Ferrocenyl flavonoid-induced morphological modifications of endothelial cells and cytotoxicity against B16 murine melanoma cells

With the aim of improving the cytotoxic and vascular disrupting activities of flavonoids, several classes of ferrocenyl-modified flavonoids were prepared and tested on cancer and endothelial cells. Three ten-member series of ferrocenyl flavonoids: chalcones ((E)-1-(R-2′-hydroxyphenyl)-3-ferrocenylprop-2-en-1-ones), aurones ((Z)-R-2-(ferrocenylidene)benzofuran-3-ones) and flavones (R-2-ferrocenyl-chromen-4-ones) were synthesized by recently reported methods. Three ferrocenyl flavonols (R-3-hydroxy-2-ferrocenyl-chromen-4-ones) and four ferrocenyl flavanones (3-ferrocenylmethylidenyl-R-2-phenylchroman-4-ones) were also obtained. All compounds were evaluated for their cytotoxic effects on a cancer cell line (B16 murine melanoma) and for their morphological effects on endothelial cells (EAhy 926). Some interesting structure–activity relationships were disclosed: of all the compounds, the halogen-substituted aurones showed the best cytotoxic activity, with IC50 values ranging between 12 and 18 μM. Ferrocenyl flavonols and ferrocenyl flavanones with substitution in the 3-position (–OH and C–Fc respectively) were not active against cancer or endothelial cells. Some of the ferrocenyl flavones caused the endothelial cells to adopt a round shape (“rounding up”) at submicromolar concentrations, which can be predictive of vascular disrupting activity. The most morphologically active flavones showed only moderate cytotoxicity against cancer cells, indicating that they may primarily act as antivascular agents.

Graphical abstractPotential antiangiogenic agents: ferrocenyl flavones have submicromolar activity on endothelial cells and low cytotoxicity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Five series of ferrocene-substituted flavonoids were synthesized. ► A ferrocenyl flavanone has been crystallographically characterized. ► Halogenated aurones show low micromolar activity on B16 murine melanoma cells. ► Halogenated flavones show submicromolar morphological effects on endothelial cells. ► Cytotoxicity does not correlate with morphological effects.