Tryptophanderived alkaloids

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Alkaloids derived from L-tryptophan hold the indole nucleus in a ring system. The ring system originates in the shikimate secondary compounds building block and the anthranilic acid pathway. It is known that the shikimate block,

in general, and anthranilic acid, in particular, are precursors to many indole alkaloids. However, there are many rearrangement reactions which can convert the indole ring system into a quinoline ring.

2.4.1. Psilocybin pathway

In this pathway, L-tryptophan is enzymatically transferred to tryptamine and subsequently, through the activity of SAM, to psilocin. By the reaction of phosphorylation, psilocin is converted into psilocybin (Figure 39).

Psilocybin and psilocin are psychoactive hallucinogenous alkaloids synthesized from the small mushroom genus Psilocybe spp. On average, the concentration of these alkaloids is 300g-3 in 100 g of mushroom mass. Structurally, these alkaloids are neurotransmitters 5-HT.

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter.

Figure 39. Psilocybin and serotonin synthesis pathway.

It is found in many cellular complexes, such as the CNS, the peripheral nervous system and the cardio vascular system, but it also appears in blood cells.

2.4.2. Elaeagnine, harman and harmine pathway

From tryptamine (derived from L-tryptophan, Figure 39), the synthesis pathway of harman and harmine, which are alkaloids based on a ^-carboline ring, also starts. Using the Schiff base formation and Mannich-like reaction, the carboline ring is synthesized. Then, by a Mannich-like reaction using keto acid and oxidative decarboxylation, harmaline is synthesized. Harmaline is converted to harmine and tetrahydroharmine. Certainly, following the above-mentioned Mannich reaction and oxidative decarboxylation, a reduction reaction can ensue and this leads to the synthesizing of elaeagnine (Figure 40). Elaeagnine is synthesized in Elaeagnus angustifolia (Elaeagnaceae). Harmine and harman are alkaloids having fully aromatic ^-carboline structures. They

Schiff base formation Mannich-like reaction Mannich-like reaction using keto acid Oxidative decarboxylation

Schiff base formation Mannich-like reaction Mannich-like reaction using keto acid Oxidative decarboxylation

Reduction reaction

Figure 40. Scheme of elaeagnine, harman and harmine synthesis pathway.

have been detected in Peganum harmala (Zygophyllaceae). These alkaloids have psychoactive properties. Harman is a very important mammalian alkaloid210.

2.4.3. Ajmalicine, tabersonine and catharanthine pathway

In this pathway, over 3000 alkaloids are synthesized. These are terpenoid indole alkaloids, one of the principal groups of alkaloids in the plant kingdom. Some of the most important alkaloids used widely in medicine belong to this group. As stated in Chapter 1, these alkaloids belong mainly to eight botanical families, of which Apocynaceae, Loganiaceae and Rubiaceae are the most important from the perspective of existing applications. Ajmalicine and akuammicine are typical alkaloids containing the Corynanthe nucleus, and tabersonine is typical for the Aspidosperma nucleus. The Iboga type of these alkaloids may be clearly seen in catharanthine and iboganine. All these alkaloids have C9 and C10 fragments in their structure, which derive from terpenoid. Molecules from these alkaloids originate partly from terpenoid, in combination with tryptamine. The synthetic pathway starts with geraniol and, via iridodial and iridotrial, is synthesized as loganin. Subsequently, through oxidation and formation of alkene and ring cleavage, loganin is converted to secologanin, which crosses tryptamine to form the Corynanthe-type nucleus. From this ring, akummicine or ajmalicine is synthesized in turn. Ajmalicine is derived from tryptamine (partly from geraniol) via secologanin, strictosidine and cathenamine. Reduction of cathenamine to ajmalicine is facilitated by enzyme NADPH activity. Again by transformation, the Aspidosperma-type tabersonine or Iboga-type catharanthine is synthesized (Figure 41). Yohimbine is a carbocyclic variant of ajmalicine. It has been found in species belonging to the Apocynaceae and Rubiaceae families. Yohimbine can be converted to reserpine and rescinnamine (trimethoxybenzoyl esters). Rescin-namine is a trimethoxycinnamoyl ester.

