luteolin Dotaz Zobrazit nápovědu
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- Klíčová slova
- biofarmakum, medicína,
- MeSH
- antioxidancia MeSH
- antitumorózní látky MeSH
- farmakologie MeSH
- flavonoidy chemie MeSH
- fytoterapie metody využití MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- luteolin * analýza aplikace a dávkování biosyntéza terapeutické užití toxicita MeSH
- rostliny MeSH
- toxikologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
The natural flavonoid compounds quercetin (3,3',4',5,7-pentahydroxyflavone) and luteolin (3',4',5,7-tetrahydroxyflavone) are important bioactive compounds with antioxidative, anti-allergic, and anti-inflammatory properties. However, both are unstable when exposed to atmospheric oxygen, which causes degradation and complicates their analytical determinations. The oxidative change of these flavonoids was observed and followed by UV-visible spectrophotometry, both in aqueous and ethanolic solutions. The distribution of the degradation products in aqueous media was monitored by LC-MS and LC-DAD analysis. The amounts of oxidative reaction products increase with the exposure time. The oxidative degradation reduces the pharmacological efficiency of these antioxidants and renders analytical determination inaccurate. The oxidative changes in flavonoid test solutions can explain the inconsistent dissociation constants reported in the literature. Dissociation constants of quercetin and luteolin were determined both by alkalimetric titration and by UV-visible spectrophotometry under deaerated conditions. The values pK(1) = 5.87 ± 0.14 and pK(2) = 8.48 ± 0.09 for quercetin, and pK(1) = 5.99 ± 0.32 and pK(2) = 8.40 ± 0.42 for luteolin were found.
The part of the influenza polymerase PA subunit featuring endonuclease activity is a target for anti-influenza therapies, including the FDA-approved drug Xofluza. A general feature of endonuclease inhibitors is their ability to chelate Mg2+ or Mn2+ ions located in the enzyme's catalytic site. Previously, we screened a panel of flavonoids for PA inhibition and found luteolin and its C-glucoside orientin to be potent inhibitors. Through structural analysis, we identified the presence of a 3',4'-dihydroxyphenyl moiety as a crucial feature for sub-micromolar inhibitory activity. Here, we report results from a subsequent investigation exploring structural changes at the C-7 and C-8 positions of luteolin. Experimental IC50 values were determined by AlphaScreen technology. The most potent inhibitors were C-8 derivatives with inhibitory potencies comparable to that of luteolin. Bio-isosteric replacement of the C-7 hydroxyl moiety of luteolin led to a series of compounds with one-order-of-magnitude-lower inhibitory potencies. Using X-ray crystallography, we solved structures of the wild-type PA-N-terminal domain and its I38T mutant in complex with orientin at 1.9 Å and 2.2 Å resolution, respectively.
Authentic standards of food flavonoids are important for human metabolic studies. Their isolation from biological materials is impracticable; however, they can be prepared in vitro. Twelve sulfated metabolites of luteolin, myricetin, and ampelopsin were obtained with arylsulfotransferase from Desulfitobacterium hafniense and fully characterized by high-performance liquid chromatography, MS, and NMR. The compounds were tested for their ability to scavenge 1,1-diphenyl-2-picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid), and N,N-dimethyl-p-phenylenediamine radicals, to reduce ferric ions and Folin-Ciocalteu reagent, and to inhibit tert-butyl hydroperoxide-induced lipid peroxidation of rat liver microsomes. The activity differed considerably even between monosulfate isomers. The parent compounds and myricetin-3'-O-sulfate were the most active while other compounds displayed significantly lower activity, particularly luteolin sulfates. No mutagenic activity of the parent compounds and their main metabolites was observed; only myricetin showed minor pro-mutagenicity. The prepared sulfated metabolites are now available as authentic standards for future in vitro and in vivo metabolic studies.
