Erythrina alkaloids, generally containing benzyl-tetrahydroisoquinoline structure, are widely distributed in Erythrina species, a genus of plants which belong to the Fabaceae family in tropical and subtropical regions. The Erythrina alkaloids can be found in several organs of Erythrina trees but are primarily found in their seeds. They display several unique properties, and are the subject of active scientific research relating to their synthesis and bioactivity.
Two kinds of alkaloids are isolated from the Erythrina plants. One is Erythrina alkaloid, the other one is HomoErythrina alkaloid. The shared feature of Erythrina alkaloids is the Erythrinane skeleton, which is a tetracyclic spiroamine structure containing 4 rings, labeled A, B, C and D, respectively. [1]
The skeletal structures of both Erythrina and HomoErythrina alkaloid contain 4 rings. The D ring is generally aromatic. It can be benzene or heterocyclic ring. The difference between Erythrina and HomoErythrina alkaloids is the C ring's member amount. The configuration of the 5-carbon is always S in all known isolated alkaloids. Some of the Erythrina alkaloids have 3-alkyloxy substituents on A ring, and the configuration of 3-carbon is always R. But in HomoErythrina alkaloids, it varies between R and S at 3-carbon. The Erythrina alkaloids have three basic categories: dienoid, alkenoid and lactonic alkaloids. Some other different types of Erythrina alkaloids are also reported but they are relatively rare. Generally, Alkenoid and Dienoid alkaloids are more common and widely researched in synthesis and pharmacology studies. Some other special Erythrina and HomoErythrina alkaloids are also identified, and they have generally lactonic and pyridine D rings. Scientists are researching the properties of these alkaloids, mostly to see if there are potential applications on neuroscience. [1]
The Erythina alkaloids include, among others erysodine, erytharbin, erythrartine and erysotramidine. [2] [3]
From early research in 1930s of the American biochemist Karl Folkers, [4] it was believed that Erythrina plant's seeds extracts have curare-like action. Other works had shown that the alkaloids could show antiepileptic, anticonvulsant and tranquilizing effects. Some alkaloids with particular bioactivities like Erythraline, plenty of them were first isolated and identified by Venancio Deulofeu in 1947. Even Karl Folkers isolated Erysodine and Erysopine in 1940, but some other free alkaloids still existed in the Erythrina seeds extract mixture. [5] A considerable amount of Erythrina alkaloids were found to be competitive neuronal nicotinic acetylcholine receptors antagonists. Thus, the structures and properties of the alkaloids do inspire new drug development. Till now, 143 compounds in the family are identified from Erythrina.
The biosynthesis pathway of this kind of alkaloid and derivatives was first proposed by D. H. R. Barton and his colleagues in 1968. [6] They had proposed a key 9-membered ring intermediate. They produce erysodienone as the primary Erythrinan derivative. Using the precursor, other kinds of Erythrina alkaloids are produced. Later on, M. H. Zenk revised it and confirmed the 9-membered ring is the biosynthetic pathway in 1999. [7] The biosynthetic pathway showed the precursor of the key intermediate erysodienone had a structure like dopamine, which also can suggest the metabolism was highly related to dopamine, a key signaling molecule in neural system.
The pathway had inspired some synthetic chemistry researchers' work to synthesize few other alkaloids in the family. Few works have been reported as the biosynthetic pathway was revealed. [8] [9] [10] In 2016, T. Fukuyama's group developed a concise route to synthesize several Erythrina alkaloids, including erythraline and erystamidine. [11] In fact, since most of the alkenoids and dienoids share the same skeletal structure, the approach can easily get most of the alkaloids with substrate adjustments.
