Indole alkaloid
Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.
History
The uses of some indole alkaloids has been known for ages: The Aztecs have used psilocybin mushrooms in religious rituals for thousands of years. Extracts of the flowering plant Rauvolfia serpentina which contain reserpine were a common medicine in India around 1000 BC. Various African tribes used the ibogaine-rich roots of the perennial rainforest shrub Iboga as a traditional medicine. An infusion of Calabar bean seed pods was given to people accused of crime in Nigeria: vomiting was regarded as a sign of innocence, otherwise, the person was killed via the action of physostigmine, which is present in the plant and causes full body paralysis.Consumption of rye and related cereals contaminated with the fungus Claviceps purpurea causes ergotism in humans and other mammals. The relationship between ergot and ergotism was established only in 1717, and the alkaloid ergotamine, one of the main active ingredients of ergot, was isolated in 1918.
The first indole alkaloid, strychnine, was isolated by Pierre Joseph Pelletier and Joseph Bienaimé Caventou in 1818 from the plants of the genus Strychnos. The correct structural formula of strychnine was determined only in 1947, although the presence of the indole nucleus in the structure of strychnine was established somewhat earlier. Indole itself was first obtained by Adolf von Baeyer in 1866 while decomposing Indigo.
Classification
Indole alkaloids are distinguished depending on their biosynthesis. The two types of indole alkaloids are isoprenoids and non-isoprenoids. The latter include terpenoid structural elements, synthesized by living organisms from dimethylallyl pyrophosphate and/or isopentenyl pyrophosphate :- Non-isoprenoid:
- *Simple derivatives of indole
- *Simple derivatives of β-carboline
- *Pyrroloindole alkaloids
- *Indole-3-carbinol
- *Indole-3-acetic acid
- *Tryptamines
- *Carbazoles
- Isoprenoid:
- *hemiterpenoids: ergot alkaloids
- *monoterpenoids.
- *Strictosidine
- *Catharanthine
- *Yohimbine
- *Vinca
- *Strychnine
- *Ellipticine
Non-isoprenoid indole alkaloids
The number of known non-isoprenoid indole alkaloids is small compared to the number of indole alkaloids.
Simple indole derivatives
One of the simplest and yet widespread indole derivatives are the biogenic amines tryptamine and 5-hydroxytryptamine. Although their assignment to the alkaloid is not universally accepted, they are both found in plants and animals. The tryptamine skeleton is part of the vast majority of indole alkaloids. For example, N,''N-dimethyltryptamine, psilocin and its phosphorylated psilocybin are the simplest derivatives of tryptamine. Some simple indole alkaloids do not contain tryptamine, such as gramine and glycozoline. Camalexin is a simple indole alkaloid produced by the plant Arabidopsis thaliana'', often used as a model for plant biology.Simple derivatives of β-carboline
The prevalence of β-carboline alkaloids is associated with the ease of forming the β-carboline core from tryptamine in the intramolecular Mannich reaction. Simple β-carboline derivatives include harmine, harmaline, harmane and a slightly more complex structure of canthinone. Harmaline was first isolated in 1838 by Göbel and harmine in 1848 by Fritzche.Pyrolo-indole alkaloids
Pyrolo-indole alkaloids form a relatively small group of tryptamine derivatives. They are produced by methylation of indole nucleus at position 3 and the subsequent nucleophilic addition at the carbon atom in positions 2 with the closure of the ethylamino group into a ring. A typical representative of this group is physostigmine, which was isolated by Jobst and Hesse in 1864.Isoprenoid indole alkaloids
Isoprenoid indole alkaloids include residues of tryptophan or tryptamine and isoprenoid building blocks derived from the dimethylallyl pyrophosphate and isopentenyl pyrophosphate.Ergot alkaloids
alkaloids are a class of hemiterpenoid indole alkaloids related to lysergic acid, which, in turn, is formed in a multistage reactions involving tryptophan and DMAPP. Many ergot alkaloids are amides of lysergic acid. The simplest such amide is ergine, and more complex can be distinguished into the following groups:- Water-soluble aminoalcohol derivatives, such as ergometrine and its isomer ergometrinine
- Water-insoluble polypeptide derivatives:
- *Ergotamine group, including ergotamine, ergosine and their isomers
- *Ergoxine groups, including ergostine, ergoptine, ergoline and their isomers
- *Ergotoxine group, including ergocristine, α-ergocryptine, β-ergocryptine, ergocornine and their isomers.
