Huperzine structure

It is interesting that, in addition to its AChE inhibitory eflfects, huperzine A is reported to inhibit NMDA receptor binding and this is also of use in treating AD/ Recently, three compounds, huprine X (42) and its F and Br analogues, huprine Y and huprine Z have been synthesized. These compounds combine the carbobicyclic structural feature of huperzine A (40) with the 4-aminoquinoline skeleton of tacrine (28). All three compounds showed a very strong selectivity for AChE over BuChE and also for human as opposed to bovine AChE and this was demonstrated in vivo as well as in vitro. 

The intramolecular Heck reaction is a powerful method for the synthesis of constrained tertiary and quaternary carbon centers and has been applied as a key step in the synthesis of a number of pyridine alkaloids. Mann et al. have accessed the bicyclononane core structure of huperzine A 150 in moderate yield by intramolecular Heck reaction of bromopyridine 151 (Equation 117). Another notable application of this methodology is the intramolecular a-arylation of the amide enolate generated from 152 to give the carbon skeleton of cytosine <20040BC1825> (Equation 118). 

Jiang, H. L. Bai, D. L. Luo, X. M. Progress in clinic, pharmacological, chemical and structural biological studies of huperzine A a drug of traditional Chinese medicine origin for the treatment of Alzheimer s disease. Curr. Med. Chem., 2003, 10 2231-2252. 

Figure 7.4. Superimposition ofthe investigated crystal structures of AChE in complex with huperzine (black), tacrine (dark-grey), edrophonium (grey) and decamethonium (light-grey). Only the amino acid residues close to the binding site are displayed.

Raves, M. L., Harel, M., Pang, Y. P., Silman, I., Kozikowski, A. P., Sussman, J. L. Structure of Acetylcholinesterase Complexed with the Nootropic Alkaloid Huperzine A, Nature Struct. Biol. 1997,... 

Huperzine A is not the only AChE inhibitor available from nature s storehouse. As one example, the unusual polyphenol hopeahainol A (94) was recently reported from Hopea hainanensis It has a comparable IC50 to huperzine A against AChE and was shown to be a reversible inhibitor of the enzyme. It is thus another example of the versatility of the plant kingdom in providing novel structures with pharmacological relevance. 

Huperzine A 5-1 has a molecular formula of Ci5H18N20 m.p. 230°C [a]D-150.4°C (C, 0.5, MeOH). Its UV spectrum absorptions at A,max (log ) 231 (4.0), 313 (3.89) nm, IR spectrum absorptions at vmax 3180,1650,1550 cm-1 and H-NMR signals (Table 1) show the presence of a-pyridone ring in its molecule. The proton and carbon signals indicate existence of an endocyclic and an exocyclic double bond in the molecule. The final structure 5-1 was further determined by spectral analyses, including decoupling experiments, NOE measurements and comparison with the known structure of selagine 5-2. The difference between 5-1 and 5-2 is the situation of the olefinic proton at the endocyclic double bond in... 

The structure of huperzine A was confirmed by total synthesis. There are several reports on total synthesis [27]. The following described was recently accomplished by Kozikowski s group [28,29]. The monoprotected diketone, 1,4-cyclohexanedione monoethylene ketal 5-4 was used as starting material. The pyrrolidine enamine of 5-5 was heated with acrylamide followed by hydrolysis to provide an 85 15 mixture of the lactam 5-6 and 5-7. After protection of the lactam nitrogen by benzylation, dehydrogenation of the latter mixtures afforded pyridone 5-8, then hydrogenolysis of its N-benzyl group, followed by O-methylation with methyl iodide and silver carbonate which yielded methoxypyridine 5-... 

Huperzine B has a molecular formula of C16H20N2O, m.p. 270-271 °C, [cx]d-54.2° (C, 0.2, MeOH). It has UV spectrum absorptions at Amax (log e) 231 (3.95), 312 (3.85), and IR spectrum absorptions at vmax 3100, 1670, 1620,1610,1560 cm-1. The whole structure was proposed by spectral analyses as shown in 5-3. Its main difference from huperzine A is the absence of exocyclic double bond which form an additional piperidine ring in 5-3. Huperzine B does not possess anticholinesterase activity. 

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)... 

Fig. 9.4 Chemical structures of tacrine (a) donepezil (b) rivastigmine (c) galantamine (d) huperzine (e) and physostigmine (f)...

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... 

Dvir H, Jiang HL, Wong DM, Harel M, Chetrit M, He XC, Jin GY, Yu GL, Tang XC, Silman I, Bai DL, Sussman JL (2002) X-ray structures of Torpedo californica acetylcholinesterase complexed with (-t)-Huperzine A and (—)-huperzine B structural evidence for an active site rearrangement. Biochemistry 41(35) 10810-10818. doi 10.1021/ bi020151-l-... 

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