Piero Zanello

On the mechanism of the antitumor activity of ferrocenium derivatives

Abstract Contradictory results exist in the literature about the antineoplastic activity of ferrocenes and their ferrocenium salts; additionally, little is known about the mechanism by which such drugs become active towards cancer cells. In the present paper we show that only ferrocenium species are able to inhibit the growth of Ehrlich ascites tumor cells in vivo and we propose that the cytotoxic activity of ferrocenium salts is not based on their direct linking to DNA, but on their ability to generate oxygen active species which induce oxidative DNA damage.

Photophysical and Electrochemical Characterisation of the Interactions between Components in Neutral π‐Associated [2]Catenanes

The electrochemical and photophysical properties of a variety of neutral pi-associated [2]catenanes have been explored by using cyclic voltammetry, absorption and luminescence spectrophotometry and the measurement of exited-state lifetimes. Several trends that could be correlated with interactions between the mechanically linked components of the structures were revealed from comparative study of catenane precursors, model compounds and the [2]catenanes themselves. Throughout, emphasis is placed on pair-wise comparisons between systems which differ in a single structural feature. Substitution in a catenane of a pyromellitic diimide unit by a naphthalene diimide yields more readily reduced derivatives, whose absorption spectra reveal charge transfer within the catenane to be a lower energy process of reduced intensity. Conversion of the butadiyne links within the diimide macrocycle of the catenanes to saturated chains results in an increase in both the energy and intensity of their charge-transfer bands; electrochemically these derivatives are all harder to reduce than the parent systems. Replacement of one of the electron-donating components of the catenanes with a less effective aromatic donor bearing a carboxy group also decreases the energy and intensity of the charge-transfer feature and is accompanied by a slightly more ready reduction. A sequence of reduction and translational events is proposed to explain the intriguing electrochemical behaviour of a catenane that contains one pyromellitic and one naphthalene diimide. For some systems the photophysical and electrochemical techniques, whilst exploring distinct physical phenomena, are shown to be in good agreement by comparison of shifts of electrochemical reduction waves with those of charge-transfer absorption features.

Adducts of Ferrocenylboranes and Pyridine Bases: Generation of Charge‐Transfer Complexes and Reversible Coordination Polymers

Compared to parent ferrocene, the redox potential of the FeII/FeIII transition is shifted to much more cathodic values in B–N adducts 1·Do and 2·(Do)2 of borylated ferrocenes FcBMe2 (1) and 1,1′-fc(BMe2)2 (2) with pyridine bases Do [Fc: (C5H5)Fe(C5H4); fc: (C5H4)Fe(C5H4); Do: γ-picoline, 4-(dimethylamino)pyridine, N-(n-propyl)-4-(4′-pyridyl)pyridinium hexafluorophosphate]. Electron donation by one single BMe2·Do substituent at the cyclopentadienyl ligand is approximately equal to the positive inductive effect of the five methyl groups in a C5Me5 (cp*) moiety. Using the bidentate nitrogen ligand 4,4′-bipyridine (bipy), the dark-purple dimetallic complex 1·bipy·1 is obtained upon reaction with 2 equiv. of 1. 1·bipy·1 has been structurally characterized by X-ray crystallography. The compound tolerates loss of two electrons at the ferrocene groups, as well as two one-electron reductions at the bipy linker. Dark purple coloured coordination polymers [2·bipy]n are accessible from bipy and 1 equiv. of the diborylated derivative 2. The intense colours of 1·bipy·1 and [2·bipy]n are indicative of charge-transfer interactions between the electron-rich ferrocene fragments and the viologen-like R3B–bipy–BR3 acceptor. Neat, solid [2·bipy]n is thermally stable up to 240 °C, but in the presence of toluene, polymerization is fully reversible at about 85 °C.

Chemical and biological profiles of novel copper(II) complexes containing S-donor ligands for the treatment of cancer.

