Indole Alkaloids

Indole alkaloids are compounds that use tryptophan or tryptamine as precursors. They are widely distributed in plants belonging to the families Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae. They have a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring, referred to as the indole ring. This indole ring with nitrogen atom gives rise to the basic properties of indole alkaloids that make them particularly biological activities. The most active indole alkaloids possessed a variety of pharmacological activities, including anticancer, antibacterial, antiviral, antimalarial, antifungal, anti-inflammatory, antidepressant, analgesic, hypotensive, anticholinesterase, antiplatelet, antidiarrheal, spasmolytic, antileishmanial, lipid-lowering, antimycobacterial, and antidiabetic activities.

Figure 1. Basic structure of the indole nucleus.

Biosynthetic reactions on the indole ring

Incorporation of the indole ring into alkaloid scaffolds endows powerful reactivity, which can lead to dramatic morphing of the compounds into complex, polycyclic structures. This is due to the unique chemistry of the benzopyrrole bicyclic ring system to undergo reactions at three sites, N1, C2 and C3. Indole can undergo a variety of electrophilic substitution modifications at C2 and C3, and can be subject to epoxidation at C2-C3, which inverts the polarity on C2 and leads to nucleophilic addition at this position.

• Electrophilic substitution/addition

Indole is an electron-rich heterocycle because of the conjugated nitrogen lone pair. Electrophilic substitution occurs readily on indole in the five-membered pyrrole ring since it is more electron rich compared to the benzene ring.

• Indole epoxidation

The C2-C3 double bond in indole can also be epoxidized by a flavin-dependent monooxygenase. The resulting indole 2,3-epoxide is in equilibrium with a hydroxyiminium ion due to the epoxide ring-opening reaction initiated by the nitrogen lone pair.

Classification

Indole alkaloids are divided into two main groups, namely non-isoprenoids, and isoprenoids.

• Non-isoprenoid indole alkaloids

The number of known non-isoprenoid indole alkaloids is relatively small and consists mainly of simple indole alkaloids, simple derivatives of β-carboline and pyrroloindole alkaloids.

➢ Simple indole alkaloids

The simple indole alkaloids are mostly derived from tryptophan or its direct precursor indole, which itself is formed from chorismate through anthranilate and indole-3-glycerol-phosphate in microorganisms and plants.

➢ 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 (non-isoprenoid) β-carboline derivatives include harmine, harmaline, harmane and a slightly more complex structure of canthinone.

➢ Pyrroloindole alkaloids

Pyrroloindole 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.

• Isoprenoid indole alkaloids

The isoprenoid indole alkaloids include hemiterpenoid indole alkaloids and monoterpenoid indole alkaloids.

➢ Hemiterpenoids indole alkaloids

The representative of tryptophan-derived hemiterpenoid indole alkaloids is ergot alkaloids. Ergot alkaloids have been considered as attractive synthetic targets due to their unique structure and potent biological activities.

➢ Monoterpenoids indole alkaloids

Monoterpenoid indole alkaloids constitute the largest and most heterogeneous group of nitrogen-containing secondary metabolites among this class of compounds, and they are widely distributed within the Apocynaceae, Loganiaceae, and Rubiaceae plant families.

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