The Cytotoxic Activity of Diiron Bis-Cyclopentadienyl Complexes with Bridging C3-Ligands

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.

Metal-based compounds containing selenium: An appealing approach towards novel therapeutic drugs with anticancer and antimicrobial effects

“…Additionally, CO can coordinate terminally to a metal center but also act as a μ 2 -and even μ 3 -ligand [187], bridging two or three metal centers as could be observed in compounds described in other sections of this review (104-107 in Fig. 8) [170,172]. Biologically, CO has important signaling, antiapoptotic and anti-inflammatory effects [188], and it is believed that its physiological and therapeutic targets are transition metals contained in enzymes [186].…”

“…These compounds (105-107 in Fig. 8) underwent a progressive release of the alkylidene ligand as a functionalized selenophene in aqueous media, and since the released selenophenes were mainly non cytotoxic, their moderately antiproliferative activity was mostly related to the Fe 2 Cp 2 (CO) 2 core [172]. Several modifications have also been considered for Ru-based half-sandwich complexes.…”

First Iron(II) Organometallic Compound Acting as ABCB1 Inhibitor

“…In this study, four compounds of general formula [Fe(II)(η 5 -C 5 H 5 )(dppe)L][CF 3 SO 3 ], where L are imidazole based ligands and dppe is ethylenebis (diphenylphosphane), were tested against ovarian A2780 (cisplatin sensitive), breast MCF7 and cervical HeLa cells showing a better cytotoxicity than cisplatin at 72 h incubation. Actually, the interest in cyclopentadienyl iron organometallic complexes (Fe( 5 -C 5 H 5 ); FeCp) has been growing in the last years [23][24][25][26][27][28][29][30][31], probably due to the large structural diversity offered by their piano-stool structure and by the nature of the π-bonded cyclopentadienyl ring that can act both as a donor and as an acceptor group, thus changing the acceptor/donor character and reactivity of other coligands [32]. F. Marchetti et al have reported a series of diiron complexes based on the [Fe 2 Cp 2 (CO) x ] skeleton (x = 2 or 3) and containing different bridging ligands (aminocarbyne, thiocarbyne, allenyl or vinyliminium) [24,26,27].…”

“…Actually, the interest in cyclopentadienyl iron organometallic complexes (Fe( 5 -C 5 H 5 ); FeCp) has been growing in the last years [23][24][25][26][27][28][29][30][31], probably due to the large structural diversity offered by their piano-stool structure and by the nature of the π-bonded cyclopentadienyl ring that can act both as a donor and as an acceptor group, thus changing the acceptor/donor character and reactivity of other coligands [32]. F. Marchetti et al have reported a series of diiron complexes based on the [Fe 2 Cp 2 (CO) x ] skeleton (x = 2 or 3) and containing different bridging ligands (aminocarbyne, thiocarbyne, allenyl or vinyliminium) [24,26,27]. Cytotoxicity studies showed that among them the aminocarbyne and vinyliminium complexes displayed the best biological profile, and some of them showed noticeable IC 50 values [24,26,27].…”

“…F. Marchetti et al have reported a series of diiron complexes based on the [Fe 2 Cp 2 (CO) x ] skeleton (x = 2 or 3) and containing different bridging ligands (aminocarbyne, thiocarbyne, allenyl or vinyliminium) [24,26,27]. Cytotoxicity studies showed that among them the aminocarbyne and vinyliminium complexes displayed the best biological profile, and some of them showed noticeable IC 50 values [24,26,27]. The mode of action for the aminocarbyne complexes seems to involve several processes and/or targets [24].…”