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Sugars in new drug design. Sugar moiety structure as a principal determinant of antitumor glycoconjugates biological activity.

Wiesław Szeja 

Silesian University of Technology, Department of Organic Chem., Bioorganic Chem. and Biotechnol., Krzywoustego 4, Gliwice 44-100, Poland

Abstract

Approximately half of the existing drugs are derived from natural compounds. Among natural products which found therapeutic applications, glycosides constitute a considerable proportion, but the role of glycon/aglycon parts are seldom clearly defined in terms of molecular pharmacology [1].

Genistein, isoflavone isolated from soy is a compound of particular significance in chemoprevention of many cancers [2]. Although numerous glycosides of genistein are known as secondary metabolites of higher plants, studies of biological activity are sharply focused on the aglycon, supported by general belief that glycosidic bond like the one present in widespread genistin cannot withstand typical biodistribution along the pathway of an orally administered xenobiotic. Carbohydrate scaffolds, adept constructs and other pro – drugs will be discussed. Biological activity of genistein may be enhanced by chemical synthesis of lipophilic glycosides[3].Based on literature data with a new synthetic flavonoid  2,3-unsaturated sugar glycoconjugates are singled out as a class of reasonably available derivatives for useful modification of pharmacological properties of structurally complex and multifunctional drug lead compounds [4]. An example of cell growth phase selective switch in mechanism of action upon isoflavone glycosylation illustrates this point.

A number of synthetic genistein glycoconjugates  have been obtained in our laboratories, using various chemical glycosidation methods, in order to study their biological activity in comparison with underivatized aglycon.. In the presented lecture we describe methods of the synthesis and properties of a new synthetic genistein derivatives, which shows much more potent cytostatic and cytotoxic effect than genistein. The results clearly demonstrated that glycone split off is not necessarily favorite biotransformation of such derivatives. Moreover, some synthetic glycoconjugates  exhibited distinctly different mechanism of antiproliferative action that the one observed for the aglycon. Effects of unsaturated genistein glycoconjugates on cycloskeleton and cell cycle in selected tumor cell lines will be discussed in some detail.

The tested compound does not undergo rapid biodegradation in cells or culture media and exerts its biological effects primarily as intact molecule. Our data show the mechanism of cytotoxicity of genistein and its new derivative is significantly different. In conclusion, we postulate that glycodiversification of drug leads by application of glycal chemistry [5] offers new opportunities in drug design and discovery. Examples of the structure – function relationship of glycons will be drawn.

References

[1] V. Kren, in: Glycoscience; Chemistry and Chemical Biology (B. Fraser-Reid, K. Tatsuta, J. Thiem, Eds.), vol 3, pp. 2471-2532, Springer Verlag, Berlin 2001[2] A.Rusin et al., Acta Biochimica Polonica 57(2010)23-34[3] K. Polkowski et al., Cancer Letters, 203 ( 2004) 59-69[4] A.Rusin et al.,Bioorganic & Medicinal Chemistry Letters,2009, 19, 4939-4943; ] A.Rusin et al., Bioorganic & Medicinal Chemistry 19 (2011) 295–305[5] G. Grynkiewicz, W. Szeja, in: “Anthracyclines Chemistry and Biology”(ed. K. Krohn), Top. Curr. Chem., Springer-Verlag Berlin Heidelberg 2008; W. Priebe, I. Fokt, G. Grynkiewicz,  in: “Glycoscience; Chemistry and Chemical Biology”2nd ed., (eds. B. Fraser-Reid, K. Tatsuta, J. Thiem), Springer-Verlag Berlin  2008

The study supported by the Ministry of Science and Education of Poland (Grant No. N N209 186338).

 

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Presentation: Invited oral at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Wiesław Szeja
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-03-14 08:59
Revised:   2012-03-14 08:59