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Polyhydroxylated indolizidine and pyrrolizidine alkaloids. Synthesis and bioactivity.

Sebastian Stecko 1Konrad Paśniczek 1Irma Panfil 1Margarita Jurczak 1Jolanta Solecka 2Marek Chmielewski 1

1. Institute of Organic chemistry of the Polish Academy of Sciences (ICHOPAS), Kasprzaka 44/52, Warsaw 01-224, Poland
2. National Institute of Public Health-National Institute of Hygiene, Warszawa 00-791, Poland


Number natural polyhydroxyleted alkaloids belonging to the pyrrolidine and piperidine classes (iminosugars) and their nitrogen bridgehead bicyclic analogues (pyrrolizidines, indolizidines), as well as a considerable number of non-natural structural analogues, are important glycomimetics [1]. They behave as an enzyme inhibitors, being able to interact with glycosidases and glycosyltransferases – enzymes deputed to the cleavage or formation of glycosidic linkages in the biosynthesis of glycoproteins. Several glycosidase inhibitors have pharmacological relevance, being currently tested or approved in the treatment of diabetes, Gaucher’s disease, osteoarthritis, HIV infection, viral infection, or cancer [1].

We have pointed out that the 1,3-dipolar cycloaddition reactions of cyclic nitrones to unsaturated 5- and 6-membered lactones [2] represent an attractive entry to variety of different type of polyhydroxylated alkaloids [3]. The used strategy consists of a cleavage of the N-O bond of isoxazolidines obtained via [3+2] cycloaddition followed by the intramolecular N-alkylation. A replacement of 5-membered nitrone by 6-membered one allows to obtained indolizidine as well as quinolizidine alkaloids [3].

Several polyhydroxylated alkaloids (iminosugars) were obtained via above methodology. Bioactivity of synthesized compounds was tested toward commercially available glycosidases (α- and β-D-glucosidase, α-D-mannosidase, β-D-galactosidase, β-D-glucuronidase and α-L-fucosidase) [3].

Acknowledgements: This work was supported by a grant PBZ-KBN-126/T09/08/2004 and by a network „Synthesis, structure and therapeutic properties of compounds and organic substances”.

[1] (a) A. Stütz, Ed.; Iminosugars as Glycosidase Inhibitors, Wiley-VCH, 1999; (b) G. Fleet, R. Molyneux, R. Nash; Phytochem. 2001, 56, 265; (c) H. Yoda; Curr. Org. Chem. 2002, 6, 223.

[2] (a) D. Socha, M. Jurczak, J. Frelek, A. Klimek, J. Rabiczko, Z. Urbańczyk-Lipkowska, K. Suwińska, M. Chmielewski, F. Cardona, A. Goti, A. Brandi, Tetrahedron: Asymmetry 2001, 12, 3163-3172; (b) K. Paśniczek, D. Socha, M. Jurczak, J. Frelek, A. Suszczyńska, Z. Urbańczyk-Lipkowska, M. Chmielewski, J. Carbohydr. Chem. 2003, 22, 613-629; (b) (c) S. Stecko, K. Paśniczek, M. Jurczak, Z. Urbańczyk-Lipkowska, M. Chmielewski, Tetrahedron 2006, 17, 68.

[3] (a) D. Socha, M. Jurczak, M. Chmielewski, Carbohydr. Res. 2001, 336, 315; (b) D. Socha, K. Paśniczek, M. Jurczak, J. Solecka, M. Chmielewski, Carbohydr. Res. 2006, 341, 2005; (c) K. Paśniczek, D. Socha, M. Jurczak, J. Solecka, M. Chmielewski, Can. J. Chem. 2006, 84, 534; (d) Panfil, I.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem. 2006, 25, 673-684; (e) Paśniczek, K.; Solecka, J.; Chmielewski, M. J. Carbohydr. Chem. 2007, 26, 195-211.


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Submitted: 2008-03-06 14:05
Revised:   2009-06-07 00:48