In the last years, we have synthesized some new platinum(II), palladium(II), gold(I/III) complexes with dithiocarbamato derivatives as potential anticancer drugs, to obtain compounds with superior chemotherapeutic index in terms of increased bioavailability, higher cytotoxicity, and lower side effects than cisplatin. On the basis of the obtained encouraging results, we have been studying the interaction of CuCl2 with methyl-/ethyl-/tert-butylsarcosine-dithiocarbamato moieties in a 1:2 molar ratio; we also synthesized and studied the N,N-dimethyl- and pyrrolidine-dithiocarbamato copper complexes for comparison purposes. The reported compounds have been successfully isolated, purified, and fully characterized by means of several spectroscopic techniques. Moreover, the electrochemical properties of the designed compounds have been studied through cyclic voltammetry. In addition, the behavior in solution was followed by means of UV-vis technique to check the stability with time in physiological conditions. To evaluate their in vitro cytotoxic properties, preliminary biological assays (MTT test) have been carried out on a panel of human tumor cell lines. The results show that cytotoxicity levels of all of the tested complexes are comparable or even greater than that of the reference drug (cisplatin).

SYNTHESIS, STRUCTURE AND ELECTROCHEMICAL STUDIES OF THE FIRST MIXED-METAL CLUSTERS WITH THE P-N-P ASSEMBLING LIGANDS (PH2P)2NH (DPPA), (PH2P)2N(CH3) ( DPPAM) AND (PH2P)2N(CH2)3SI(OET)3 (DPPASI)

Heterometallic triangular palladium–cobalt clusters stabilized by three bridging diphosphine ligands such as Ph 2 PNHPPh 2 (dppa), (Ph 2 P) 2 N(CH 3 ) (dppam), (Ph 2 P) 2 N(CH 2 ) 3 Si(OEt) 3 (dppaSi), or mixed ligand sets Ph 2 PCH 2 PPh 2 (dppm)/dppa, dppm/dppam or dppm/dppaSi have been prepared with the objectives of comparing the stability and properties of the clusters as a function of the short-bite diphosphine ligand used and of making possible their use in the sol–gel process (case of dppaSi). The crystal structure determination of [CoPd 2 ( μ 3 -CO) 2 ( μ -dppam) 3 ]PF 6 confirms the triangular arrangement of the metal core, with each edge bridged by a dppam ligand, although disorder problems prevent a detailed discussion of the bonding parameters. Different approaches are given to functionalize the heterometallic clusters: alkylation of the nitrogen atom of co-ordinated dppa ligands or introduction of a third bridging diphosphine in a precursor tetranuclear cluster containing only two bridging diphosphine ligands. In the latter case, it was found that their nature critically determined whether or not the reaction occurred. The diversity of bridging ligands allowed an investigation of their influence on the electrochemical properties of the clusters. By comparison with [CoPd 2 ( μ 3 -CO) 2 (CO) 2 ( μ -dppm) 2 ] + which contains only two assembling ligands, it is generally observed that trinuclear cationic CoPd 2 clusters containing three (identical or different) edge-bridging bidentate diphosphine ligands show increased redox flexibility. A notable stabilisation of the metal core is observed when three dppm ligands bridge the metal–metal bonds and [CoPd 2 ( μ 3 -CO) 2 ( μ -dppm) 3 ] reversibly undergoes either a single-step two-electron oxidation or two distinct one-electron reductions. Complexes with the other diphosphines exhibit similar redox behaviour, but the stability of their redox congeners depends upon the nature of the diphosphine: a lower redox aptitude is exhibited by the dppa and dppam derivatives [CoPd 2 ( μ 3 -CO) 2 ( μ -dppa) 3 ] + and [CoPd 2 ( μ 3 -CO) 2 ( μ -dppam) 3 ] + .

The redox behaviour of some bis-ferrocenyl compounds: crystal and molecular structures of diferrocenylmethane and diferrocenylmethanol☆

Abstract Electrochemistry of diferrocenylmethane (1), diferrocenylketone (2), diferrocenylmethanol (3), diferrocenyl(phenyl)methanol (4), bis(1-ferrocenylpropyl) ether (5), 3,3-bis(ferrocenylmethyl)pentane-2,4-dione (6), 2,2-bis(ferrocenylmethyl)cyclohexane-1,3-dione (7) and trans-1,2-diferrocenylethene (8) shows that one-electron oxidation of the individual ferrocenyl sub-units takes place through: (i) separated charge transfers for 2 and 4; (ii) nearly overlapping steps for 1, 3 and 8; and (iii) single steps for each of 5, 6 and 7. This reflects the extent of electronic communication between the two redox centres, which is relatively high in the first case, decreases for the second series and is negligible for the third series. The crystal structure of diferrocenylmethanol 3 demonstrates that in the solid state the molecules are aggregated into centrosymmetric pairs with an O … O distance of 3.020(3) A. The hydroxyl hydrogen atoms are disordered, but one pattern of site occupancy gives rise to a closed (OH)2 dimer with hydrogen-bonding graph set R22(4). The crystal structure of diferrocenylmethane 1 contains isolated molecules having almost the same conformation and molecular volume as 3.

