Huperzine isolation

Traditionally, plants are a rich source of AChE inhibitors. People from the Caucasus used bulbs of snowdrops Galanthus sp.) to treat forgetfulness [25]. The active compound in this plant has been isolated and called galanthamine. Other plant-derived AChE inhibitors used for treatment of Alzheimer s disease include Huperzine A from Huperzia serrata and Rivastigmine (Excelon). The latter is a derivative from physostigmine isolated from the calabar bean, Physos-tigma vmmosum. 

IC50 curves were also recorded for various other inhibitors and the corresponding IC50 values were calculated. The determined IC50 values of 9-aminoacridine, galanthamine, gallamine, (—)-Huperzine A and thioflavin T were 0.12 pM, 0.38 pM, 6.4 pM, 0.46 pM, and 3.2 pM, respectively. It was difficult to compare these values with comparable values in literature since often different types of AChE, or AChE isolated from different organisms were used and different assay conditions were applied. However, the relative activities of the used inhibitors compared well with those reported in literature, except for (—)-huperzine A, which was found to be relatively less active then was expected. 

Only four inhibitors of AChE have been approved as therapeutic drugs for combating dementia diseases. The very first is tacrine or Cognex [Figure 2] from Parke-Davis8 and the second is aricept from Eisai [Japan] and Pfizer [U.S.].9 A third inhibitor available is huperzine A, a "nootropic" agent isolated from a Chinese folk medicine and used by Chinese for centuries to improve memory.10 Other known reversible AChE inhibitors... 

Acetate is also a precursor of several groups of alkaloids in the form of a polyketide chain that interacts with an unknown nitrogen source (as in the terpene alkaloids). Examples of acetate-derived alkaloids are coniine—the toxic principle of Conium maculatum, pinidine—from several Pinus species, and the naphthy-lisoquinoline alkaloids (e.g., ancistrocladine)—showing antimalarial and anti-HIV activity. The latter alkaloids are apparently derived from the oxidative coupling of two pentaketide units. Huperzine A, currently in clinical trials for the treatment of Alzheimer s disease and isolated from the club moss (Serrata huperzia), is derived from a polyacetate precursor (Fig. 46). 

The impact of Traditional Chinese Medicine on modern western drugs is demonstrated not only by commercialized therapeutic agents such as camptothecin or artemisinin but also by clinical candidates like huperzine A, an acetylcholinesterase inhibitor to treat Alzheimer s disease [103]. Huperzine A can be isolated from both, Huperzia serrata, and H. selago [104,105]. Because huperzine A is produced only at very low levels a synthetic approach has been developed in order to provide sufficient quantities for preclinical toxicology studies and clinical trials. 

Huperzine A, isolated from the Chinese herb Huperzia serrata (Thunb) Trev, is a novel reversible and selective AChE inhibitor. ZT-1 is a novel analog of huperzine A. ZT-1 is a prodrug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers [173],... 

Now days we talk about active constituents of phyto drugs. An active constituent is truly responsible for therapeutic activity of medicinal plant. The extracts are further subjected to chemical tests for identification of the plant constituents. The isolated constituents are of further importance to the pharmaceutical industry for applied research. A number of constituents like hyperforin, schizandrins, huperzine, andrographolide, andpicrrorhizin are being investigated for application in medical field. 

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)... 

Gao X, Zheng CY, Yang L, Tang XC, Zhang HY (2009) Huperzine A protects isolated rat brain mitochondria against P-amyloid peptide. Free Rad Biol Med 46 1454—1462... 

Huperzine A [(5R, 9R, ll )-5-amino-ll-ethylidine-5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta-[h]-piridin-2 (IH)-one] Eig. 49.3 is an alkaloid isolated... 

Huperzine A (49) is a sesquiterpene alkaloid isolated from a traditional Chinese herbal remedy, Huperzia serrata ( Qian Ceng Ta ) in 1986 [128], This compound has been proved to be a potent, selective and reversible acetylcholinesterase (AChE) inhibitor, and demonstrated memory enhancement and neuroprotective functions in clinical trials as a therapeutic against Alzheimer s disease (AD) in the People s Republic of China [129, 130], In 2004, a phase II clinical trial focused on its cognitive function was initiated by the National Institute on Aging (NIA) in the United States [131], ZT-1 (50), considered more selective than huperzine A, was developed as a semi-synthetic derivative of 49 by cooperation of the Shanghai Institute of Materia Medica and Debiopharm of Switzerland and is currently... 

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. 

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. 

Miyoshianines A (75) and B (76) with a lycopodane skeleton were isolated from Huperzia miyoshiana and their structures were determined by means of spectroscopic techniques (50). Five new alkaloids (77-78,80-82) belonging to the phlegmarane skeleton were isolated from Huperzia serrata (51,53). The structure of isofordine (79), which is the isomer of huperzine A (1), was isolated from Phlegmariurus fordii (52). 

Huperzine A (1), isolated from the club moss Huperzia serrata (syn. Lycopodium serratum), has been used in the treatment of Alzheimer s disease (AD). The club moss... 

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