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Cite this: Nat. Prod. Rep., 2012, 29, 555
REVIEW
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Cytisine: a natural product lead for the development of drugs acting at nicotinic acetylcholine receptors
Downloaded by UNIVERSIDAD DE CHILE on 16 May 2012 Published on 27 February 2012 on http://pubs.rsc.org | doi:10.1039/C2NP00100D
Edwin G. P erez,ab Carolina M endez-G alvezc and Bruce K. Cassels*ac Received 1st December 2011 DOI: 10.1039/c2np00100d
Covering: up to the end of 2011 This review covers classical and modern structural modifications of the alkaloid, the more recent (since 2007) syntheses of cytisine and analogues, and the pharmacology of these compounds, with emphasis on their interactions with nicotinic receptors. 89 references are cited. 1 2 3 4 5 6 7
Introduction Structural modification of cytisine Total syntheses of cytisine and analogues Pharmacology of cytisine and analogues Perspectives Acknowledgements References
1 Introduction ( )-Cytisine ((1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8Hpyrido[1,2-a][1,2]diazocin-8-one, Fig. 1) may be regarded as the prototype of the tricyclic quinolizidine alkaloids of the legume family. It is widespread in the Faboideae, often accumulates in the seeds, and is obtained on a commercial scale from Laburnum anagyroides Medik, Sophora alopecuroides L., Thermopsis alterniflora Regel & Schmalh., Thermopsis lanceolata R. Br., and Caragana sinica (Buc’hoz) Rehder. Although it was first isolated in the mid-19th century,1 its structure (without stereochemistry)
Fig. 1 Structure and numbering of cytisine. A) projection structure with traditional numbering; B) three-dimensional structure with IUPAC numbering.
a Millennium Institute for Cell Dynamics and Biotechnology, Santiago, Chile b Faculty of Chemistry, Pontificia Universidad Cat olica de Chile, Santiago, Chile c Faculty of Sciences, University of Chile, Santiago, Chile
This journal is ª The Royal Society of Chemistry 2012
was only determined in 1932,2 and its absolute configuration was demonstrated almost thirty years later.3 X-Ray crystal structures are available for cytisine and N-methylcytisine, and the structures of cytisine in solution and in the crystal phase are congruent.4–6 Although the cytisine skeleton has traditionally been numbered starting at the pyridone nitrogen atom, some authors prefer to use the systematic numbering advocated by the IUPAC. Although some other activities have been recorded, cytisine is best known – and has been most studied – with regard to its interaction with nicotinic acetylcholine receptors, which are involved in a large array of pathologies. The main current interest in this alkaloid seems to arise from its use as an aid to quit tobacco smoking, for which it is still marketed, at least in Poland and Russia,7 but its activity is far from optimal and its molecular scaffold is therefore an inspiration for the development of more effective drugs.
2
Structural modification of cytisine
The earliest known modifications of ( )-cytisine date back to the late 19th century. In connection with its structure assignment, it was proposed to be a secondary amine after conversion into its nitroso, acetyl, N-methyl- and N-ethyl derivatives.8,9 Cytisine was also shown to give a ‘‘nitronitrosocytisine’’ and dibromo and dichloro derivatives, and later a monobromocytisine, dibromoN-methylcytisine, and its methiodide.10,11 ‘‘Nitronitrosocytisine’’ was found to be accompanied by an isomer, both forms (‘‘a’’ and ‘‘b’’) were hydrolysed giving the respective nitrocytisines, and reduction of the former led to an aminocytisine, which was diacetylated; treatment with formaldehyde gave a ‘‘methylenedicytisine’’. Moreover, a-nitronitrosocytisine could be brominated to produce an a-bromonitronitrosocytisine, which, like its precursor, underwent hydrolysis giving a-bromonitrocytisine; treatment of dibromocytisine with nitric acid only gave dibromonitrosocytisine, confirming that nitro and bromo Nat. Prod. Rep., 2012, 29, 555–567 | 555