Structural aspects of antioxidant activity of flavonoids.
Flavonoids, a group of naturally occurring antioxidants and iron chelators, might be used as cardioprotective agents in doxorubicin-induced cardiotoxicity, which is believed to be caused by the formation of oxygen free radicals. To investigate the underlying molecular mechanism, we tested a large group of flavonoids from all major structural subclasses on their ability to inhibit doxorubicin (enzymatically)-induced and Fe2+/ascorbate (nonenzymatically)-induced microsomal lipid peroxidation (LPO) and to chelate Fe2+. In addition, we measured half peak oxidation potentials (Ep/2). LPO inhibition data gave a good qualitative correlation with the oxidation potentials. Most flavonoids tested chelated Fe2+, but there were large differences in the chelating capacity. For good scavenging activity, a catechol moiety on ring B is required. The 3-OH moiety can function as a chelation site and can also be oxidized. The 3-OH group in combination with a C2 C3 double bond, increases the scavenging activity. Fe2+ chelation only plays a role in the LPO inhibition by less active scavengers. Chelation can then raise the activity to the level of the most active scavengers, possibly by site-specific scavenging. It can be concluded that Ep/2 values and iron chelating activity can almost completely describe the LPO inhibiting behaviour of the flavonoids.
van Acker
S A
SA
Department of Pharmacochemistry, Vrije Universiteit, Netherlands.
van den Berg
D J
DJ
Tromp
M N
MN
Griffioen
D H
DH
van Bennekom
W P
WP
van der Vijgh
W J
WJ
Bast
A
A
D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D001205:Ascorbic Acid; D005296:Ferrous Compounds; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D005609:Free Radicals; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D015227:Lipid Peroxidation; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism; D012044:Regression Analysis; D013329:Structure-Activity Relationship
D000975:Antioxidants; D005296:Ferrous Compounds; D005419:Flavonoids; D005609:Free Radicals; D007502:Iron Chelating Agents; C051140:iron(II)-ascorbic acid complex; D007501:Iron; D001205:Ascorbic Acid