Skeleton diversity

The skeleton nucleus of the alkaloid is the main criterion for alkaloid precursor determination. Many skeletons are produced in the process of alkaloid synthesis. Figure 24 illustrates some nuclei and skeletons supplied in the synthesis. Alkaloid

SECONDARY

Pyrroloindole alkaloids

Indole alkaloids Quinoline alkaloids Ergot alkalo

Terpenoid indole alkaloids

Indolizine alkaloids Piperidine alkaloids

Quinolizidine alkaloids

Indolizine alkaloids Piperidine alkaloids

Pyridine alkaloids

Phenylethylamin' alkaloids

Simple tetra-PRIMARY hydroisoquinoline

L-Tyrosine alkaloids Quinazoline

Nicotinic Glucose acid glycolysis

ADP NAD L -Tryptophan ATP QH NADH2

Pyrroloindole alkaloids

Acridine alkaloids

Ephedra alkaloids Tropane

Terpenoid indole alkaloids

Quinolizidine alkaloids

Nicotinic Glucose acid glycolysis

ADP NAD L -Tryptophan ATP QH NADH2

Quinolizidine

METABOLISM

Figure 23. General scheme of alkaloid synthesis.

METABOLISM

Figure 23. General scheme of alkaloid synthesis.

relates only to the reactions of this stage of the synthesis. Moreover, skeletons can change their form during the synthesis. A case in point is the synthesis of quinine, where the indole nucleus is reconstructed to form the quinoline nucleus.

During biosynthetic processes, L-lysine can produce at least 4 alkaloid skeletons with different alkaloid nuclei: piperidine nucleus (C5N skeleton), indolizine nucleus (C5NC3 skeleton), quinolizidine nucleus (C5NC4 skeleton) and pyridon nucleus (with the variated quinolizidine nucleus and C5NC4 skeleton). The ability of L-lysine to provide different alkaloid nuclei is related to the role of this DNA amino acid in plant and animal organisms. In plants, this amino acid is an endogenous compound synthesis that is used in both primary and secondary metabolisms. In the animal kingdom, lysine is principally an exogenous amino acid, mainly of dietary origin. Consequently, L-lysine-derived

NH2 TNH2

Piperidine nucleus H

Indolizine nucleus

C5NC3 skeleton

Quinolizidine nucleus

C5NC4 skeleton

Pyridon nucleus Figure 24. L-lysine-derived nuclei.

C5NC4 skeleton alkaloids with different type of skeletons have a very different biological impact on the organisms. Piperidine, indolizine, quinolizidine and pyridon alkaloids have different effects on the digestive and nervous systems of herbivores. Their acute toxicity and ability to temporarily or permanently change cell numbers or the functional metabolism differ markedly. Moreover, skeleton structure also influences taste. In this regard, the position of the N atom is important. In all the skeletons derived from L-lysine, the position of N is the same as in the substrate.

In the case of the izidine alkaloids (Figure 25) the position of the nitrogen atom is the same, but the number of C atoms should be different. The difference lies in the rings of these alkaloids. They represent different structural groups of alkaloids, although they have two rings and are two cyclic compounds. This structural point is key to their biological activity. Pyrrol-, indol- and quinolizidine rings display structural similarities but diversity in both their origin and, what is very important, bioimpact. Even small differences in nucleus can effect huge changes in the alkaloid activity213.

L-ornithine (Figure 26) produces the pyrrolidine nucleus (C4N skeleton). This nucleus is also constructed within tropane alkaloids (C4N skeleton +) (Figure 26). Alkaloids which contain the pyrrolidine and tropane nuclei are

C5N skeleton co Co CO

Pyrrolizidine Indolizidine Quinolizidine

Figure 25. Nuclei and skeletons of izidine alkaloids.

NH2 ^NH2 N C4N skeleton

Pyrrolidine nucleus

Pyrrolidine nucleus

Figure 26. The source and forms of the pyrrolidine ring.

Figure 26. The source and forms of the pyrrolidine ring.

very vigorous in their biological activity. Common pyrrolidine nucleus alkaloids include hygrine, hyoscyamine, cocaine, cuscohygrine and so on. The best-known plants alkaloids with pyrrolidine nuclei are henbane (Hyoscyamus niger), deadly nightshade (Atropa belladonna) and Jamestown weed (Datura stramonium).

The imidazole nucleus (Figure 27) is supplied during alkaloid biosynthesis by L-histamine. Typical alkaloids with the imidazole nucleus include histamine,

Figure 27. L-histidine and the nuclei of imidazole and manzamine alkaloids.

histidine, procarpine and pilosine. They are found as basic alkaloids in two principal families, Cactaceae and Rutaceae.