Binding of nitrite and its reductive activation to nitric oxide at biomimetic copper centers

Abstract The reactivity of nitrite towards the copper(II) and copper(I) centers of a series of complexes with tridentate nitrogen donor ligands has been investigated. The ligands are bis[(1-methylbenzimidazol-2-yl)methyl]amine (1-bb), bis[2-(1-methylbenzimidazol-2-yl)ethyl]amine (2-bb), and bis[2-(3,5-dimethyl-1-pyrazolyl)ethyl]amine (ddah) and carry two terminal benzimidazole (1-bb, 2-bb) or pyrazole (ddah) rings and a central amine donor residue. While 2-bb and ddah form two adjacent six-membered chelate rings on metal coordination, 1-bb forms two smaller rings of five members. The binding affinity of nitrite and azide to the Cu(II) complexes (ClO4− as counterion) has been determined in solution. The association constants for the two ligands are similar, but nitrite is a slightly stronger ligand than azide when it binds as a bidentate donor. The X-ray crystal structure of the nitrite complex [Cu(ddah)(NO2)]ClO4 (final R=0.056) has been determined: triclinic P1¯space group, a=8.200(2) Å, b=9.582(3) Å, c=15.541(4) Å. It may be described as a perchlorate salt of a “supramolecular” species resulting from the assembly of two complex cations and one sodium perchlorate unit. The copper stereochemistry in the complex is intermediate between SPY and TBP, and nitrite binds to Cu(II) asymmetrically, with Cu-O distances of 2.037(2) and 2.390(3) Å and a nearly planar CuO2N cycle. On standing, solutions of [Cu(ddah)(NO2)]ClO4 in methanol produce the dinuclear complex [Cu(ddah)(OMe)]2(ClO4)2, containing dibridging methoxy groups. In fact the crystal structure analysis (final R=0.083) showed that the crystals are built up by dinuclear cations, arranged on a crystallographic symmetry center, and perchlorate anions. Electrochemical analysis shows that binding of nitrite to the Cu(II) complexes of 2-bb and ddah shifts the reduction potential of the Cu(II)/Cu(I) couple towards negative values by about 0.3 V. The thermodynamic parameters of the Cu(II)/Cu(I) electron transfer have also been analyzed. The mechanism of reductive activation of nitrite to nitric oxide by the Cu(I) complexes of 1-bb, 2-bb, and ddah has been studied. The reaction requires two protons per molecule of nitrite and Cu(I). Kinetic experiments show that the reaction is first order in [Cu(I)] and [H+] and exhibits saturation behavior with respect to nitrite concentration. The kinetic data show that [Cu(2-bb)]+ is more efficient than [Cu(1-bb)]+ and [Cu(ddah)]+ in reducing nitrite.

Iron- and Ruthenium-Containing Triple-Decker Complexes with a Central Pentaphospholyl Ligand − X-ray Structures of [(η-C5H5)Fe(μ-η:η-P5)Ru(η-C5Me5)]PF6 and [(η-C5Me5)Ru(μ-η:η-P5)Ru(η-C5Me5)]PF6

Triple-decker cationic complexes with a central pentaphospholyl (pentaphosphacyclopentadienyl) ligand [Cp*M(μ-η:η-P5)M′(η-C5R5)]+ (3b: M = M′ = Fe, R = Me; 4a: M = Ru, M′ = Fe, R = H; 4b: M = Fe, M′ = Ru, R = H; 4c: M = Fe, M′ = Ru, R = Me; 5a: M = M′ = Ru, R = H; 5b: M = M′ = Ru, R = Me) were synthesized by exploitation of the stacking reactions of pentaphosphametallocenes Cp*M(η-P5) (1: M = Fe; 2: M = Ru) with half-sandwich fragments [(η-C5R5)M′]+. They were isolated as salts with BF4− or PF6− anions, and the structures of 4aPF6 and 5bPF6 were determined by X-ray diffraction. Triple-decker complexes with a central pentaphospholyl ligand are less reactive in nucleophilic degradation reactions than analogous complexes with C4Me4P and Cp* ligands in the bridging position. Only 4a and the previously known analogue 3a (M = M′ = Fe, R = H), containing the CpFe fragment, are nucleophilically destroyed by MeCN and NaI. The electrochemical properties of 2, 3a, 3b, 4a−c, 5a and 5b and the related cobalt-containing complexes [(η-C4Me4)Co(μ-η:η-P5)MCp*]+ (6: M = Fe; 7: M = Ru) were investigated. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis, properties and structures of the two “electron rich” cobalt-sulphur clusters [Co6(μ3-S)8(PEt3)6]1+,0

