Structural identification of diindole agonists of the aryl hydrocarbon receptor derived from degradation of indole-3-pyruvic acid

Goutam Chowdhury, Miroslav Dostalek, Erin L. Hsu, Linh P. Nguyen, Donald F. Stec, Christopher A. Bradfield, F. Peter Guengerich

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Aerobic incubation of the tryptophan transamination/oxidation product indole-3-pyruvic acid (I3P) at pH 7.4 and 37°C yielded products with activity as Ah receptor (AHR) agonists. The extracts were fractionated using HPLC and screened for AHR agonist activity. Two compounds were identified as agonists: 1,3-di(1H-indol-3-yl)propan-2-one (1) and 1-(1H-indol-3-yl)-3-(3H- indol-3-ylidene) propan-2-one (2), with the potency of 2 being 100-fold > 1 [Nguyen et al. (2009) Chem. Res. Toxicol., DOI: 10.1021/tx900043s.]. Both 1 and 2 showed UV spectra indicative of indole. The molecular formulas were established by high-resolution mass spectrometry (HRMS), and the structures were determined by a combination of NMR methods, including 1H, natural abundance 13C, and two-dimensional methods. An intermediate in the oxidation of I3P to 1 is 3-hydroxy-2,4-di(1H-indol-3-yl)butanal (HRMS established the presence of a compound with the formula C20H 19N2O2). Compound 1 was converted to 2 in air or (faster) with mild oxidants, and 2 could be further oxidized to 1,3-di(3H-indol-3-ylidene)propan-2-one. Determination of the structures allowed estimation of the molar Ah receptor agonist activity of these natural products, similar in potency to known classical AHR inducers.

Original languageEnglish (US)
Pages (from-to)1905-1912
Number of pages8
JournalChemical Research in Toxicology
Volume22
Issue number12
DOIs
StatePublished - Dec 21 2009

ASJC Scopus subject areas

  • Toxicology

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