Beer constituents as potential cancer chemopreventive agents

Flavonoids are widely occurring polyphenol compounds of plant origin with multiple biological and chemical activities. Due to the presence of carbonyl and hydroxyl groups they can coordinate metal ions and form complexes. Metal complexes of flavonoids have many interesting properties: they are colored, often fluorescent, anti- or pro-oxidant, antimicrobial, antiproliferative and biologically active in many other ways. There are many papers covering specific aspects of activity of flavonoid metal complexes, e.g. their antioxidant properties, enzyme-mimicking behavior, therapeutic potential or use in chemical analysis. However, for a researcher interested in this theme, it would be useful to find an extensive review on more than one selected area. Our aim was to cover a wide spectrum of possible activities and potential applications of flavonoids coordinated to metal ions in order to give our readers a broad view on the topic of this class of compounds, their activity and potential applications. While a significant amount of information on the chemical properties and biological activity of flavonoid metal complexes can be found in the literature, an in-depth understanding of structure–property relationships is still lacking. In an attempt to address this issue, a comprehensive discussion of the available data is presented.

Properties and applications of flavonoid metal complexes

The physiological functions and bioavailability of flavonoids have been widely investigated since their bioactivities were identified about 80 years ago. Quercetin is a typical flavonoid ubiquitously contained in vegetables and fruits with several biological effects demonstrated in vitro and in vivo including antioxidative, anti-inflammatory, anticancer, and antidiabetic activities. After the ingestion of vegetables and fruits, quercetin glycosides are metabolized, absorbed, and circulated as types of conjugates in the blood. Thereafter, quercetin-3-O-β-D-glucuronide (Q3GA), a major metabolite of quercetin, is distributed throughout the body where it may exert beneficial functions in target tissues. Hydrophilic Q3GA has been found to be deconjugated into hydrophobic quercetin aglycone at injured sites which, in turn, may improve the pathological conditions. This review presents updated information on the biological aspects and mechanisms of action of quercetin and its related polyphenols. In particular, new insights into their beneficial health effects on the brain, blood vessels, muscle, and intestine will be discussed.

Quercetin and related polyphenols: new insights and implications for their bioactivity and bioavailability

Nuclear Localization of Flavonoid Enzymes in Arabidopsis

Catechins are the main ingredients of green tea extracts and have been shown to possess versatile biological activities, including antimicrobial. We determined that the catechins inhibit bacterial DNA gyrase by binding to the ATP binding site of the gyrase B subunit. In the group of four tested catechins, epigallocatechin gallate (EGCG) had the highest activity, followed by epicatechin gallate (ECG) and epigallocatechin (EGC). Specific binding to the N-terminal 24 kDa fragment of gyrase B was determined by fluorescence spectroscopy and confirmed using heteronuclear two-dimensional NMR spectroscopy of the EGCG-15N-labeled gyrase B fragment complex. Protein residues affected by binding to EGCG were identified through chemical shift perturbation. Molecular docking calculations suggest that the benzopyran ring of EGCG penetrates deeply into the active site while the galloyl moiety anchors it to the cleft through interactions with its hydroxyl groups, which explains the higher activity of EGCG and ECG.

Green Tea Catechins Inhibit Bacterial DNA Gyrase by Interaction with Its ATP Binding Site

Specific interactions of quercetin and other flavonoids with target proteins are revealed by elicited fluorescence.

The estrogenic flavanone rac -8-prenylnaringenin (8-PN) and 3 derivatives ( rac -7-(O-prenyl)naringenin-4′-acetate (7-O-PN), rac -5-(O-prenyl)narin

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Toxicity and Cell Cycle Effects of Synthetic 8-Prenylnaringenin and Derivatives in Human Cells

In model teleost fishes like the medaka and the zebrafish many genes which have been identified in genome sequencing projects await their functional characterization. Techniques for the effective generation of transgenic animals are a prerequisite for this challenging task, and, due to their transparency, fish offer the possibility to combine the use of fluorescent proteins and developmental analysis in vivo. Here we describe the application of the Ac/Ds transposon system to generate transgenic medaka reporter and gene trap lines. We determined a germline transmission rate of 30% in our experiments using constructs ranging in size from 1.8 to 6 kilobase pairs. The genomic integration site of the Ds-elements can be easily identified which is an important feature for gene trap mutagenesis experiments and similar approaches. We constructed gene trap vectors with functional elements of medaka sequences that produce in frame fusions of the endogenous sequence to EGFP. These vectors mimic endogenous expression of the trapped allele in transgenic animals and are capable to interfere with the expression of the wild type allele in the homozygous individuals.

Effective generation of transgenic reporter and gene trap lines of the medaka (Oryzias latipes) using the Ac/Ds transposon system.

The biological activity of eleven structurally closely related flavonoids (flavones and flavonols) with different number of hydroxyl groups was analysed and an attempt was made to correlate the observed effects with structural features of the tested flavonoids. Using human myeloid leukemia (HL-60) cells we investigated the toxicity of the flavonoids, their effect on cell proliferation (by metaboilic conversion of Resazurin and by flow cytometry) and their protection against reactive oxygen species (ROS) using fluorescent indicator 2', 7'-dichlorofluorescin-diacetate (quantified by flow cytometry). Among the substances tested 3, 3', 4', 5, 5', 7-hexahydroxyflavone (myricetin) 3, 3', 4', 5, 7-pentahydroxyflavone (quercetin), 3, 3', 4', 7-tetrahydroxyflavone (fisetin) and 3, 4', 5, 7-tetrahydroxyflavone (kaempferol) are characterised by the highest degree of hydroxylation and these compounds induced apoptosis after 48h of culture in a dose dependent manner while flavone, 3-hydroxyflavone (flavonol), 5-hydroxyflavone (primuletin) and 7-hydroxyflavone were ineffective. A similar correlation was apparent when cell proliferation was quantified in the presence of the test compounds (20μM). For example, quercetin increased the percentage of non-cycling cells to 60±3% while the compounds flavone and primuletin did not inhibit cell cycle progression at all. The analysis of the ROS scavenging activity showed a correlation with the degree of hydroxylation. Myricetin, querctin, fisetin and kamepferol lowered the ROS level by a factor of 3-5 while flavone was ineffective. The observation are difficult to interpret at present but altered hydrophobicity by hydroxylation and the possible consequences for the intracellular distribution must be taken into account as well as the different binding propertie of strongly hydroxylated flavonoids with cellular proteins.

Yvonne Henker

Papers

Specific interactions of quercetin and other flavonoids with target proteins are revealed by elicited fluorescence.

Toxicity and Cell Cycle Effects of Synthetic 8-Prenylnaringenin and Derivatives in Human Cells

Effective generation of transgenic reporter and gene trap lines of the medaka (Oryzias latipes) using the Ac/Ds transposon system.

Biological activity of flavonoids correlate with the degree of hydroxylation