Mesembrine-type alkaloids

The mood elevating properties of Sceletium tortuosum have been attributed to mesembrine [9], an alkaloid with potent selective serototun (5-HT) re-uptake inhibition activity 86). Other sceletium alkaloids as they are now referred to are mesembrenone, mesembrenol and tortuosamine. The use of mesembrine-type alkaloids was patented 92). Selective serotoiun (5-HT) re-uptake inhibitors (SSRls), like mesembrine, have become important treatments in the therapeutic management of depression 93). Several southern African medicinal plants, in particular Amaryllidaceae, have shown in vitro affinity for serotoiun re-uptake transporters 94,95). Several active alkaloids have been identified from Boophone and Crinum species 95, 96). 

Few isolations of mesembrine-type alkaloids have been reported. Two examples are the isolation of amisine (379) (from Hymenocallis arenicola) (183) and of mesembrenol (380) (from Crinum oliganthum) (184) from the Amaryllidaceae family. A third example is the isolation of mesembrenone (381), belonging to the mesembrine group, from the aerial parts of Narcissus palladulus (77) growing in Iberia. The structure was elucidated by spectroscopic and chemical methods (Fig. 22). 

The synthesis of mesembrine-type alkaloids belonging to the Sceletium alkaloid family has been carried out extensively in order to seek a... 

Several experiments provided interlocking evidence for the sequence tyrosine - tyramine -> iV-methyltyramine occurring during the biosynthesis of mesembrine-type alkaloids. These included the observation that both... 

Although both the Amaryllidaceae and Sceletium-type alkaloids have common biogenetic precursors, further investigations have revealed that the biosyntheses of these two classes of alkaloids are fundamentally different (185). Therefore, the presence of mesembrenone in Narcissus plants is of chemotaxonomic interest because mesembrines seem to be restricted to Aizoaceae-Mesembrylanthemoidaceae (Dicotyledons) (186). The present finding reveals the presence in the Amaryllidaceae of such unexpected alkaloids as those found in some Sceletium species. 

Ketene-Alkene Cycloadditions and Aza-Ring Expansion of Cyclobutanones in the Synthesis of Mesembrine and Joubertiamine-Type Alkaloids... 

D.i.a. Synthesis of Natural Products by Allylation of the Cyclohexenyl Moiety. Many alkaloids have a di-3a-aryloctahydroindole skeleton like mesembrane, mesembrine, or crinane-type alkaloids (Scheme 44). They have been of interest as synthetic targets due to the wide range of biological activities they exhibit. 

This type of action is found in kanna, or Sceletium expansum and Sceletium tortuosum (Aizoaceae), which have been used by South African shamans from prehistoric times to enhance animal spirits, sparkle the eyes, and to stimulate gaiety. The active constituent of kanna is a serotonin-like alkaloid called mesembrine, which is a potent serotonin re-uptake inhibitor—hence, some potential for the treatment of anxiety and depression however, careful clinical trials must be performed. 

Previous studies45 have demonstrated that tyrosine and phenylalanine follow separate pathways in providing the hydroaromatic C6—C2—N unit and the aromatic C6 unit of mesembrine. In this respect mesembrine follows the pattern, already established for the biosynthesis of the structurally related Amaryllidaceae alkaloids derived from O-methylnorbelladine, e.g. haemanthamine (70). The present investigation46 followed this lead and started with a reasonable working hypothesis (Scheme 12) in which the biosynthesis proceeds via O-methylnor-belladine (68) and intermediates of the crinine type such as (75). However, feeding... 

The investigators then tested ortho-tritiated phenylalanine, which would be expected to label the intermediate (68) with tritium as indicated. If intermediates of the crinine type are involved, a 50% loss of tritium with respect to an internal standard would be expected as a result of the phenol coupling process. Surprisingly, mesembrine was produced without loss of tritium and the alkaloid was found to have the tritium labelling pattern shown in (76) (Scheme 12). 

The mesembrine alkaloids, e.g. mesembrine (97), bear a strong structural resemblance to the Amaryllidaceae alkaloids of the crinine type, e.g. haemanthamine (91), but careful investigation has shown that the only aspect of biosynthesis... 

The approximately 25 compounds of this group possess several types of ring systems the mesembrine alkaloids are major among these. 

The spectral data suggested that the alkaloid was represented as 42. Confirmation of this structure was obtained by establis g the identity of the alkaloid with the product obtained from treating (—)-mesembrine methiodide (43) with aqueous base. Because at the time of isolation this represented the first member of the jouberdamine type having a dioxyaryl ring, the possibility that it was an artifact, being produced from a (—)-mesembrine metho salt as a result of the basic isolation conditions, could not be discounted. This eventuality would now seem to be unlikely, for several other dioxyarylsecomesembranes have been isolated subsequently from S. namaquense. 

The group of alkaloids exemplified by mesembrine (6.202), shows a structural kinship with Amaryllidaceae alkaloids of the haemanthamine (6.187) type. However, the only aspect of biosynthesis common to these two groups of alkaloids is their origin in phenylalanine and tyrosine results, crucially with doubly labelled precursors, showed that various norbelladine (6.180) derivatives were only incorporated after fragmentation [148]. 

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