Two series of ten chalcones and ten aurones, where ferrocene replaces the C ring and with diverse substituents on the A ring were synthesized. The compounds were tested against two antibiotic-sensitive bacterial strains, E. coli ATCC 25922 and S. aureus ATCC 25923, and two antibiotic-resistant strains, S. aureus SA-1199B and S. epidermidis IPF896. The unsubstituted compound and those with methoxy substitution showed an inhibitory effect on all bacterial strains at minimum inhibitory concentrations ranging between 2 and 32 mg L(-1). For four of these compounds, the effect was bactericidal, as opposed to bacteriostatic. The corresponding organic aurones did not show growth inhibition, underscoring the role of the ferrocene group. The methoxy-substituted aurones and the unsubstituted aurone also showed low micromolar (IC(50)) activity against MRC-5 non-tumoral lung cells and MDA-MB-231 breast cancer cells, suggesting non-specific toxicity.

A novel approach for developing prodrugs based on masked carboxylic acids is described. Rather than using conventional esterase-based activation, thiazolidinone protecting groups have been identified that can reveal carboxylic acid groups upon activation by hydrogen peroxide. This may prove valuable in the continuing development of prodrug strategies that rely on reactive oxygen species (ROS) as a trigger.

In the context of our studies on the modification of bioactive molecules with ferrocene, we here report the first examples of ferrocenyl flavonoids, where ferrocene replaces the B ring of the flavonoid skeleton. Ferrocenyl aurones possessing an electron-withdrawing or an electron-donating group in the 5′-position were obtained from 5′-R-2′-hydroxy-3-ferrocenyl chalcones via 1,5 oxidative exocyclization using Hg(OAc)2 or AgOTf. Treatment of the ferrocenyl aurones with LDA resulted in a ring opening to form ferrocenyl ynones, which could then be selectively recyclized to the flavone isomer by treatment with NaOEt. Ferrocenyl flavones were also obtained by isomerization of the aurones with KCN and were hydroxylated in the 3-position to form ferrocenyl flavonols with oxone in a biphasic reaction. In many cases the reactivity of the ferrocenyl compounds was significantly different from that of their organic analogues. This reactivity and regioselectivity can be rationalized by ferrocene’s particular ability to destabilize α-anions in reaction intermediates. Representative examples of ferrocenyl aurones, ynones, and flavones were characterized by 2D NMR and X-ray crystallography, and the molecules all show a planar arrangement of the organic skeleton with the cyclopentadienyl ring of the ferrocene group. Putative MLCT bands in the visible region are responsible for the variety of highly saturated colors observed.

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The oxidation of the ferrocenyl group of 2'-hydroxyferrocenyl chalcones activates the beta-position of the unsaturated ketone to nucleophilic attack to yield the first examples of ferrocenyl flavones. These compounds are significantly more cytotoxic than their organic analogs on B16 melanoma cells, with IC(50) values in the low micromolar range.

International audienceWith 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 tenmember series of ferrocenyl flavonoids: chalcones ((E)-1-(R-2'-hydroxypheny1)-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-hydroxy2-ferrocenyl-chromen-4-ones) and four ferrocenyl flavanones (3-ferrocenylmethylidenyl-R-2-phenyl-chroman-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 mu M. 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. (C) 2013 Elsevier B.V. All rights reserved

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Synthesis of Cytotoxic Ferrocenyl Flavones via a Ferricenium-Mediated 1,6-Oxidative Cyclization. -The oxidation of the ferrocenyl group of 2'-hydroxyferrocenyl chalcones (II) activates the β-position of the unsaturated ketone to nucleophilic attack to yield the first examples of ferrocenyl flavones (III). These compounds show cytotoxic activity in B16 melanoma cells with IC50 values in the low micromolar range. -(MONSERRAT, J.-P.; CHABOT, G. G.; HAMON, L.; QUENTIN, L.; SCHERMAN, D.; JAOUEN, G.; HILLARD*, E. A.; Chem. Commun. (Cambridge) 46 (2010) 28, 5145-5147, DOI:10.1039/c0cc01290d ; Lab. Charles Friedel, Ec. Natl. Super. Chim., F-75231 Paris, Fr.; Eng.) -M. Paetzel 47-177