Modern methodologies of drug development create a need for synthesis of large number of compounds. Ideally, the compounds should be easily accessible, structurally related and, at the same time, diversified - a dream summarized as Click Chemistry [1,2].

Our program is aimed at search for new analogs of flawonoids bearing biological activity. Concerning chemistry, we explore syntheses starting with 4-acetyl-5-hydroxy-2-oxo-benz[1,3]oxathiole (1) and leading to compounds comprising o-hydroxy substituted flavonoid unit 2.

The four-substituted benzene derivative 1 provides access to a remarkable number of diversified chemical entities comprising the desired structural fragment 2 (Scheme).

Scheme

We have already described compound 1 as a convenient substrate for synthesis of large group of thioaurones 3 [3,4], some of the compounds posses significant cytotoxic activity. We have also prepared chalcones 4, flavanones 5 and thioflavanones 6. The prepared compounds could be elaborated further, some possibilities are shown in the Scheme. Ultimately, starting from benzoxathiole 1, we are able to prepare compounds comprising flavonoid structural fragments 2, and characterized by different rigidity, lipophilicity, acidity and other pharmacologically important parameters.

References

1. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Angew. Chem. Int. Ed. Engl. 2001, 40, 2004-2021, Click Chemistry: Diverse Chemical Function from a Few Good Reactions.
2. Kolb, H,C.; Sharpless, K.B. Drug Discov. Today 2003, 8, 1128-1137, The growing impact of click chemistry on drug discovery.
3. Konieczny, M.T.; Konieczny, W.; Wolniewicz, S.; Wierzba, K.; Suda, Y.; Sowiński, P. Tetrahedron, 2005, 61, 8648-8655; "New Domino Reaction. One Pot Synthesis of 4,7-Dihydroxythioaurone Derivatives from Benzaldehydes and 4-Acetyl-2-oxo-benz[1,3]oxathiole."
4. Konieczny, M.T.; Konieczny, W.; Okabe, S.; Tsujimoto, H.; Suda, Y.; Wierzba, K., Chem. Pharm. Bull. 2006, in press; "Synthesis and Cytostatic Activity of 4,7-Dihydroxythioaurone Derivatives. Effect of B Ring Substitution on the Activity"

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1. Anitiviral activity of chalcones
2. Synthesis of new class of cytotoxic chalcone derivatives
3. Application of privileged structures in new drug discovery
4. Comparison of traditional and new methods of drug discovery