Synthesis and Tumor Cell Growth Inhibitory Effects of New Flavonosides and Xanthonosides

Natural flavonoid and xanthone glycosides display several biological activities [1-3], with the glycoside moiety playing an important role in the mechanisms of action of these metabolites. Herein, to give further insights into the inhibitory cell growth activity of these classes of compounds, the synthesis of new flavonoid and xanthone derivatives containing one or more acetoglycoside moieties was carried out to evaluate their in vitro cell growth inhibitory activity in human tumor cell lines.

The introduction of one or two acetoglycoside moieties in the skeleton of a hydroxylated flavonoid was performed using three synthetic methods: Michael reaction, Koenigs-Knorr reaction, and through a copper-catalyzed azide-alkyne cycloaddition. Acetyl groups were introduced in rutin, diosmin, and mangiferin using acetic anhydride under microwave irradiation. The in vitro cell growth inhibitory activity of seven synthesized compounds was investigated in six human tumor cell lines: A375- C5 (malignant melanoma IL-1 insensitive), MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), U251 (glioblastoma astrocytoma), U373 (glioblastoma astrocytoma), and U87MG (glioblastoma astrocytoma). The most active compound in all tumor cell lines tested was a flavonoside and showed GI50 values below 10 μM.

[1] Leong, C.N.A., et al., Food Chemistry, 2008. 109(2): p. 415-420.

[2] Kumar, M., et al., Fitoterapia, 2010. 81(4): p. 234-242.

[3] Reutrakul, V., et al., Planta Medica, 2007. 73(7): p. 683-688.

Acknowledgments:

The authors want to thank Fundação da Ciência e Tecnologia (FCT/MCTES, PIDDAC) and European Regional Development Fund (ERDF) for funding this research through the COMPETE – Programa Operacional Factores de Competitividade (POFC) programme (POCI-01-0145‐FEDER-016790 and POCI-01-0145-FEDER-016793), Reforçar a Investigação, o Desenvolvimento Tecnológico e a Inovação (RIDTI, Project 3599 and 9471), and INNOVMAR, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR, under the projects PTDC/ MAR-BIO/4694/2014 and PTDC/AAG-TEC/0739/2014 and the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT and ERDF, in the framework of the programme PT2020. Ana R. Neves wants to thank FCT for the Ph.D. fellowship (SFRH/BD/114856/2016).