Indole

Indole-3-carbinol comes from a substance called glucobrassicin, which is found in cruciferous vegetables such as broccoli, cauliflower, and kale.

The amount of glucobrassicin found in vegetables varies depending on the plant, soil, rainfall, amount of sunlight, and other factors. Indole-3-carbinol is formed when these vegetables are cut, chewed or cooked. It might have effects that prevent the growth of certain types of cancer cells.

People use indole-3-carbinol for cancer prevention, liver disease, fibromyalgia, and many other conditions, but there is no good scientific evidence to support these uses.

Don't confuse indole-3-carbinol with cruciferous vegetables, such as broccoli, or with other chemicals found in these vegetables such as ascorbigen, diindolylmethane, or sulforaphane. These are not the same.

CONDITIONS OF USE AND IMPORTANT INFORMATION: This information is meant to supplement, not replace advice from your doctor or healthcare provider and is not meant to cover all possible uses, precautions, interactions or adverse effects. This information may not fit your specific health circumstances. You should always speak with your doctor or health care professional before you start, stop, or change any prescribed part of your health care plan or treatment and to determine what course of therapy is right for you.

Basicity
Unlike most amines, indole is not basic: just like pyrrole, the aromatic character of the ring means that the lone pair of electrons on the nitrogen atom is not available for protonation. Strong acids such as hydrochloric acid can, however, protonate indole. Indole is primarily protonated at the C3, rather than N1, owing to the enamine-like reactivity of the portion of the molecule located outside of the benzene ring. The protonated form has a pKa of −3.6. The sensitivity of many indolic compounds (e.g., tryptamines) under acidic conditions is caused by this protonation.

Electrophilic substitution
The most reactive position on indole for electrophilic aromatic substitution is C3, which is 1013 times more reactive than benzene. For example, it is alkylated by phosphorylated serine in the biosynthesis of the amino acid tryptophan. Vilsmeier–Haack formylation of indole will take place at room temperature exclusively at C3. Since the pyrrolic ring is the most reactive portion of indole, electrophilic substitution of the carbocyclic (benzene) ring generally takes place only after N1, C2, and C3 are substituted. A noteworthy exception occurs when electrophilic substitution is carried out in conditions sufficiently acidic to exhaustively protonate C3. In this case, C5 is the most common site of electrophilic attack. Gramine, a useful synthetic intermediate, is produced via a Mannich reaction of indole with dimethylamine and formaldehyde. It is the precursor to indole-3-acetic acid and synthetic tryptophan.

N–H acidity and organometallic indole anion complexes
The N–H center has a pKa of 21 in DMSO, so that very strong bases such as sodium hydride or n-butyl lithium and water-free conditions are required for complete deprotonation. The resulting organometalic derivatives can react in two ways. The more ionic salts such as the sodium or potassium compounds tend to react with electrophiles at nitrogen-1, whereas the more covalent magnesium compounds (indole Grignard reagents) and (especially) zinc complexes tend to react at carbon 3. In analogous fashion, polar aprotic solvents such as DMF and DMSO tend to favour attack at the nitrogen, whereas nonpolar solvents such as toluene favour C3 attack.

Carbon acidity and C2 lithiation
After the N–H proton, the hydrogen at C2 is the next most acidic proton on indole. Reaction of N-protected indoles with butyl lithium or lithium diisopropylamide results in lithiation exclusively at the C2 position. This strong nucleophile can then be used as such with other electrophiles.

Oxidation of indole
Due to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole.

Cycloadditions of indole
Only the C2–C3 pi bond of indole is capable of cycloaddition reactions. Intramolecular variants are often higher-yielding than intermolecular cycloadditions. For example, it have developed this Diels-Alder reaction to form advanced strychnine intermediates. In this case, the 2-aminofuran is the diene, whereas the indole is the dienophile. Indoles also undergo intramolecular] and cycloadditions. Despite mediocre yields, intermolecular cycloadditions of indole derivatives have been well documented. One example is the Pictet-Spengler reaction between tryptophan derivatives and aldehydes,which produces a mixture of diastereomers, leading to reduced yield of the desired product.