The basic alkaloid in Pilocarpus jaborandi (Rutaceae) is pilocarpine, a molecule of which contains an imidazole nucleus and is also used as a clinical drug. During alkaloid synthesis, L-histidine can produce the manzamine nucleus (Figure 27). These alkaloids are quite widespread, though they were first isolated in the late 1980s in marine sponges57. They have an unusual polycyclic system and a very broad range of bioactivities. Common alkaloids with this nucleus include manzamine A, manzamine B, manzamine X, manzamine Y, sextomanzamine A and so on.

In the case of C6C2N skeletons (Figure 28) converted from the antranilic acid into the alkaloids quinazoline, quinoline and acridine, nuclei are constructed inside the cyclic system. Only this part is derived from the precursor, while the rest of the ring system comes from other sources32. Alkaloids with the C6C2N skeleton occur in many species, such as Peganum harmala, Dictamus albus, Skimmia japonica and Ruta graveolens. The best known alkaloids containing these nuclei are peganine (vasicine), dictamine, skimmianine, melicopicine, acronycine and rutacridone.

All alkaloids with the C6C2N skeleton are bioactive; since they constitute a very large group of compounds, they display different properties. As already stated, anthranilic acid provides these alkaloids with a nucleus (Figure 28) but the rest of the skeleton comes from other donors. Simply this can have an influence on the characteristic activities of alkaloids.

Nicotinic acid (Figure 29) provides alkaloids with the pyridine nucleus in the synthesizing process. This nucleus appears in such alkaloids as anabasine, anatabine, nicotine, nornicotine, ricine and arecoline. Moreover, many alkaloids

,co2h

,co2h

Quinazoline nucleus n n

C6C2N skeleton

Quinazoline nucleus

C6C2N skeleton

Quinolizidine Alkaloids
Figure 28. The nuclei produced by anthranilic acid in alkaloids.

Nicotinic acid = Niacin = Vitamin B3

,CO2H

,CO2H

Pyridine nucleus

C6N skeleton

(Niacin + Acetate) Sesquiterpene pyridine nucleus

Figure 29. The nucleus of alkaloids derived from nicotinic acid.

contain the pyridine nucleus as part of their total skeleton. For example, anaba-sine is derived from nicotinic acid and lysine18. Alkaloids with the pyridine nucleus occur in such plants as tobacco (Nicotiana tabacum), castor (Ricinus communis) and betel nuts (Areca catechu). The sesquiterpene pyridine nucleus derives partly from nicotinic acid, and partly from the acetate pathway. There are more than 200 known alkaloids in this group58.

In the alkaloid synthesis, L-phenylalanine (Figure 30) provides to alkaloid the phenyl or phenylpropyl nucleus. These kinds of nuclei occur in cathionine, cathine, ephedrine, pseudoephedrine and norpseudoephedrine. Such alkaloids are found especially in many species of Ephedra. Natural alkaloid molecules from these plants have similar properties to synthetic compounds used as narcotics (e.g., amphetamine).

L-tyrosine (Figure 31) is an aromatic amino acid (similar in compound from L-phenylalanine) which also provides phenyl (Figures 30-31) and phenylpropyl

Figure 30. L-phenylanine-derived nuclei in alkaloid biosynthesis.

Phenyl nucleus

C6C2N skeleton

Phenylpropyl nucleus

C6C3 skeleton

Figure 31. Nuclei supplied to alkaloids by L-tyrosine in the synthesizing process.

(Figures 30-31) nuclei for alkaloids. Molecules containing nuclei from L-tyrosine include, for example, mescaline, anhalamine, papaverine, curare and morphine. They are biologically very strong natural compounds and occur relatively widely in the plant kingdom (Table 10).

Another aromatic amino acid, L-tryptophan (Figure 32), contains the indole nucleus. This nucleus is synthesized in a large number of alkaloids, such as psilocin, psilocybin, harmine, catharanthine, reserpine, ajmalicine, vindoline, vincristine, strychnine, quinine, ergotamine and other ergot alkaloids. The alkaloid nucleus as a fragment of the precursor structure given to the new molecule during its synthesis is very interesting and relatively unknown. The evident original donor of each carbon in the alkaloid ring is still not exactly comprehended. However, along the alkaloid pathways from the secondary building blocks to the synthesis of alkaloids is a long chain of reactions. The nucleus translocation into the alkaloid molecule is the most important step in this alkaloid synthesis.

The indole nucleus can change during the synthesizing reaction into quino-line nucleus (Figure 32). Moreover L-tryptophan, the precursor, provides both ^-carboline and pyrroloindole nuclei. Iboga, Corynanthe and Aspidosperma nuclei also originate from L-tryptophan (Figure 32). Alkaloids with nuclei derived from this amino acid tend to be very active compounds with a relatively widespread provenance in nature (Table 10).

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