The health benefits of cranberries have long been recognized. However, the mechanisms behind its function are poorly understood. We have investigated the iron-binding properties of quercetin, the major phenolic phytochemical present in cranberries, and other selected phenolic compounds (chrysin, 3-hydroxyflavone, 3',4'-dihydroxy flavone, rutin, and flavone) in aqueous media using UV/vis, NMR and EPR spectroscopies and ESI-Mass spectrometry. Strong iron-binding properties have been confirmed for the compounds containing the "iron-binding motifs" identified in their structures. The apparent binding constants are estimated to be in the range of 10(6) M(-1) to 10(12) M(-2) in phosphate buffer at pH 7.2. Surprisingly, quercetin binds Fe(2+) even stronger than the well known Fe(2+)-chelator ferrozine at pH 7.2. This may be the first example of an oxygen-based ligand displaying stronger Fe(2+)-binding affinity than a strong nitrogen-based Fe(2+)-chelator. The strong Fe-binding properties of these phenolics argue that they may be effective in modulating cellular iron homeostasis under physiological conditions. Quercetin can completely suppress Fenton chemistry both at micromolar levels and in the presence of major cellular iron chelators like ATP or citrate. However, the radical scavenging activity of quercetin provides only partial protection against Fenton chemistry-mediated damage while Fe chelation by quercetin can completely inhibit Fenton chemistry, indicating that the chelation may be key to its antioxidant activity. These results demonstrate that quercetin and other phenolic compounds can effectively modulate iron biochemistry under physiologically relevant conditions, providing insight into the mechanism of action of bio-active phenolics.
Baicalein and baicalin, the major bioactive compounds found in the Chinese herb Scutellaria baicalensis, have been shown to be effective against cancer, bacterial infections and oxidative stress diseases. However, little is known about their mechanisms of action. To probe whether iron homeostasis modulation may play a role in their bioactivity, we have investigated their iron binding characteristics under physiologically relevant conditions. A 2:1 baicalein-ferrous complex was readily formed in 20 mM phosphate buffer, pH 7.2, with a binding constant ~2-9 × 10 11 M -2 , whereas a 1:1 baicalein-ferric complex was formed, under the same conditions, with an apparent binding constant ~1-3 × 10 6 M -1 . Baicalein appears to bind the ferrous ion more strongly than ferrozine, a well known iron(II) chelator. Using 1 H NMR and Zn 2+ and Ga 3+ as probes, the iron-binding site on baicalein was elucidated to be at the O6/O7 oxygen atoms of the A-ring. No binding was observed for baicalin under the same NMR conditions. Furthermore, baicalein strongly inhibits the Fepromoted Fenton chemistry via a combination of chelation and radical scavenging mechanism while baicalin can provide only partial protection against radical damage. These results indicate that baicalein is a strong iron chelator under physiological conditions and hence may play a vital role in modulating the body's iron homeostasis. Modulation of metal homeostasis and the inhibition of Fenton chemistry may be one of the possible mechanisms for herbal medicine.
Flavonoids have attracted increased attention due to their broad bioactivities related to health and diseases. Modulating metal homeostasis may play an important role in their bioactivities. Recent studies have suggested that dietary flavonoids may affect zinc homeostasis, uptake, and transport. In this work, the zinc-binding sites on a few selected flavonoids have been investigated by (1)H NMR spectroscopy under physiological relevant pH and the species formed were verified by mass spectrometry. Zinc binding induces distinct changes in the proton resonances on the flavonoid rings, providing useful information to locate the Zn-binding sites. No Zn-binding was observed with flavone which lacks a chelation site. Zinc was found to bind to the 3-hydroxyl-4-keto, catechol, and 5-hydroxyl-4-keto chelation sites of flavonol, 3',4'-dihydroxylflavone and chrysin, respectively. Kaempferol and myricetin chelate zinc at the 3-hydroxyl-4-keto site while rutin binds zinc preferentially at the 5-hydroxyl-4-keto site. However, morin appears to bind zinc at the 1-ether-2-hydroxyl site.
An eye for an iron: A highly sensitive, selective and reversible turn-on Fe(3+) sensor for imaging labile Fe(3+) in live cells at subcellular resolution is reported. The sensor can respond to changes in intracellular Fe(3+) levels and was used to image endogenous chelatable Fe(3+) in live human neuroblastoma SH-SY5Y cells, with two Fe(3+) pools being identified in mitochondria and endosomes/ lysosomes for the first time.
Fenton antidote: The prochelator 2‐boronobenzaldehyde isonicotinoyl hydrazone (SIH‐B) reacts with H2O2 to yield the active chelator salicylaldehyde isonicotinoyl hydrazone (SIH), which sequesters copper and iron ions (see scheme; M=Fe, Cu). This process attenuates both Fe‐ and Cu‐promoted Fenton reactions under physiologically relevant conditions.
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