Protection of flavonoids against lipid peroxidation: the structure activity relationship revisited.
The inhibition of the lipid peroxidation, induced by iron and ascorbate in rat liver microsomes, by phenols and flavones was studied. The activity of phenol was enhanced by electron donating substituents, denoted by the Hammett sigma (sigma). The concentration of the substituted phenols giving 50% inhibition (IC50) of lipid peroxidation gave a good correlation with the sigma of the substituent (ln(1/IC50) = -8.92sigma + 5.80 (R = 0.94, p < 0.05)). In flavones two pharmacophores for the protection against lipid peroxidation were pinpointed: (i) a catechol moiety as ring B and (ii) an OH-group at the 3 position with electron donating groups at the 5 and/or 7 position in the AC-ring. An example of a flavone with the latter pharmacophore is galangin (3,5,7-trihydroxyflavone) where the reactivity of the 3-OH-group is enhanced by the electron donating effect of the 5- and 7-OH-groups. This is comparable to the effect of electron donating substituents on the activity of phenol. The prooxidant activity of flavones has been related to a low half peak oxidation potential (Ep/2). All flavones with a catechol as ring B have very low Ep/2, suggesting that they display a prominent prooxidant activity. In contrast, the Ep/2 varies within the group of flavones with a 3-OH, e.g. TUM 8436 (5,7,3',4'-tetra-O-methyl-quercetin) has a relatively high Ep/2 and is an excellent protector against lipid peroxidation. Apparently amongst the flavones with the pharmacophore in the AC-ring there are good antioxidants that are expected to display no or limited prooxidant properties.
Heijnen
Chantal G M
CG
Faculty of Medicine, Department of Pharmacology and Toxicology, University of Maastricht, The Netherlands.
Haenen
Guido R M M
GR
Oostveen
R Minou
RM
Stalpers
Eva M
EM
Bast
Aalt
A
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005609:Free Radicals; D007501:Iron / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D005419:Flavonoids; D005609:Free Radicals; D010636:Phenols; D007501:Iron; D001205:Ascorbic Acid