The role of redox active copper(II) on antioxidant properties of the flavonoid baicalein: DNA protection under Cu(II)-Fenton reaction and Cu(II)-ascorbate system conditions

Polyphenols occur in plants, of which >8000 such compounds are known. They are classified into several groups, of which flavonoids are the most abundant naturally occurring type. In plants, flavonoids are known to provide protection against the damaging effect of reactive oxygen species (ROS) formed during the process of photosynthesis [1].

The protective effect of flavonoids in living organisms is associated with their ability to help maintain the physiological redox state of cells and so prevent oxidative damage of all important biomolecules. This has been documented in oxidative stress related diseases such as neurological conditions (Alzheimer's disease), cancer, heart ailments and other disorders [2].

The protective effect of flavonoids against oxidative damage is mediated by their functional hydroxyl groups, which are capable of both scavenging free radicals and chelating redox active metal ions [[3], [4], [5], [6]]. A therapeutic chelation approach toward free (unbound) redox metals using suitable ligands is a promising methodology for the treatment of various pathological conditions that are associated with a disrupted metal homeostasis, such as Wilson's disease, which is characterized by an excessive amount of free copper having accumulated particularly in the liver and brain [7]. Alzheimer's disease and some cancers are also characterized by a disrupted metabolism of copper (and other metals), so resulting in a pathological accumulation of free (unbound) copper [7]. Since free copper acts as a catalyst in the Fenton reaction, which results in the formation of damaging hydroxyl radicals, an appropriate chelation of copper by suitable ligands such as flavonoids usually results in a suppressed formation of ROS and corresponding protection against DNA damage [8]. Depending on the exact conditions, for example the presence of redox-active metals, flavonoids can undergo a switch from antioxidant (protective) properties to pro-oxidant properties, which can be used in the design of anticancer drugs. The anticancer activity of flavonoids, documented in some studies, can be explained by their mild prooxidant properties, which can boost the formation of ROS that are capable of causing damage to all important biomolecules in cancer cells [7].

Three main sites of flavonoids, where binding of redox metals may occur, include (i) the acetylcholine-like site, involving the 5-OH group (ring A) and 4-C=O group (ring C), (ii) the maltol-like site, specifically the 3-OH group and 4-C=O group (both in the ring C) and the catechol-like site, with the 3′-OH and 4′-OH groups of the ring B (Fig. 1) [9]. The strongest interaction between copper and flavonoids occurs at the maltol-like site (4-CO, 3-OH) groups, followed by the acetylacetone-like coordination site (4-CO, 5-OH groups), followed by hydroxyl groups from the catechol-like site and the hydroxyl groups of the A ring.

Recently, we studied a series of flavonoids, each containing an appreciable number of hydroxyl groups capable of either chelating redox active metals and/or directly scavenging free radicals: myricetin (six-OH groups), morin (five-OH groups), taxifolin (five-OH groups), kaempferol (four-OH groups) and luteolin (four-OH groups) [10].

In contrast to our previous studies, the aim of the present work is to investigate the flavone, baicalein, which contains just three hydroxyl groups, and therefore more finely tailors the possible binding action of the ligand to Cu ions (Fig. 1). Baicalein belongs to the flavone subfamily of flavonoids, first extracted from the roots of the Chinese herbs, Scutellaria baicalensis and Scutellaria lateriflora [[11], [12], [13], [14], [15], [16], [17], [18]].

Baicalein has been shown to exhibit antioxidant, neuroprotective and anti-inflammatory properties, and its efficacy has been demonstrated in suppressing motor deficits and enhancing the action of neurotransmitters such as dopamine [19,20].

Baicalein lacks both hydroxyl groups on the B ring (catechol site) and a 3-hydroxyl group on the ring C (maltol-like site): hence, the only possible locations where Cu(II) can be accommodated are the acetyl-acetone site and the hydroxyl groups on the A ring [9].

Since the preparation of single crystals of Cu-complexes with flavonoids, in the absence of an auxiliary ligand for X-ray analysis, is problematic, studies of the interaction of metals with flavonoids have mainly been limited to the solution phase. The aim of the present work is to study the antioxidant vs prooxidant properties of the Copper(II) - baicalein interaction in fluid media by means of radical scavenging measurements using spectroscopic techniques, and of the interaction of baicalein and its Cu(II) complexes with DNA using absorption titrations. The determinations of DNA damage protection by baicalein and its Cu(II) complexes under the conditions of Fenton reactions and the Cu-ascorbate system were made using gel electrophoresis. In addition, results from viscometric measurements are presented.

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