Elsevier

Toxicology in Vitro

Volume 15, Issue 1, February 2001, Pages 3-6
Toxicology in Vitro

Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups

https://doi.org/10.1016/S0887-2333(00)00053-9Get rights and content

Abstract

It has been reported that flavonoids efficiently protect against peroxynitrite toxicity. Two pharmacophores have been identified in flavonoids, namely the catechol group in ring B and the hydroxyl (OH) group at the 3-position. In this study, this structure–activity relationship was further examined. It was found that catechol (1,2-dihydroxybenzene) is a potent peroxynitrite scavenger, whereas phenol (hydroxybenzene) is not. Of the flavonols tested without a catechol group in ring B, kaempferol (OH groups at positions 3,5,7,4′) and galangin (OH groups at positions 3,5,7) are also potent scavengers, whereas apigenin (OH groups at positions 5,7,4′) and chrysin (OH groups at positions 5,7) are not. This confirms the importance of the OH group at the 3-position. However, the synthetic flavonol TUM 9761 and 3-hydroxyflavone (OH group only at position 3) are poor scavengers. Based on these results, the structure–activity relationship on the peroxynitrite scavenging activity of flavonols was refined. The catechol in ring B remains important. Also the 3-OH group remains important, but the activity of this pharmacophore is influenced by the substituents at position 5 and at position 7.

Introduction

Flavonoids are a group of naturally occurring compounds abundantly present in our diet. Some of these flavonoids possess a strong antioxidant effect (Pannala, 1997, Diplock, 1998). It has been reported that flavonoids have a protective effect against several diseases, for example, atherosclerosis (Duarte, 1993, Hertog, 1993). This effect is linked to their antioxidant property. In general, it is considered that a higher number of OH substituents in a flavonoid results in a higher antioxidant activity. Recently, their ability to protect against peroxynitrite [oxoperoxonitrate (1)] toxicity has gained much interest. Peroxynitrite toxicity is associated with several diseases, for instance airway diseases (Sadeghi Hashjin et al., 1998), cardiovascular (Digerness, 1999, Wattanapitayakul, 2000) and neurological diseases (e.g. amyotrophic lateral sclerosis) (Beckman, 1996, Estévez et al., 1999). Two pharmacophores have been identified in flavonols, a subgroup of the flavonoids that can be held responsible for this effect, that is, a catechol group in ring B and the OH group at position 3 (Haenen et al., 1997). The aim of the present study was to further examine this structure–activity relationship with a selected group of natural occurring compounds and a flavonoid that was designed according to the structure–activity relationship.

Section snippets

Chemicals

Kaempferol and apigenin were purchased from Fluka. Galangin and chrysin were purchased from Sigma Aldrich. All other chemicals were of analytical grade.

Synthesis of peroxynitrite

ONOOK was produced from the reaction of solid KO2 with NO gas as described by Koppenol et al. (1996).

Synthesis of 3′4′-dibenzyloxy-3-hydroxyflavone, TUM 9761

A suspension of 31.4 mmol 3,4-dibenzyloxybenzaldehyde and 31.4 mmol 2-hydroxyacetophenone in 80 ml ethanol and 50 ml dioxane was cooled to 10°C and 25 ml 40% (w/v) KOH solution was added dropwise. The reaction mixture was stirred for 66 h at room

Results and discussion

It was found that catechol (1,2-dihydroxybenzene) is a potent scavenger in our assay, whereas phenol (hydroxybenzene) is not (Table 1), indicating that the catechol in ring B is indeed important for the peroxynitrite scavenging of flavonoids. Hydroquinone also proved to be a potent peroxynitrite scavenger. Kaempferol and galangin, flavonoids that lack the catechol but do contain the 3-OH group were also potent scavengers of peroxynitrite (Table 2). Apigenin and chrysin, flavonoids that contains

Acknowledgements

We thank Sonja Tibi for her helpful comments on the peroxynitrite synthesis.

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