Abstract
Diiron bis-cyclopentadienyl bis-carbonyl cationic complexes with a bridging vinyliminium ligand, [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C3(R′)C2HC1NMe(R″)}]CF3SO3 (R = Xyl = 2,6-C6H3Me2, R′ = Ph, R″ = H, 2a; R = Xyl, R′ = R″ = Me, 2b; R = R′ = Me, R″ = H, 2c; R = Me, R′ = 2-naphthyl, R″ = H, 2d; R = Me, R′ = R″ = Ph, 2e), are easily available from commercial chemicals, robust in aqueous media and exert a variable in vitro cytotoxicity against cancer cell lines depending on the nature of the substituents on the vinyliminium ligand. The anticancer activity is, at least in part, associated to fragmentation reactions, leading to iron oxidation and active neutral and well-defined monoiron species. We report an innovative synthetic procedure for the preparation of 2a,c,d, and a facile method to access the monoiron derivative of 2a, i.e., [FeCp(CO){C1(NMeXyl)C2HC3(Ph)C(O)}] (3a). According to IC50 analyses at different times of incubation of the complexes, 3a is significantly faster in inhibiting cell viability compared to its diiron precursor 2a. The neutral complexes [Fe2Cp2(CO)(μ-CO){μ-k1N:k1C:k1C-C3(R′)C2(Se)C1(NMe2)C4(CO2Y)C5(CO2Y)}] (R′ = Y = Me, 4a; R′ = Pr, Y = tBu, 4b; R′ = Y = Et, 4c) are obtained via the two-step modification of the vinyliminium moiety and comprise a bridging selenophene-decorated alkylidene ligand. The antiproliferative activity exhibited by 4a-c is moderate but comparable on the ovarian cancer cell line A2780 and the corresponding cisplatin resistant cell line, A2780cisR. Complexes 4a-c in aqueous solutions undergo progressive release of the alkylidene ligand as a functionalized selenophene, this process being slower in cell culture medium. Since the released selenophenes SeC1{C(O)R′}C2(NMe2)C3(CO2Y)C4(CO2Y) (R′ = Y = Me, 5a; R′ = Pr, Y = tBu, 5b) are substantially not cytotoxic, it is presumable that the activity of 4a-c is largely ascribable to the {Fe2Cp2(CO)2} scaffold.
Highlights
There is a current great interest in developing new anticancer drugs based on transition metals [1,2,3,4], due to the peculiar properties provided by the presence of the metal center [5] and the opportunity to overcome the drawbacks associated to the use of platinum compounds currently employed in clinical treatments against several types of tumors [6,7].In this regard, iron is an appealing choice as a metal element, being available, implicated in diverse biological processes in the human body, essentially nontoxic in many forms and displaying a rich redox chemistry [8,9]
Various iron compounds have been investigated for their anticancer potential, studies on diiron complexes are still in their infancy, despite several advantages provided by the presence of two cooperating metal centers
Following our recent description of the promising cytotoxic activity of cationic diiron complexes with a bridging vinyliminium ligand, here we report additional studies on a selection of such category of complexes
Summary
There is a current great interest in developing new anticancer drugs based on transition metals [1,2,3,4], due to the peculiar properties provided by the presence of the metal center (e.g., redox activity and broad possibility of geometries, stereochemical configurations and kinetic behaviors) [5] and the opportunity to overcome the drawbacks associated to the use of platinum compounds currently employed in clinical treatments against several types of tumors (in particular, severe side effects and acquired resistance towards the drug) [6,7] In this regard, iron is an appealing choice as a metal element, being available, implicated in diverse biological processes in the human body, essentially nontoxic in many forms and displaying a rich redox chemistry [8,9]. IC50 values in the nanomolar range have been recognized on A2780 and A2780cisR cells for some complexes of the series
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