15, afforded selectivity for human A3 vs rat A1 or A2A receptors. The 2-styryl-6-propoxy derivative, 20, of the furanochromone visnagin was 30-fold selective for human A3 receptors vs either rat A1 or A2A receptors. Several of the more potent derivatives effectively antagonized the effects of an agonist in a functional A3 receptor assay, i.e. inhibition of adenylyl cyclase in CHO cells expressing cloned rat A3 receptors. In conclusion, these series of flavonoids provide leads for the development of novel potent and subtype selective A3 antagonists.

Topics: Animals; Brain Chemistry; CHO Cells; Cricetinae; Drug Design; Flavonoids; Humans; Kinetics; Molecular Structure; Nerve Tissue Proteins; Protein Binding; Purinergic P1 Receptor Antagonists; Radioligand Assay; Rats; Receptor, Adenosine A2A; Receptors, Purinergic P1; Recombinant Fusion Proteins; Structure-Activity Relationship