Synthesis of new glycosylated flavonoids with inhibitory activity on cell growth

Natural flavonoids and xanthone glycosides display several biological activities, with the glycoside moiety playing an important role in the mechanism of action of these metabolites. Herein, to give further insights into the inhibitory activity on cell growth of these classes of compounds, the synthesis of four flavonoids (5, 6, 9, and 10) and one xanthone (7) containing one or more acetoglycoside moieties was carried out. Acetyl groups were introduced using acetic anhydride and microwave irradiation. The introduction of one or two acetoglycoside moieties in the framework of 3,7-dihydroxyflavone (4) was performed using two synthetic methods: the Michael reaction and the Koenigs-Knorr reaction. The in vitro cell growth inhibitory activity of compounds 5, 6, 7, 9, and 10 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 new flavonoid 3-hydroxy-7-(2,3,4,6-tetra-O-acetyl-β-glucopyranosyl) flavone (10) was the most potent compound in all tumor cell lines tested, with GI50 values < 8 µM and a notable degree of selectivity for cancer cells. © 2018 by the authors.

Funding: This work was supported through national funds provided by Foundation for Science and Technology from the Minister of Science, Technology and Higher Education (FCT/MCTES-PIDDAC) and European Regional Development Fund (ERDF) through the COMPETE—Programa Operacional Factores de Competitividade (POFC) (POCI-01-0145-FEDER-016790), PPCDT—Promover a Produção Científica e Desenvolvimento Tecnológico e a Constituição de Redes Temáticas (Project 3599), under the project PTDC/MAR-BIO/4694/2014 in the framework of the programme PT2020 and INNOVMAR—Innovation and Sustainability in the Management and Exploitation of Marine Resources, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR in the framework of North Portugal Regional Operational Programme (NORTE 2020). Acknowledgments: Marta Correia-da-Silva thanks FCT for the postdoctoral fellowship SFRH/BPD/81878/2011 and Ana R. Neves and Patrícia M.A. Silva for the Ph.D. fellowships SFRH/BD/114856/2016 and SFRH/BD/90744/2012, respectively.