Abstract The reaction of hydrogen sulphide with [Co(H 2 O) 6 ](BF 4 ) 2 and triethylphosphine in the presence of sodium tetraphenylborate or tetrabutylammonium hexafluorophosphate gave the paramagnetic clusters [Co 6 (μ 3 -S) 8 (PEt 3 ) 6 ]( Y ) ( Y = BPh 4 , ( 1 ), PF 6 , ( 2 )). These compounds can be easily reduced by sodium napthalenide to the diamagnetic species [Co 6 (μ 3 -S) 8 (PEt 3 ) 6 ] · 2C 4 H 8 O ( 3 ). The molecular structures of 1 and 3 have been established by single-crystal X-ray diffraction methods. Crystal data: ( 1 ) space group P 1 , a = 19.481(9), b = 15.562(7), c = 12.390(b) A, α = 92.70(8), β = 94.50(7), γ = 94.10(9)°, Z = 2, ( 3 ) space group R 3 , a = 11.780(6) A, α = 92.50(7)°, Z = 1. Both structures were solved by the heavy atom method and refined by full-matrix least-squares techniques to the conventional R factors values of 0.050 for 1 and 0.044 for 3 on the basis of 4251 and 1918 observed reflections, respectively. The two clusters [Co 6 (μ 3 -S) 8 )(PEt 3 ) 6 ] 1+,0 are isostructural, the inner core consisting of an octahedron of cobalt atoms with all the faces symmetrically capped by triply bridging sulphur atoms. Each metal centre is additionally linked to a triethylphosphine group so that each cobalt atom is co-ordinated by four sulphur atoms and one phosphorus in a distorted square pyramidal environment. The addition of one electron whilst leaving unchanged the geometry of the inner framework, induces small changes in the structural parameters, the average CoCo and CoP distances being 2.794 (3) and 2.162 (2) A for 1 and 2.817 (3) and 2.138 (2) A for 3 respectively. Electrochemistry in non-aqueous solvents shows the electron-transfer sequence The tricationic species is stable only in the short time of cyclic voltammetric tests.

The redox behaviour of ferrocene derivatives: VI. Benzylferrocenes. The crystal structure of decabenzylferrocenium tetrafluoroborate☆

The electrochemical behaviour of the benzyl-substituted ferrocenes [(η5-C5Bz5)2Fe] and [(η5-C5Bz5)Fe(η5- C5H5)] in non-aqueous solutions has been examined. As expected, they undergo reversible one-electron removal more easily than ferrocene itself, but with significantly more difficulty than [(η5-C5R5)2Fe] (R = Me or Et). In dichloromethane solution, the formal electrode potentials (vs. SCE) are as follows: E°′([(C5Bz5)2Fe]+/0) = +0.38 V, E°′([(C5Me5)2Fe] +/0) = −0.10 V, E°′([(C5Et5)2Fe]+/0) = −0.06 V, E°′([(C5H5)2Fe]+/0) = +0.45 V. The electrochemical properties suggest that the [(C5Bz5)2Fe]+/0 redox change should be accompanied by minor, but detectable geometrical strains. In order to define more quantitatively the geometrical reorganization accompanying such electron removal processes, the X-ray structure of [(C5Bz5)2Fe][BF4] has been determined. Comparison with the previously determined structure of neutral [(C5Bz5)2Fe] shows an elongation of about 0.05 A of the FeC(cyclopentadienyl) distances, which is a common feature of all ferrocene/ferrocenium couples, but this is also accompanied by reorganization of the peripheral benzyl substituents. In the neutral precursor, the methylene fragments are tilted away from the plane of the cyclopentadienyl rings towards the iron atom, whereas in the monocation they become coplanar.