Naturally occuring polyphenols – Relationship of Structure to Antioxidant activity

Hydroxylation.

The activity of flavonoids as antioxidants, depend on the way functional groups are arranged about the nuclear structure. The hydohyxl (OH) functional groups that substitute for Hydrogen atoms in the flavan backbone affect antioxidant activity of flavanoids (Heim et al. 576). The extent of hydroxylation (number of OH substituents) and OH-groups’ configuration determines the reactivity of flavonoids. Such aspects determine how readily a flavonoid can donate electrons to electron deficient species (e.g. free radicals and reactive oxygen species; ROS), thus determining its antioxidant capacity (Heim et al. 576). For ROS and reactive nitrogen species (RNS), hydroxylation on the B ring increases flavonoids scavenging capacity, donating a hydrogen atom and an electron to such reactive species, with the remaining flavonoid compound being a relatively stable radical (Heim et al. 576).

Figure 1:Structures of Basic Flavonoids showing nomenclature of atoms in the Flavonoid backbone

polyphenols

A catechol substituent at the 3′4′ position also enhances the antioxidant activity of flavonoids by inhibiting lipid peroxidation (Heim et al. 576). Such catechol substitution ensures that oxidation of the flavonoid results into a relatively stable radical (ortho-semiquinone) as opposed to the radicals that result when the catechol substituent is lacking (Heim et al. 577). The effect of the catechol substituent for instance explains the higher scavenger ability of Luteolin for peroxyl radicals compared to kaempferol, which lacks the catechol substituent at the B ring, despite both compounds having equivalent levels of hydroxylation.

Hydroxylation configurations in the A ring could also contribute to antioxidant activity of flavonoids but in a more curtailed manner compared to B-ring hydroxylation. For instance, a 5-OH substituent is thought to improve antioxidant activity but loss of a free 6-OH does not affect antioxidant activity with respect to lipid peroxidation induced by Fe(II)/ascorbate and CCl4 (Heim, et al. 577). Although a closed C ring may not offer significant antioxidant benefits (e.g. Chalcones have antioxidant activity despite lacking a closed ring C), a free 3-OH and a ring C configuration that permits conjugation between ring A and B improves the antioxidant activity of flavonoids.

O-methylation.

Substitution with a methoxy group in ring B increases hydrophobicity, alters molecular planarity of flavonoids, and suppresses antioxidant activity in some methylated flavonoids (Heim et al. 577). Such effect may be due to high sensitivity of the B-ring to the position of the methoxy (OMe) group with alternation of a “6′-OH/4′-OMe configuration to 6′-OMe/4′-OH completely abolish[ing]” antioxidant activity for DPPH, a radical that does not occur naturally but generated in in vitro experiments (Heim et al. 277). A 4′ methoxy group that presents steric obstruction of the 3′4′ – catechol structure also reduces the antioxidant capacity of flavonoids (Heim et al. 577). Such steric hindrance of methoxy group on effect of a B ring catechol substituent are also noted with multiple methoxy substitutions in the A ring (Heim et al. 577). However, O-methylation increases antioxidant activity in some microsomal systems, but such increases could be a result of multiple mechanisms of antioxidant activity that occur in microsomal systems than the sole effect of o-methylation (Heim et al. 578).

2-3 double bond, 4-oxo function and carbohydrate moieties.

Although various studies have not found a correlation between the combination 2-3 unsaturation and 4 carbonyl substituent with differential antioxidant activity (as cited in Heim et al. 578), such groups could delineate the better antioxidant between alternatives fulfilling other structural requirements (Heim et al. 578). With respect to carbohydrate moieties, multiple substitutions with carbohydrates and polymerization reduce the antioxidant capacity of flavonoids (Heim et al. 578). Carbohydrate moieties influence the antioxidant activity according to the number and position to which they attach. For instance, a 4′-sugar substituent retards antioxidant activities of flavonoids more than a 3- or 7- substituent (Heim et al. 578). Go to part five here.

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