3-Methylindole

Description

Skatole, or 3-methylindole, is a foul-smelling constituent of mammalian feces; it is produced by the decomposition of tryptophan in the digestive tract. It has a floral aroma at low concentrations, contributing to the pleasant smell of flowers such as jasmine and orange blossoms. Skatole also occurs naturally in substances as diverse as beetroot and coal tar.

Chemical properties

Skatole has a characteristic putrid, fecal odor at high concentrations, becoming pleasant, jasmine-like, fruity sweet, warm at very low concentrations. It has a warm overripe fruity flavor below 1 ppm.

Physical properties

White crystals or slightly brown platelets. soluble in 3 volumes of 95% ethanol and oily fragrance. 3-Methylindole has a salty and strong indole-like animal fragrance, which is very powerful, has strong diffusion and is very durable. The smell at high concentrations is disgusting, only at very low concentrations there is a large civet-like animal aroma, and the taste is warm and overripe fruit-like.

Occurrence

Skatole is an indole derivative with a strong fecal odor that occurs naturally in feces formed due to the degradation of tryptophan. It is found in several flowers such as jasmine owing to its flowery smell when present in low concentration. Skatole is also one of the key contributors to the development of boar taint in fat samples.
Reported found in beetroot, feces, coal tar, Swiss cheese, Gruyere cheese, mozarella cheese, butter, milk, goat and sheep milk, boiled egg, fatty fish, coffee, tea, trassi, rice bran, dried bonito and squid.

The Uses of 3-Methylindole

3-Methylindole is a naturally abundant pneumotoxin, found primarily in mammalian feces providing its strong fecal odor. In lower concentrations however, the compound has a pleasent aroma, giving orange blossoms and ja smine their pleasing scent. It is often a component of commercial fragrances and perfumes.It helps fluorescent guanosine analogue, which in a dimethoxytrityl, phosphoramidite protected form, can be site-specifically inserted into oligonucleotides through a 3'-5' phosphodiester linkage using an automated DNA synthesizer.

What are the applications of Application

3-Methylindole is a naturally abundant pneumotoxin

Definition

ChEBI: 3-Methylindole, or skatole, belongs to the indole family and has a methyl substituent in position 3 of the indole ring. It is produced during the anoxic metabolism of L-tryptophan in the mammalian digestive tract. It has a role as a mammalian metabolite and a human metabolite.

Preparation

Prepared synthetically from the phenylhydrazone of propionaldehyde or by cyclization of o-toluidides (Bedoukian, 1967).
Industrial synthesis of 3-Methylindole: Propionaldehyde phenylhydrazone is obtained by heating propionaldehyde and phenylhydrazine to remove water molecules, and then heating with zinc chloride or sulfuric acid to remove ammonia molecules to obtain 3-Methylindole.
3 Step Synthesis of 3-Methylindole (Skatole) via Hydroboration and Cyclization

Aroma threshold values

Detection: 0.2 ppb

Synthesis Reference(s)

Journal of the American Chemical Society, 99, p. 3532, 1977 DOI: 10.1021/ja00452a073
The Journal of Organic Chemistry, 45, p. 2709, 1980 DOI: 10.1021/jo01301a032
Tetrahedron Letters, 28, p. 5291, 1987 DOI: 10.1016/S0040-4039(00)96710-8

General Description

3-Methylindole (3-MI), commonly found in wine, dairy products, and other foodstuffs, leads to an unpleasant fecal like odor in pig meat products. It is reported to be produced in the intestines of several species by the microbial degradation of tryptophan.

