Synthesis and in vitro antioxidant activity of glycyrrhetinic acid derivatives tested with the cytochrome P450/NADPH system.
Five glycyrrhetinic acid (Ib) derivatives have been synthesized to try to improve the antioxidant activity. Their in vitro antioxidant activities were studied using a cytochrome P450/NADPH reductase system from rat liver microsomes. The generation of microsomal free radicals was followed by oxidation of the DCFH-DA probe, while evaluating the capacity to inhibit reactive oxygen species (ROS) formation. Two hydroxylated derivatives, 18beta-olean-12-ene-3beta,11alpha,30-triol (II) and 18beta-olean-12-ene-3beta,11beta,30-triol (IV), exhibited strong antioxidant activities. At a concentration of 1.0 mg/ml, these derivatives inhibited ROS formation by 50% and 51%, respectively. Moreover, two homo- and heterocyclic diene derivatives, 18beta-olean-11,13(18)-diene-3beta,30-diol (III) and 18beta-olean-9(11),12-diene-3beta,30-diol (V), were also effective in ROS-scavenging activity (inhibition of 41% and 44% of ROS activity, respectively). In the same conditions, the lead compound (Ib) and the reference vitamin E inhibited ROS activity by 31% and 32%, respectively. Our results suggest that the chemical reduction of the 11-keto and 30-carboxyl groups into hydroxyl function (example, II, IV) can increase the antioxidant activity of Ib significantly. In view of these results, our study represents a further approach to the development of potential therapeutic agents from Ib derivatives for use in pathologic events in which, free radical damage could be involved.
Ablise
Mourboul
M
INSERM Unité 525, Centre du Médicament, Faculté de Pharmacie, Université Henri Poincaré Nancy 1, Nancy, France.
Leininger-Muller
Brigitte
B
Wong
Choi Dal
CD
Siest
Gérard
G
Loppinet
Vincent
V
Visvikis
Sophie
S
D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D005609:Free Radicals; D000960:Hypolipidemic Agents; D007202:Indicators and Reagents; D017382:Reactive Oxygen Species; D014810:Vitamin E; D009251:NADPH-Ferrihemoprotein Reductase; D006034:Glycyrrhetinic Acid