Structural identification of Diindole agonists of the aryl hydrocarbon receptor derived from degradation of indole-3-pyruvic acid.
Aerobic incubation of the tryptophan transamination/oxidation product indole-3-pyruvic acid (I3P) at pH 7.4 and 37 degrees 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 (1)H, natural abundance (13)C, 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 C(20)H(19)N(2)O(2)). 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.
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Goutam
G
Chowdhury
Miroslav
M
Dostalek
Erin L
EL
Hsu
Linh P
LP
Nguyen
Donald F
DF
Stec
Christopher A
CA
Bradfield
F Peter
FP
Guengerich
D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature
C547592:1,3-di(1H-indol-3-yl)propan-2-one; C547593:1-(1H-indol-3-yl)-3-(3H-indol-3-ylidene)propan-2-one; D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; C008122:indol-3-yl pyruvic acid