**3. Antioxidant and prooxidant activity of flavonoids and their metal complexes**

Flavonoids have been reported to possess various biological effects: anticarcinogenic [9–11], antiviral [12], anti‐inflammatory, immune stimulation [13, 14], antiallergic [15], and reducing the risk of cardiovascular disease [16–18].

Many of these beneficial health effects, including anticancer activity, arise from the antioxidant properties of these polyphenolic compounds [19], which are based on the following mechanisms:

(1) Direct radical scavenging: the flavonoid molecules are oxidized by free radicals (R●) resulting in more stable, less reactive radicals [20]:

$$\text{FIOH} + \text{R} \bullet \rightarrow \text{FIO} \bullet + \text{RH} \tag{1}$$

where R● refers to either reactive oxygen species, ROS (hydroxyl, superoxide, peroxyl, alkyl peroxyl), or reactive nitrogen species, RNS (nitric oxide, peroxynitrite).


$$\rm M^{n+} + H\_2O\_2 \rightarrow \rm M^{(n+)+} + OH^- + OH\bullet \tag{2}$$


Many studies have correlated the antioxidant activity of flavonoids with the following structural features (**Figure 3**):

**1.** *ortho*-dihydroxy substitution in the ring B;

Cornard and Merlin [8] have reported that in acidic conditions, the 3‐hydroxy‐4‐ketone or the 5‐hydroxy‐4‐keto groups of quercetin (Q) are involved in coordination, whereas in alkaline milieu, the second chelating site, 3',4'‐dihydroxy group, located on the B‐ring, is also involved.

Flavonoids have been reported to possess various biological effects: anticarcinogenic [9–11], antiviral [12], anti‐inflammatory, immune stimulation [13, 14], antiallergic [15], and reducing

Many of these beneficial health effects, including anticancer activity, arise from the antioxidant properties of these polyphenolic compounds [19], which are based on the following mechanisms:

(1) Direct radical scavenging: the flavonoid molecules are oxidized by free radicals (R●) re-

FlOH + R ● →FlO ● + RH (1)

**3. Antioxidant and prooxidant activity of flavonoids and their metal** 

**Flavonoid subclass General structure Representatives**

**Anthocyanidins** Pelargonidin: 5=7=4'=OH Cyanidin: 5=7=3'=4'=OH Delphinidin: 5=7=3'=4'=5'=OH Malvidin: 5=7=4'=OH, 3'=5'=OCH **Anthocyanins** Cyanidin 3‐glucoside Cyanidin 3‐galactoside Cyanidin 3‐rutinoside

Malvidin 3‐glucoside

**complexes**

**Anthocyanidins, anthocyanins**

**Table 1.** Main flavonoid [21] subclasses.

308 Flavonoids - From Biosynthesis to Human Health

the risk of cardiovascular disease [16–18].

sulting in more stable, less reactive radicals [20]:

**Figure 2.** Typical chelation sites in forming the flavonoid complexes [2].


**Figure 3.** Main structural features required for antioxidant activity of flavonoids.

Among these main structural properties, it was observed that the antioxidant activity increases with the number of hydroxyl substituents and that the aglycones are more potent antioxidants than their corresponding glycosides [22].

Apart from the antioxidant activity, flavonoids can also exhibit prooxidant activity. This behavior is associated with the low one‐electron reduction potentials; some of them may autoxidize slowly under neutral conditions and faster in alkaline media, generating ROS [23]. Another mechanism of prooxidant activity is correlated with their ability to reduce Cu2+ and Fe3+, thus generating Fe2+ and Cu+ which in turn reduces hydrogen peroxide to hydroxyl radicals [24]. Prooxidant activity is thought to be directly proportional to the total number of hydroxyl groups [25], especially in the B‐ring [26], and the concentration of the flavonoid [27].

Commonly, the prooxidant activity of flavonoids has been associated with various toxic effects, but it is also possible for it to generate beneficial properties. For example, the apoptotic and bactericidal activity of epigallocatechin gallate is based on its ability to reduce O<sup>2</sup> to yield H2 O2 [28]. Likewise, the capacity of flavonoids to stimulate the activity of the detoxifying enzymes is a major mechanism for the chemopreventive properties of flavonoids, thus protecting the organism against mutagens and carcinogens [29].

