Indole-3-carbaldehyde

Indole-3-carbaldehyde
Names
	IUPAC name 1H-Indole-3-carbaldehyde
	Other names 3-Formylindole; Indole-3-carboxaldehyde; Indole-3-aldehyde
Identifiers
CAS Number	487-89-8;
3D model (JSmol)	Interactive image;
Beilstein Reference	5-21-08-00246
ChEMBL	ChEMBL147741;
ChemSpider	9838;
ECHA InfoCard	100.006.969
EC Number	207-665-8;
PubChem CID	10256;
UNII	7FN04C32UO;
CompTox Dashboard (EPA)	DTXSID5060069 ;
	InChI InChI=1S/C9H7NO/c11-6-7-5-10-9-4-2-1-3-8(7)9/h1-6,10H Key: OLNJUISKUQQNIM-UHFFFAOYSA-N;
	SMILES C1=CC=C2C(=C1)C(=CN2)C=O;
Properties
Chemical formula	C9H7NO
Molar mass	145.161 g·mol−1
Melting point	198 °C (388 °F; 471 K)
Structure
Crystal structure	Orthorhombic
Space group	Pca21
Lattice constant	a = 14.076, b = 5.8059, c = 8.6909
Lattice volume (V)	710.3
Formula units (Z)	4
Hazards
	GHS labelling:
Pictograms
Signal word	Warning
Hazard statements	H315, H319, H335
Precautionary statements	P261, P264, P271, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Indole-3-carbaldehyde (I3A), also known as indole-3-aldehyde and 3-formylindole, is a metabolite of dietary L-tryptophan which is synthesized by human gastrointestinal bacteria, particularly species of the Lactobacillus genus.^[2]^[3] I3A is a biologically active metabolite which acts as a receptor agonist at the aryl hydrocarbon receptor in intestinal immune cells, in turn stimulating the production of interleukin-22 which facilitates mucosal reactivity.^[4]^[3]^[2]

Biosynthesis in humans and cellular effects

Tryptophan metabolism by human gut microbiota ()

Tryptophan

Clostridium
sporogenes

Lacto-
bacilli

Tryptophanase-
expressing
bacteria

Intestinal
immune
cells

Intestinal
epithelium

PXR

Mucosal homeostasis:
↓TNF-α
↑Junction protein-
coding mRNAs

L cell

GLP-1

T J

Neuroprotectant:
↓Activation of glial cells and astrocytes
↓4-Hydroxy-2-nonenal levels
↓DNA damage
–Antioxidant
–Inhibits β-amyloid fibril formation

Maintains mucosal reactivity:
↑IL-22 production

Associated with vascular disease:
↑Oxidative stress
↑Smooth muscle cell proliferation
↑Aortic wall thickness and calcification

Associated with chronic kidney disease:
↑Renal dysfunction
–Uremic toxin

Kidneys

This diagram shows the biosynthesis of bioactive compounds (indole and certain other derivatives) from tryptophan by bacteria in the gut.^[2] Indole is produced from tryptophan by bacteria that express tryptophanase.^[2] Clostridium sporogenes metabolizes tryptophan into indole and subsequently 3-indolepropionic acid (IPA),^[5] a highly potent neuroprotective antioxidant that scavenges hydroxyl radicals.^[2]^[6]^[7] IPA binds to the pregnane X receptor (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.^[2] Following absorption from the intestine and distribution to the brain, IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.^[2] Lactobacillaceae (Lactobacillus s.l.) species metabolize tryptophan into indole-3-aldehyde (I3A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.^[2] Indole itself triggers the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells and acts as a ligand for AhR.^[2] Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.^[2] AST-120 (activated charcoal), an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.^[2]

Chemistry

Indole-3-carbaldehyde has reactivity typical of aromatic aldehydes. It can is easily oxidized to indole-3-carboxylic acid. It condenses with nitromethane in a Henry reaction to give 3-nitrovinyl indole.

