Lycopodium alkaloids huperzine

In an effort to synthesize the lycopodium alkaloid huperzine Q 437 the Pauson-Khand cyclization, leading to the very promising intermediate 436, was investigated in detail. 

Among the alkaloids in Lycopodium plants, huperzine A (2) was isolated from Lycopodium serratum Thunb. in 1986 and has been shown to have acetylcholine esterase (AChE) inhibitory activity and to improve memory disorders in Alzheimer s disease [13-15]. In addition to these unique activities, it was recently reported that some Lycopodium alkaloids possessing skeletons different from that of huperzine A (2) are able to enhance nerve growth factor (NFG) mRNA expression and production in human glial cells [16, 17]. Because of their useful biological activities, Lycopodium alkaloids are an attractive target in natural product chemistry, synthetic chemistry, and medicinal chemistry. 

Hemscheidt and Spenser conducted feeding experiments and found that Lycopodium alkaloids are secondary metabolites of lysine (3) [18] (Scheme 1). The decarboxylation of lysine (3) yields cadaverine (4), which consists of five carbons, and this, in turn, is converted into A -piperideine (5). The condensation of A -piperideine (5) with 3-oxoglutaric acid (6) produces 4-(2-piperidyl)acetoacetic acid (7) and this is converted into pelletierine (8) after a decarboxylation reaction. The biosynthetic process from this point to structurally complex Lycopodium alkaloids, such as lycopodine (1) and huperzine A (2), is deduced from the structures of the isolated alkaloids. The condensation of pelletierine (8) with 4-(2-piperidyl)... 

Acetylcholinesterase Alzheimer s disease biological activity clinical trials club mosses huperzine A Lycopodiaceae lycopodium alkaloids pharmacology... 

The (+)-enantiomeric form of huperzine A has been synthesized and tested for AChE inhibition in vitro and the activity compared to the natural (—)-enantiomer. The (—)-enantiomer of huperzine A was shown to be the more active form, as well as being the most potent of all lycopodium alkaloids currently reported [13, 30]. 

This review describes the recent studies on Lycopodium alkaloids isolated from the genus Lycopodium and Huperzia, the proposed biogenetic pathway, and the syntheses of Lycopodium alkaloids based on these biogenetic proposals. In section II, all of the Lycopodium alkaloids isolated so far, and including our recent work, are surveyed, while sections III and IV mainly deal with the biogenetic pathways and the total syntheses of the Lycopodium alkaloids, respectively. In sections V, VI, and VII, pharmacology, total synthesis, and SAR studies, respectively of huperzine A (I) are briefly surveyed. 

Huperzine A (1) has undergone clinical trials in China in patients suffering from various memory disorders, including Alzheimer s disease. Significant effects of huperzine A (1) were noted in these patients in terms of their quality of life and it has become available to numerous individuals for the treatment of memory problems. Since the other pharmacological activities of the various types of Lycopodium alkaloids have been poorly studied, this area should also be developed. Similarly, the biosynthesis of Lycopodium alkaloids has been only preliminarily studied, and the pathways have not been characterized with respect to the intermediates and the relevant enzymes. It will further be of value to elucidate the structural and pharmacological features of more Lycopodium alkaloids. 

Huperzine A, a potent anticholinesterase alkaloid, and huperzine B were separated from a Chinese medicinal herb, Huperzia serrata (Thunb) Trev. Lycopodium serratum Thunb.), (Lycopodiaceae), by Liu et al [25]. The plant was used in Zhejiang Province of China for treatment of some mental disorders. 

Ayer WA, Browne LM, Orszanska H, Valenta Z, Liu JS (1989) Alkaloids of Lycopodium selago - on the identity of selagine with huperzine-A and the structure of a related alkaloid. Can J Chem-Revue Canadienne De Chimie 67(10) 1538-1540. doi 10.1139/v89-234... 

A series of lycoposerramines isolated by Takayama et al. were fawcettimane-type and fawcettidane-type alkaloids from the same species Lycopodium serratum in Japan which contains huperzines in China. The structure of lycoposerramine-A (21), which has a l,2,4-oxadiazolidin-5-one residue in the molecule, was elucidated through spectroscopic data and X-ray analysis (31,32). Seven new alkaloids, lycoposerramines B (22), C (23), D (24), E (25), P (26), Q (27), S (28), and U (29), with novel, fawcettimine-related structures were isolated from the club moss Lycopodium serratum in Japan (33). Their relative and absolute stereochemistries were analyzed by spectroscopic data. X-ray analysis, and chemical correlations. The skeleton of lycoposerramine A (21) may be constructed by the incorporation of NH3, NH2OH, and a Ci unit into a fawcettimine-type skeleton. 

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