- MeSH
- antioxidancia chemie farmakologie MeSH
- arylsulfotransferasa chemie MeSH
- bakteriální proteiny chemie MeSH
- biofyzikální jevy MeSH
- biokatalýza MeSH
- Desulfitobacterium enzymologie MeSH
- flavonoidy chemie metabolismus farmakologie MeSH
- isomerie MeSH
- jaterní mikrozomy účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- luteolin chemie metabolismus farmakologie MeSH
- molekulární struktura MeSH
- peroxidace lipidů účinky léků MeSH
- sírany chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Luteolin and naringenin are flavonoids found in various foods/beverages and present in certain dietary supplements. After a high intake of these flavonoids, their sulfate and glucuronide conjugates reach micromolar concentrations in the bloodstream. Some pharmacokinetic interactions of luteolin and naringenin have been investigated in previous studies; however, only limited data are available in regard to their metabolites. In this study, we aimed to investigate the interactions of the sulfate and glucuronic acid conjugates of luteolin and naringenin with human serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Our main findings are as follows: (1) Sulfate conjugates formed more stable complexes with albumin than the parent flavonoids. (2) Luteolin and naringenin conjugates showed no or only weak inhibitory action on the CYP enzymes examined. (3) Certain conjugates of luteolin and naringenin are potent inhibitors of OATP1B1 and/or OATP2B1 enzymes. (4) Conjugated metabolites of luteolin and naringenin may play an important role in the pharmacokinetic interactions of these flavonoids.
- MeSH
- cytochrom P-450 CYP3A * metabolismus MeSH
- cytochrom P450 CYP2C19 metabolismus MeSH
- cytochrom P450 CYP2C9 metabolismus MeSH
- flavonoidy farmakologie MeSH
- glukuronidy MeSH
- lidé MeSH
- lidský sérový albumin metabolismus MeSH
- luteolin farmakologie MeSH
- přenašeče organických aniontů * metabolismus MeSH
- sírany metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Herein, we report the use of the Suzuki-Miyaura cross-coupling reaction for the preparation of a library of synthetic derivatives of flavonoids for biological activity assays. We have investigated the reactivity of halogenated flavonoids with aryl boronates and with boronyl flavonoids. This reaction was used to prepare new synthetic derivatives of flavonoids substituted at C-8 with aryl, heteroaryl, alkyl, and boronate substituents. The formation of flavonoid boronate enabled a cross-coupling reaction with halogenated flavones yielding biflavonoids connected at C-8. This method was used for the preparation of natural compounds including C-8 prenylated compounds, such as sinoflavonoid NB. Flavonoid boronates were used for the preparation of rare C-8 hydroxyflavonoids (natural flavonoids gossypetin and hypolaetin). A series of previously unknown derivatives of quercetin and luteolin were prepared and fully characterized.
The biological effects of flavonoids on mammal cells are diverse, ranging from scavenging free radicals and anti-cancer activity to anti-influenza activity. Despite appreciable effort to understand the anti-influenza activity of flavonoids, there is no clear consensus about their precise mode-of-action at a cellular level. Here, we report the development and validation of a screening assay based on AlphaScreen technology and illustrate its application for determination of the inhibitory potency of a large set of polyols against PA N-terminal domain (PA-Nter) of influenza RNA-dependent RNA polymerase featuring endonuclease activity. The most potent inhibitors we identified were luteolin with an IC50 of 72 ± 2 nM and its 8-C-glucoside orientin with an IC50 of 43 ± 2 nM. Submicromolar inhibitors were also evaluated by an in vitro endonuclease activity assay using single-stranded DNA, and the results were in full agreement with data from the competitive AlphaScreen assay. Using X-ray crystallography, we analyzed structures of the PA-Nter in complex with luteolin at 2.0 Å resolution and quambalarine B at 2.5 Å resolution, which clearly revealed the binding pose of these polyols coordinated to two manganese ions in the endonuclease active site. Using two distinct assays along with the structural work, we have presumably identified and characterized the molecular mode-of-action of flavonoids in influenza-infected cells.
- MeSH
- antivirové látky chemie metabolismus MeSH
- endonukleasy antagonisté a inhibitory chemie metabolismus MeSH
- enzymatické testy metody MeSH
- flavonoidy chemie metabolismus MeSH
- inhibitory enzymů chemie metabolismus MeSH
- krystalografie rentgenová MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- preklinické hodnocení léčiv MeSH
- proteinové domény MeSH
- RNA-dependentní RNA-polymerasa antagonisté a inhibitory chemie metabolismus MeSH
- vazba proteinů MeSH
- virové proteiny antagonisté a inhibitory chemie metabolismus MeSH
- virus chřipky A enzymologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
- MeSH
- antioxidancia metabolismus MeSH
- antitumorózní látky alkylující farmakologie MeSH
- chromozomální aberace MeSH
- DNA MeSH
- lidé MeSH
- melanom farmakoterapie metabolismus MeSH
- quercetin farmakologie chemie terapeutické užití MeSH
- scavengery volných radikálů farmakologie chemie metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