**Complex Molar ratio metaion:ligand Effect on the flavonoid antioxidant activity Ref. Flavonoid subclass: flavones** VO(II)‐luteolin 1:2 Increase [30] Ge(IV)‐chrysin 1:1 Increase [31] VO(II)‐chrysin 1:2 Increase [32], [33] Ce(IV)‐chrysin 1:2 Increase [34] VO(II)‐diosmin 1:1 Increase the scavenging activity only for ROO●, not for O2 ●−, DPHH●, OH● [35] **Flavonoid subclass: flavonols** Mg(II)‐quercetin 1:1 Increase [36] Al(III)‐quercetin 2:1 Increase [37] Ge(IV)‐quercetin 2:1 ? [38] Sn(II)‐quercetin Not determined Slightly decrease [39] Fe(II)‐quercetin 1:2 Increase [40] Co(II)‐quercetin 2:1 Increase [41] Cu(II)‐quercetin 1:1 Increase [42] Cu(II)‐quercetin 2:1 Increase [43] Cd(II)‐quercetin 1:1 Decrease [44]

A great number of metal complexes of flavonoid derivatives have been obtained, in order to improve the antioxidant activity of the parent flavonoid (**Table 2**).


**Table 2.** Metal complexes of flavonoids investigated for their antioxidant activity.

Among these main structural properties, it was observed that the antioxidant activity increases with the number of hydroxyl substituents and that the aglycones are more potent

Apart from the antioxidant activity, flavonoids can also exhibit prooxidant activity. This behavior is associated with the low one‐electron reduction potentials; some of them may autoxidize slowly under neutral conditions and faster in alkaline media, generating ROS [23]. Another mechanism of prooxidant activity is correlated with their ability to reduce Cu2+

radicals [24]. Prooxidant activity is thought to be directly proportional to the total number of hydroxyl groups [25], especially in the B‐ring [26], and the concentration of the flavonoid [27]. Commonly, the prooxidant activity of flavonoids has been associated with various toxic effects, but it is also possible for it to generate beneficial properties. For example, the apoptotic and

[28]. Likewise, the capacity of flavonoids to stimulate the activity of the detoxifying enzymes is a major mechanism for the chemopreventive properties of flavonoids, thus protecting the

A great number of metal complexes of flavonoid derivatives have been obtained, in order to

bactericidal activity of epigallocatechin gallate is based on its ability to reduce O<sup>2</sup>

**metaion:ligand**

VO(II)‐diosmin 1:1 Increase the scavenging activity only for

VO(II)‐luteolin 1:2 Increase [30] Ge(IV)‐chrysin 1:1 Increase [31] VO(II)‐chrysin 1:2 Increase [32], [33] Ce(IV)‐chrysin 1:2 Increase [34]

Mg(II)‐quercetin 1:1 Increase [36] Al(III)‐quercetin 2:1 Increase [37] Ge(IV)‐quercetin 2:1 ? [38] Sn(II)‐quercetin Not determined Slightly decrease [39] Fe(II)‐quercetin 1:2 Increase [40] Co(II)‐quercetin 2:1 Increase [41] Cu(II)‐quercetin 1:1 Increase [42] Cu(II)‐quercetin 2:1 Increase [43] Cd(II)‐quercetin 1:1 Decrease [44]

ROO●, not for O2

which in turn reduces hydrogen peroxide to hydroxyl

**Effect on the flavonoid antioxidant activity Ref.**

●−, DPHH●, OH●

to yield H2

[35]

O2

antioxidants than their corresponding glycosides [22].

and Fe3+, thus generating Fe2+ and Cu+

310 Flavonoids - From Biosynthesis to Human Health

organism against mutagens and carcinogens [29].

**Complex Molar ratio** 

**Flavonoid subclass: flavones**

**Flavonoid subclass: flavonols**

improve the antioxidant activity of the parent flavonoid (**Table 2**).

By analyzing the data from **Table 2** and the scientific literature, some observations appear to be relevant:

