Plant catechols and their S-glutathionyl conjugates as antinitrosating agents: expedient synthesis and remarkable potency of 5-S-glutathionylpiceatannol

Chem Res Toxicol. 2008 Dec;21(12):2407-13. doi: 10.1021/tx800283d.

Abstract

With a view to elucidating the structural requisites for effective antinitrosating properties in plant polyphenolics and their metabolites, we have undertaken a comparative investigation of the nitrite scavenging effects of representative catechol derivatives of dietary relevance in the 2,3-diaminonaphthalene (DAN) nitrosation and tyrosine nitration assays. Compounds tested included caffeic acid (1), chlorogenic acid (2), piceatannol (3), hydroxytyrosol (4), and the corresponding S-glutathionyl conjugates 5-8, which were prepared using either tyrosinase (5 and 6) or a novel, o-iodoxybenzoic acid (IBX)-based oxygenation/ conjugation methodology (7b and 8). In the DAN nitrosation assay at pH 4.0, the rank order of inhibitory activities was found to be 5-S-glutathionylpiceatannol (7b) > 3 > 1 > 2 > 2-S-glutathionylcaffeic acid (5) > 2-S-glutathionylchlorogenic acid (6) > 4 approximately 5-S-glutathionylhydroxytyrosol (8). Quite unexpectedly, in the tyrosine nitration assay in 0.5 M HCl, 2 was the most efficient inhibitor followed by 1 > 4 > 3 > 7b approximately 5 > 8 > 6. Under the assay conditions, the glutathionyl conjugates were usually consumed at faster rates than the parent catechols (decomposition rates: 3 > 1 > 4 > 2). The 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assay indicated that the most effective hydrogen donors were 4 > 7b > 1 approximately 3. Overall, these results indicated that catechol compounds and their glutathionyl conjugates may exhibit profoundly different inhibitory properties depending on the specific conditions of the assay, including especially pH, and that their antinitrosating properties do not correlate tout-court with their hydrogen donor capacity. The glutathionyl-piceatannol conjugate 7b was found to be one of the most potent inhibitors in the physiologically relevant DAN assay and may provide a new structural lead for the design of effective antinitrosating agents based on dietary polyphenolic compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Naphthylamine / analogs & derivatives
  • 2-Naphthylamine / chemistry
  • Caffeic Acids / pharmacology
  • Catechols / metabolism
  • Catechols / pharmacology*
  • Chlorogenic Acid / pharmacology
  • Free Radical Scavengers / metabolism
  • Free Radical Scavengers / pharmacology*
  • Glutathione / metabolism
  • Nitrosation
  • Phenylethyl Alcohol / analogs & derivatives
  • Phenylethyl Alcohol / pharmacology
  • Plant Extracts / metabolism
  • Plant Extracts / pharmacology*
  • Reactive Nitrogen Species / antagonists & inhibitors
  • Stilbenes / pharmacology

Substances

  • Caffeic Acids
  • Catechols
  • Free Radical Scavengers
  • Plant Extracts
  • Reactive Nitrogen Species
  • Stilbenes
  • 3,4-dihydroxyphenylethanol
  • 2,3-diaminonaphthalene
  • Chlorogenic Acid
  • 3,3',4,5'-tetrahydroxystilbene
  • 2-Naphthylamine
  • Glutathione
  • Phenylethyl Alcohol
  • caffeic acid