In 2013, Tadahiro Etoh and Yong Pil Kim found that transforming growth factor (TGF)-β-activated kinase (TAK1) was one of the target molecules of erythraline likely involved in its anti-inflammatory effect. Therefore, erythraline may show the effect on inflammatory diseases, such as rheumatism and hepatitis, through inhibition of TAK1. [12]
Still, few alkaloids showed selectivity for b2-containing nAChRs, particularly thea4b2 subtype. W. P. Santos has reported in vitro and ex vivo anti-cholinesterase activities of Erythrina velutina leaf extracts, containing a relatively high fraction of the alkaloids. Aqueous extract and alkaloids rich extract crossed the blood-brain barrier to inhibit cholinesterase activity in the brain. Aqueous extract and alkaloids rich extract also exhibited a dual inhibitory action on acetylcholinesterase and butyrylcholinesterase. [13]
M. M. Mohammed's research in 2012 found that crude alkaloidal fraction caused a reduction in the viability of mock-infected MT-4 cells with a CC50 of 53 μM and a 50% protection of MT-4 cells against HIV-1 induced cytopathogenicity with an EC50 of >53 μM, compared with EFV as a positive control, which had a CC50 of 45 μM and an EC50 of 0.003 μM. [14]
Ginkgolides are biologically active terpenic lactones present in Ginkgo biloba. They are diterpenoids with 20-carbon skeletons, which are biosynthesized from geranylgeranyl pyrophosphate.
Harmine is a beta-carboline and a harmala alkaloid. It occurs in a number of different plants, most notably the Syrian rue and Banisteriopsis caapi. Harmine reversibly inhibits monoamine oxidase A (MAO-A), an enzyme which breaks down monoamines, making it a Reversible inhibitor of monoamine oxidase A (RIMA). Harmine does not inhibit MAO-B. Harmine is also known as banisterin, banisterine, telopathin, telepathine, leucoharmine and yagin, yageine.
Noscapine is a benzylisoquinoline alkaloid, of the phthalideisoquinoline structural subgroup, which has been isolated from numerous species of the family Papaveraceae. It lacks significant hypnotic, euphoric, or analgesic effects affording it with very low addictive potential. This agent is primarily used for its antitussive (cough-suppressing) effects.
Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower shikimi, from which it was first isolated in 1885 by Johan Fredrik Eykman. The elucidation of its structure was made nearly 50 years later.
Phosphoribosyl pyrophosphate (PRPP) is a pentose phosphate. It is a biochemical intermediate in the formation of purine nucleotides via inosine-5-monophosphate, as well as in pyrimidine nucleotide formation. Hence it is a building block for DNA and RNA. The vitamins thiamine and cobalamin, and the amino acid tryptophan also contain fragments derived from PRPP. It is formed from ribose 5-phosphate (R5P) by the enzyme ribose-phosphate diphosphokinase:
Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction:
Substitution of the heterocycle isoquinoline at the C1 position by a benzyl group provides 1‑benzylisoquinoline, the most widely examined of the numerous benzylisoquinoline structural isomers. The 1-benzylisoquinoline moiety can be identified within numerous compounds of pharmaceutical interest, such as moxaverine; but most notably it is found within the structures of a wide variety of plant natural products, collectively referred to as benzylisoquinoline alkaloids. This class is exemplified in part by the following compounds: papaverine, noscapine, codeine, morphine, apomorphine, berberine, tubocurarine.
Pristinamycin IIA is a macrolide antibiotic. It is a member of the streptogramin A group of antibiotics and one component of pristinamycin. Pristinamycin IIA was first isolated from the Streptomyces virginiae, but has been isolated from other microorganisms and thus has been given a variety of other names such as Virginiamycin M1, Mikamycin A, and Streptogramin A. Pristinamycin IIA structure was determined by chemical and instrumental techniques, including X-ray crystallography. Pristinamycin IIA is of interest from a biosynthetic viewpoint because it contains the unusual dehydroproline and oxazole ring systems. The only experimental evidence bearing on the formation of the oxazole ring is found in work on the biosynthesis of the alkaloid annuloline.
