Synthesis and in vitro antioxidant activity of glycyrrhetinic acid derivatives tested with the cytochrome P450/NADPH system

Chem Pharm Bull (Tokyo). 2004 Dec;52(12):1436-9. doi: 10.1248/cpb.52.1436.

Abstract

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.

MeSH terms

  • Animals
  • Antioxidants / chemical synthesis*
  • Antioxidants / pharmacology
  • Free Radicals / metabolism
  • Glycyrrhetinic Acid / analogs & derivatives*
  • Glycyrrhetinic Acid / chemical synthesis*
  • Glycyrrhetinic Acid / pharmacology
  • Hypolipidemic Agents / chemical synthesis
  • Hypolipidemic Agents / pharmacology
  • In Vitro Techniques
  • Indicators and Reagents
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • NADPH-Ferrihemoprotein Reductase / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Vitamin E / pharmacology

Substances

  • Antioxidants
  • Free Radicals
  • Hypolipidemic Agents
  • Indicators and Reagents
  • Reactive Oxygen Species
  • Vitamin E
  • NADPH-Ferrihemoprotein Reductase
  • Glycyrrhetinic Acid