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.
Chowdhury
Goutam
G
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Dostalek
Miroslav
M
Hsu
Erin L
EL
Nguyen
Linh P
LP
Stec
Donald F
DF
Bradfield
Christopher A
CA
Guengerich
F Peter
FP
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