Steroidal alkaloids have the basic steroidal skeleton with nitrogen-based functional groups attached to the skeleton. More specifically, they are distinguished by their tetracyclic cyclopentanoperhydrophenanthrene skeleton that marks their close relationship with sterols. They fall in two major categories: Solanum alkaloids and Veratrum alkaloids. A Steroidal alkaloid has also been found in Chonemorpha fragrans, 'chonemorphine' was used to treat intestinal infections in Wistar rats..
Fumigaclavine A is an antibacterial ergoline alkaloid produced by endophytic Aspergillus.
Communesin B is a cytotoxic chemical compound isolated from Penicillium strains found on the marine alga Ulva intestinalis. It exhibits cytotoxicity in vitro against human lung carcinoma, prostate carcinoma, colorectal carcinoma, cervical adenocarcinoma, and breast adenocarcinoma cell lines.
Akuammicine is a monoterpene indole alkaloid of the Vinca sub-group. It is found in the Apocynaceae family of plants including Picralima nitida, Vinca minor and the Aspidosperma.
Gigactonine is a naturally occurring diterpene alkaloid first isolated from Aconitum gigas. It occurs widely in the Ranunculaceae plant family. The polycyclic ring system of this chemical compound contains nineteen carbon atoms and one nitrogen atom, which is the same as in aconitine and this is reflected in its preferred IUPAC name.
Tambjamines are a group of natural products that are structurally related to the prodiginines. They are enamine derivatives of 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC).
Erysodienone is a key precursor in the biosynthesis of many Erythrina-produced alkaloids. Early work was done by Derek Barton and co-workers to illustrate the biosynthetic pathways towards erythrina alkaloids. It was demonstrated that erysodienone could be synthesized from simple starting materials by a similar approach as its biosynthetic pathway, which led to the development of the biomimetic synthesis of erysodienone.
N-Feruloylserotonin an alkaloid and polyphenol found in safflower seed. Chemically, it is an amide formed between serotonin and ferulic acid. It has in vitro anti-atherogenic activity.
Salutaridinol is a modified benzyltetrahydroisoquinoline alkaloid with the formula C19H23NO4. It is produced in the secondary metabolism of the opium poppy Papaver somniferum (Papaveraceae) as an intermediate in the biosynthetic pathway that generates morphine. As an isoquinoline alkaloid, it is fundamentally derived from tyrosine as part of the shikimate pathway of secondary metabolism. Salutaridinol is a product of the enzyme salutaridine: NADPH 7-oxidoreductase and the substrate for the enzyme salutaridinol 7-O-acetyltransferase, which are two of the four enzymes in the morphine biosynthesis pathway that generates morphine from (R)-reticuline. Salutaridinol's unique position adjacent to two of the four enzymes in the morphine biosynthesis pathway gives it an important role in enzymatic, genetic, and synthetic biology studies of morphine biosynthesis. Salutaridinol levels are indicative of the flux through the morphine biosynthesis pathway and the efficacy of both salutaridine: NADPH 7-oxidoreductase and salutaridinol 7-O-acetyltransferase.
Apparicine is a monoterpenoid indole alkaloid. It is named after Apparicio Duarte, a Brazilian botanist who studied the Aspidosperma species from which apparicine was first isolated. It was the first member of the vallesamine group of alkaloids to be isolated and have its structure established, which was first published in 1965. It has also been known by the synonyms gomezine, pericalline, and tabernoschizine.
Pyonitrins are a family of highly hydrogen-deficient alkaloids discovered from an insect-associated Pseudomonas protegens strain. In vivo, pyonitrins A-D show activity against pathogen Candida albicans, which commonly cause bloodstream infections.
Jamaicamide A is a lipopeptide isolated from the cyanobacterium Moorea producens, formerly known as Lyngbya majuscula. Jamaicamide A belongs to a family of compounds collectively called jamaicamides, which are sodium channel blockers with potent neurotoxicity in a cellular model. Jamaicamide A has several unusual functionalities, including an alkynyl bromide, vinyl chloride, β-methoxy eneone system, and pyrrolinone ring.