Pharmacology

Skatole (l00mg dissolved in 2 ml sesame oil administered by gastric intubation) failed to prevent apoplexy in the adrenals of rats when administered 24 hr before injection of 5 mg of 7,12-dimethylbenz[a]anthracene (Huggins & Fukunishi, 1964).
In rat costal cartilage, skatole inhibited ³⁵SO4^2-incorporation into chondroitin sulphate and ¹⁴C-labelled proline incorporation into protein (Liberti & Rogers, 1970). In concentrations of 5-10 mM, it inhibited oxygen uptake in slices of rat liver and rat-brain cortex (Lascelles & Taylor, 1968; Walshe et al. 1958). Skatole has also shown depressant (catatonic-like) activity on the swimming behaviour of guppies and the exploratory behaviour of rats (Sprince, 1969). When injected ip, 1 mmol/kg did not have any radioprotective effect in mice, the survival effect (ratio of mean survival time in a treated group to that of the control in 30 days after irradiation) being 0.97 or 0.70 when skatole was administered 30 or 5 min, respectively, before X-irradiation with 800 R (Shinoda et al 1974).
Skatole (1.0mM) caused >50% inhibition of the anaphylactic release of histamine from chopped, sensitized guinea-pig lung by chymotrypsin substrates and inhibitors (Austen & Brocklehurst, 1961). It had a non-specific excitatory action on the heart of the marine mollusc Venus mercenaria (Greenberg, 1960) and in a 194 μM concentration produced half-maximal positive inotropic activity in isolated left guinea-pig atria (Zetler, 1974).

Toxicology

3-Methylindole (3MI), an abnormal metabolite of tryptophan, causes acute pulmonary edema and emphysema. 3MI toxicity is species-, tissue- and cell-specific and is an excellent model for understanding the processes of chemically-induced lung injury. This 3-methylindole (3-MI) is absorbed through the rumen wall and circulated around the body. The 3-MI is toxic to the primary cells that line the interior surface of the lungs. Thus, as the high levels of 3-MI move from the rumen to the lungs more and more lung tissue is destroyed.
Toxicity of 3-Methyleneoxindole, a Proposed Reactive Intermediate in the Metabolism of 3-Methylindole
The metabolic basis of 3-methylindole-induced pneumotoxicity
Association of 3-methyleneindolenine, a toxic metabolite of 3-methylindole, with acute interstitial pneumonia in feedlot cattle
Mechanisms of 3-methylindole pneumotoxicity

Safety Profile

Poison by ingestion, intravenous, and intraperitoneal routes. Moderately toxic by subcutaneous route. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Indoles (skatole) with various substituents in the 2 and 3 position can be synthesized via the Fisher indole synthesis, which involves two steps and utilizes a phenylhydrazine and an aliphatic or aromatic aldehyde or ketone as starting materials.

Metabolic pathway

Three major metabolites of 14C-skatole are found in the plasma/urine of pigs given skatole and are identified as 6-sulfatoxyskatole, 3-hydroxy-3- methyloxindole, and the mercapturate adduct of skatole, 3-[(N-acetylcysteine-S-yl)methyl]indole. For other pathways, see the references in the text.

Metabolism

3-Methylindole (skatole) has been reported by several authors to be excreted as an ethereal sulphate by dogs, rats and man; distillation of the urine results in the formation of indole, which might well be derived by decarboxylation of indolyl-3-carboxylic acid, an expected oxidation product of skatole (Williams, 1959). Oral administration of skatole to rats resulted in the urinary excretion of a mixture of sulphate esters of hydroxyskatoles (Dalgliesh, Kelly & Horning, 1958; Horning, Sweeley, Dalgliesh & Kelly, 1959). The faeces of rats fed a chow diet were found to contain typtophan metabolites, including up to 0.78 ?g skatole/g wet faeces (Anderson, 1975). Metabolites of skatole were detected in the urine of a human subject fed skatole (Sano & Miyanoki, 1955). In man, skatole has been shown to undergo hydroxylation mainly at position 6. In rats and man, 6-hydroxyskatole is excreted chiefly as the sulphate (Horning et al. 1959), but it may also be excreted as the glucuronide (Sohler, 1966). The metabolites of skatole excreted in the urine of man and 16 species of domestic and wild mammals were also studied by Decker & Gerdemann (1959). After administration of skatole to cattle in a dose of 0.1-0.2 g skatole/kg intraruminally or 0.06g/kg by jugular infusion, the mean plasma concentration of skatole became maximal at 3 and 9hr, respectively (Carlson et al. 1975).

Purification Methods

Crystallise skatole from *benzene or pet ether (m 96.5o). It has also been purified by zone melting. The picrate has m 182o (from Et2O or Et2O/MeOH). [Beilstein 20 III/IV 3206, 20/7 V 69.]