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A series of bioactive molecules were synthesized from the condensation of aspirin or chlorambucil with terminal alkynes bearing alcohol or amine substituents. Insertion of the resulting alkynes into the iron-carbyne bond of readily accessible diiron bis(cyclopentadienyl) mu-aminocarbyne complexes, [1a,b]CF3SO3, afforded novel diiron complexes with a bridging vinyliminium ligand, [2-10]CF3SO3, functionalized with a bioactive moiety. All compounds were characterized by elemental analysis and IR and multinuclear NMR spectroscopy and in three cases by single-crystal X-ray diffraction. Moreover, the D2O solubility, stability in D2O and cell culture media, and octanol-water partition coefficients of diiron complexes were determined spectroscopically. The cytotoxicity of the complexes was assessed in the tumorigenic A2780 and A2780cisR and the nontumorigenic HEK 293T cell lines. Some complexes exhibit high potency and the ability to overcome resistance in A2780cisR cells (aspirin complexes) or high selectivity relative to HEK 293T cells (chlorambucil complexes). Further studies indicate that the complexes significantly trigger intracellular ROS production, irrespective of the nature of the bioactive fragment. DNA alkylation and protein binding studies were also undertaken.

Regio- and stereoselective nucleophilic attack of cyanide (from NBu4CN) to cationic diiron vinyliminium compounds [Fe2Cp2(CO)(mu-CO){mu-eta(1):eta(3)-C-(R')C(R '')-CNMe2}]CF3SO3 ([1a-f]CF3SO3) affords the nitrile-aminoallylidene derivatives 2a-f in good to excellent yield. The analogous reaction of [1g]CF3SO3, comprising two different N substituents, gives 4 (63%) as a mixture of two stereoisomers. The new products [lg]CF3SO3, 2a-f, and 4 were characterized by IR and NMR spectroscopy and in a number of cases by IR-spectroelectrochemistry and single-crystal X-ray diffraction. The allylidene complexes are air-stable and robust in aqueous solution; however, in general they undergo oxidation within a biologically relevant range of potentials. DFT calculations were carried out to rationalize the observed stereoselectivity of the synthesis reaction and other structural and thermodynamic aspects. The cytotoxicity of 2a-f was assessed on cisplatin-sensitive and -resistant human ovarian carcinoma (A2780 and A2780cisR) cell lines and human embryonic kidney (HEK-293) cells. Experiments reveal that treatment with the compounds leads to ROS production, with an absence of direct interactions with double-stranded DNA (calf thymus) and bovine serum albumin.

A series of diiron/tetrairon compounds containing a S- or a Se-function (2a&ndash, d, 4a&ndash, d, 5a&ndash, b, 6), and the monoiron [FeCp(CO){SeC1(NMe2)C2HC3(Me)}] (3) were prepared from the diiron &mu, vinyliminium precursors [Fe2Cp2(CO)( &mu, CO){ &mu, &eta, 1: &eta, 3-C3(R&rsquo, )C2HC1N(Me)(R)}]CF3SO3 (R = R&rsquo, = Me, 1a, R = 2,6-C6H3Me2 = Xyl, R&rsquo, = Ph, 1b, R = Xyl, R&rsquo, = CH2OH, 1c), via treatment with S8 or gray selenium. The new compounds were characterized by elemental analysis, IR and multinuclear NMR spectroscopy, and structural aspects were further elucidated by DFT calculations. The unprecedented metallacyclic structure of 3 was ascertained by single crystal X-ray diffraction. The air-stable compounds (3, 4a&ndash, b, 6) display fair to good stability in aqueous media, and thus were assessed for their cytotoxic activity towards A2780, A2780cisR, and HEK-293 cell lines. Cyclic voltammetry, ROS production and NADH oxidation studies were carried out on selected compounds to give insights into their mode of action.

A facile route to Pt-II complexes doubly functionalized with bioactive molecules through a bipyridine-type ligand is described. Initially, ligands L-EE (containing two ethacrynic acid units), L-EF (ethacrynic acid+flurbiprofen) and L-EB (ethacrynic acid+biotin) were obtained in moderate to good yields from 2,2 '-bipyridine-4,4 '-dicarboxylic acid. Subsequent reaction of the ligands with [PtCl2(DMSO)(2)] afforded complexes [PtCl2(L-EE)] (2), [PtCl2(L-EF)] (3) and [PtCl2(L-EB)] (4) in high yields. All compounds were fully characterized by analytical and spectroscopic methods. Complexes 2-4 are highly stable in water/DMSO solution at 37 degrees C after 72 h, whereas progressive release of the bioactive fragments was detected in a cell culture medium. The compounds were assessed for their in vitro antiproliferative activity towards tumorigenic A2780, A2780cisR and Y79 cells and non-tumourigenic HEK293 cells. In particular, the combination of ethacrynic acid and flurbiprofen in 3 overcomes cisplatin-based resistance and provides strong cancer cell selectivity. Enzyme inhibition assays on human GST P1 and human COX-2 and cross-experiments with complex 1, analogous to 2-4 but lacking bio-groups, revealed a clear synergy between the Pt-II frame and the bioactive organic components.