2.4.4. Vindoline, vinblastine and vincristine pathway

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants: vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle (Catharanthus roseus). The vindo-line synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin's disease (a form of lym-phoid cancer), while vincristine is used clinically in the treatment of children's leukaemia. Vincristine is more neurotoxic than vinblastine.

Figure 41. Pattern of the ajmalicine, tabersonine and catharanthine pathway.
Diagram Alkaloids
Figure 42. Diagram of the vindoline, vinblastine and vincristine pathway.

2.4.5. Strychnine and brucine pathway

The synthetic pathway starts with the preakuammicine structure (Figure 42) by hydrolysis, decarboxylation and condensation reactions to aldehyde (Wieland-Gumlich), and subsequently reacts with acetyl-CoA to make a hemiacetal form of aldehyde (Wieland-Gumlich) and strychnine (Figure 43).

Strychnine and brucine are extremely toxic alkaloids. Strychnine binds itself to receptor sites in the spinal cord and accommodates glycine. Brucine is a dimethoxy form of strychnine, and is less toxic.

2.4.6. Quinine, quinidine and cinchonine synthesis pathway

As noted in Chapter 1, quinine, quinidine, cinchonidine and cinchonine alkaloids are found particularly in the genus Cinchona from the botanical family Rubiaceae. They have a powerful bioimpact and are important anti-malarial drugs. Quinidine is also used to treat cardiac arrhythmias because it inhibits fibrillation, where there is no coordinated contraction of muscle fibres in the heart. During the synthesis of these alkaloids, a change occurs in the nucleus. The indole nucleus is transformed into the quinoline nucleus. This is one reason why these compounds are known as quinoline alkaloids. The synthesis pathway starts with strictosidine, which is transformed by hydrolysis and the decarboxylation reaction into corynantheal (Figure 44). At this point, the indole nucleus and cinchoamine are synthesized. Cinchonamine is an indole derivative and an intermediate compound in the quinine pathway. At the next stage of the synthesis, the transformation of the nucleus occurs and the resultant intermediate cinchoninone no longer contains the indole nucleus. By the enzymatic reaction of NADPH, cinchonidine is synthesized from cinchoninone and subsequently changes to quinine. Cinchonidine and quinine are similar alkaloids. The difference is only that cinchonidine has H while quinine has OCH3 in the same position. By epimerization and NADPH activity, cincho-nine or quinine are synthesized from cinchoninone. The difference between cinchonine and quinidine is very similar to that between cinchonidine and quinine.

Figure 43. Diagram of the strychnine and brucine pathway.
Quinine Alkaloid
Figure 44. Diagram of the quinine, quinidine and cinchonine synthesis pathway.

2.4.7. Eserine synthesis pathway

Eserine (physostigmine) has a pyrroloindole skeleton. This alkaloid is used as an anticholinesterase drug, which is fairly important in the treatment of Alzheimer's disease. Eserine is synthesized in Physostigma venenosum and stored in the seeds of this leguminous plant. The synthesis pathway starts with tryptamine, which is transformed into eserine (Figure 45).

2.4.8. Ergotamine synthesis pathway

Ergotamine is one of the ergot alkaloids produced by the fungus genus Claviceps, which lives on cereal kernels and grass seeds. Toxicity of ergot kernels and grass seeds is extreme. The ergotamine synthesis pathway starts from L-tryptophan and, continuing via chanoclavine-I and chanoclavine-2, then agroclavine, elymo-clavine and pispalic acid, is converted into D-(+)-lysergic acid. This compound is very important in ergotamine synthesis. By powerful enzymatic activity (ATP and SH) and hydroxylation, ergotamine is synthesized (Figure 46). Ergotamine also contains a peptide fragment in its structure.

Figure 45. Diagram of the eserine synthesis pathway.
Synthesis Ergotamine
Figure 46. Diagram of the ergotamine synthesis pathway.

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