Antifungal properties

Indole-3-carbaldehyde has antifungal properties, and partially accounts for the protection from chytridiomycosis seen in amphibian species which carry Janthinobacterium lividum on their skin.^[8]

References

^ Dileep, C. S; Abdoh, M. M. M; Chakravarthy, M. P; Mohana, K. N; Sridhar, M. A (2012). "1H-Indole-3-carbaldehyde". Acta Crystallographica Section E. 68 (11): o3135. doi:10.1107/S1600536812040573. PMC 3515237. PMID 23284457.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi:10.1186/s13073-016-0296-x. PMC 4840492. PMID 27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease
^ ^a ^b "Indole-3-carboxaldehyde". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 11 November 2017. Retrieved 17 November 2017.
^ ROMANI LUIGINA, TERESA ZELANTE (2013). "Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22". Immunity. 39 (2): 372–385. doi:10.1016/j.immuni.2013.08.003. PMID 23973224.
^ Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A. 106 (10): 3698–3703. Bibcode:2009PNAS..106.3698W. doi:10.1073/pnas.0812874106. PMC 2656143. PMID 19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes.
IPA metabolism diagram
^ "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018.
^ Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (July 1999). "Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid". J. Biol. Chem. 274 (31): 21937–21942. doi:10.1074/jbc.274.31.21937. PMID 10419516. S2CID 6630247. [Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.
^ Brucker, Robert M.; Harris, Reid N.; Schwantes, Christian R.; Gallaher, Thomas N.; Flaherty, Devon C.; Lam, Brianna A.; Minbiole, Kevin P. C. (2008-11-01). "Amphibian chemical defense: antifungal metabolites of the microsymbiont Janthinobacterium lividum on the salamander Plethodon cinereus". Journal of Chemical Ecology. 34 (11): 1422–1429. doi:10.1007/s10886-008-9555-7. ISSN 0098-0331. PMID 18949519. S2CID 9712168.

[1] Dileep, C. S; Abdoh, M. M. M; Chakravarthy, M. P; Mohana, K. N; Sridhar, M. A (2012). "1H-Indole-3-carbaldehyde". Acta Crystallographica Section E. 68 (11): o3135. doi:10.1107/S1600536812040573. PMC 3515237. PMID 23284457.

[Microbial_biosynthesis_of_bioactive_compounds-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k Zhang LS, Davies SS (April 2016). "Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions". Genome Med. 8 (1): 46. doi:10.1186/s13073-016-0296-x. PMC 4840492. PMID 27102537. Lactobacillus spp. convert tryptophan to indole-3-aldehyde (I3A) through unidentified enzymes [125]. Clostridium sporogenes convert tryptophan to IPA [6], likely via a tryptophan deaminase. ... IPA also potently scavenges hydroxyl radicals
Table 2: Microbial metabolites: their synthesis, mechanisms of action, and effects on health and disease
Figure 1: Molecular mechanisms of action of indole and its metabolites on host physiology and disease

[PubChem_-_Indole-3-carboxaldehyde-3] "Indole-3-carboxaldehyde". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 11 November 2017. Retrieved 17 November 2017.

[4] ROMANI LUIGINA, TERESA ZELANTE (2013). "Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22". Immunity. 39 (2): 372–385. doi:10.1016/j.immuni.2013.08.003. PMID 23973224.

[Microbiome_IPA-5] Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, Siuzdak G (March 2009). "Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites". Proc. Natl. Acad. Sci. U.S.A. 106 (10): 3698–3703. Bibcode:2009PNAS..106.3698W. doi:10.1073/pnas.0812874106. PMC 2656143. PMID 19234110. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacterium Clostridium sporogenes.
IPA metabolism diagram

[Human_metabolome_IPA-6] "3-Indolepropionic acid". Human Metabolome Database. University of Alberta. Retrieved 12 June 2018.

[Indolepropionic_acid_scavenging-7] Chyan YJ, Poeggeler B, Omar RA, Chain DG, Frangione B, Ghiso J, Pappolla MA (July 1999). "Potent neuroprotective properties against the Alzheimer beta-amyloid by an endogenous melatonin-related indole structure, indole-3-propionic acid". J. Biol. Chem. 274 (31): 21937–21942. doi:10.1074/jbc.274.31.21937. PMID 10419516. S2CID 6630247. [Indole-3-propionic acid (IPA)] has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. ... In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity.

[8] Brucker, Robert M.; Harris, Reid N.; Schwantes, Christian R.; Gallaher, Thomas N.; Flaherty, Devon C.; Lam, Brianna A.; Minbiole, Kevin P. C. (2008-11-01). "Amphibian chemical defense: antifungal metabolites of the microsymbiont Janthinobacterium lividum on the salamander Plethodon cinereus". Journal of Chemical Ecology. 34 (11): 1422–1429. doi:10.1007/s10886-008-9555-7. ISSN 0098-0331. PMID 18949519. S2CID 9712168.

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