Hydrogenation
Indoles are susceptible to hydrogenation of the imine subunit to give indolines.

Multiple bacterial species in environmental niches developed quorum sensing (QS) to adapt and survive in natural communities. Many bacteria release diffusible chemical communication signals to sense the local environmental condition and eventually to regulate diverse physiological processes. Indole and its derivatives are among these bacterial signalling molecules, being produced by more than 85 Gram-positive and Gram-negative bacterial species primarily from the phyla Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. In many cases, however, indoles are involved not just in intra-species signalling, but also in inter-species and even inter-kingdom signalling between bacteria and their eukaryotic hosts. While indole-producing bacteria employ indole for QS, many non-indole-producing bacteria as well as eukaryotes sense and metabolise indole via oxygenases affecting their physiology in different ways. The following section describes the influence of indole in coordinating actions within organisms as well as its ubiquitous role in intercellular communication.

As an extracellular signal molecule in Escherichia coli, indole was observed to activate the transcription of genes gabT and astD involved in the degradation pathway of amino acids to pyruvate or succinate [8], suggesting that indole signalling may play a role in preparing the cells for a nutrient-poor environment when the catabolism of amino acids becomes important for energy production. Aside from being an active signal in metabolic control, indole also participates in cell cycle regulation by delaying cell division in E. coli until plasmid dimers are resolved to monomers contributing to the maintenance of plasmid copies and genetic stability. Bacterial cell division begins with the assembly of a large number of proteins that form a macromolecular complex called divisome. Cells exposed to indole were observed to have FtsZ, filamenting temperature-sensitive mutant Z, fluorescence uniformly distributed throughout the cytoplasm in contrast to cells not exposed to indole which had FtsZ localised at the cell mid-point as the cell cycle progressed. Since formation of the FtsZ ring is a prerequisite for division, prevention of its generation by indole effectively inhibits cell division. Moreover, as early as 1982, it has already been recognised that as little as 0.5 mM indole can uncouple the mitochondrial oxidative phosphorylation, the final biochemical pathway in the production of ATP. Both preventing FtsZ localisation and mitochondrial uncoupling may explain the role of indole in cell cycle regulation.

Several studies also reported that indole modulates bacterial persistence, the resistance and tolerance to antibiotics of some bacteria. Investigations in E. coli show that indole at physiologic concentrations induces the transition to a persistent state against lethal concentrations of ofloxacin, ampicillin and kanamycin. By contrast, toxic concentrations of indole, i.e. 1–2 mM where indole behaves as a membrane ionophore, lead to decreased persister frequency with ampicillin, ciprofloxacin and rifampicin. Interestingly, sub-minimal inhibitory concentrations of the aminoglycoside tobramycin elicited increased indole production in the pathogen Vibrio cholerae which causes the deadly disease cholera. This indole secretion induced increased persistence to lethal concentrations of aminoglycoside of V. cholerae through the action of RaiA, increasing the protection of ribosomes during stress, a novel pathway in which indole mediates bacterial persistence. In addition, indole also uses other mechanism to induce persistence namely, by reducing the production of ribosomes and hence, slowing down the metabolism. Notably, another opportunistic pathogen Pseudomonas aeruginosa can be resuscitated with the amino acid L-Pro after inducing the persister phenotype by reducing translation through depleting ATP levels. However, physiological concentrations of indole inhibited cell resuscitation of P. aeruginosa persister cells hinting on the positive role of indole produced by the commensal E. coli in preventing waking of the persister pathogenic P. aeruginosa in the gut. Consequent to the dissimilar observations on the effect of indole in bacterial persistence, more research is needed to demystify the role of indole in pathways leading to persistence of some bacteria.