Monoterpenoid Indoles Alkaloids or Secologanin Tryptamine Alkaloids
Most monoterpenoid alkaloids include a 9 or 10 carbon fragment , and the configuration allows grouping to Corynanthe, Iboga and Aspidosperma classes. The monoterpenoid part of their carbon skeletons are illustrated below on the example of alkaloids ajmalicine and catharanthine. The circled carbon atoms are missing in the alkaloids which contain the C9 fragment instead of C10.Corynanthe alkaloids include the unaltered skeleton of secologanin, which is modified in Iboga alkaloids and Aspidosperma alkaloids. Some representative monoterpenoid indole alkaloids:
There is also a small group of alkaloids present in the plant Aristotelia – about 30 compounds, the most important of which is peduncularine – which contain a monoterpenoid C10 part originating not from secologanin.
Bisindole alkaloids
Dimers of strictosidine derivatives, loosely called bisindoles but more complicated than that. More than 200 of dimeric indole alkaloids are known. They are produced in living organisms through dimerization of monomeric indole bases, in the following reactions:- Mannich reaction
- Michael reaction
- Condensation of aldehydes with amines
- Oxidative coupling of tryptamines ;
- Splitting of the functional group of one of the monomers.
Distribution in nature
The plants that are rich in non-isoprenoid indole alkaloids include Syrian rue, which contains harmane, harmine and harmaline, and Calabar bean containing physostigmine. Some members of the family Convolvulaceae, in particular Ipomoea violacea and Turbina corymbosa, contain ergolines and lysergamides. Despite the considerable structural diversity, most of monoterpenoid indole alkaloids is localized in three families of dicotyledon plants: Apocynaceae, Rubiaceae and Loganiaceae.Indole alkaloids are also present in fungi. For example, Psilocybe stuntzii contains derivatives of tryptamine and Claviceps purpurea contains derivatives of lysergic acid. The skin of many toad species of the genus Bufo contains a derivative of tryptamine, bufotenin, and the skin and venom of the species Bufo alvarius contains 5-MeO-DMT. Serotonin, which is an important neurotransmitter in mammals, can also be attributed to simple indole alkaloids.
Biosynthesis
Biogenetic precursor of all indole alkaloids is the amino acid tryptophan. For most of them, the first synthesis step is decarboxylation of tryptophan to form tryptamine. Dimethyltryptamine is formed from tryptamine by methylation with the participation of coenzyme of S-adenosyl methionine. Psilocin is produced by spontaneous dephosphorylation of psilocybin.In the biosynthesis of serotonin, the intermediate product is not tryptamine but 5-hydroxytryptophan, which is in turn decarboxylated to form 5-hydroxytryptamine.
Biosynthesis of β-carboline alkaloids occurs through the formation of Schiff base from tryptamine and aldehyde and subsequent intramolecular Mannich reaction, where the C carbon atom of indole serves as a nucleophile. Then, the aromaticity is restored via the loss of a proton at the C atom. The resulting tetrahydro-β-carboline skeleton then gradually oxidizes to dihydro-β-carboline and β-carboline. In the formation of simple β-carboline alkaloids, such as harmine and harmaline, pyruvic acid acts as the keto acid. In the synthesis of monoterpenoid indole alkaloids, secologanin plays the role of the aldehyde. Pirroloindole alkaloids are synthesized in living organisms in a similar way.
Biosynthesis of ergot alkaloids begins with the alkylation of tryptophan by dimethylallyl pyrophosphate, where the carbon atom C in the indole nucleus plays the role of the nucleophile. The resulting 4-dimethylallyl-L-tryptophan undergoes N-methylation. Further products of biosynthesis are chanoclavine-I and agroclavine – the latter is hydroxylated to elymoclavine, which in turn oxidizes into paspalic acid. In the process of allyl rearrangement, paspalic acid is converted to lysergic acid.
Biosynthesis of monoterpenoid indole alkaloids begins with the Mannich reaction of tryptamine and secologanin; it yields strictosidine which is converted to 4,21-dehydrogeissoschizine. Then, the biosynthesis of most alkaloids containing the unperturbed monoterpenoid part proceeds through cyclization with the formation of cathenamine and subsequent reduction to ajmalicine in the presence of nicotinamide adenine dinucleotide phosphate. In the biosynthesis of other alkaloids, 4,21-dehydrogeissoschizine first converts into preakuammicine which gives rise to other alkaloids of subtype strychnos and of the types Iboga and Aspidosperma. Bisindole alkaloids vinblastine and vincristine are produced in the reaction involving catharanthine and vindolin.