Franco Laschi

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.

Spectroscopic and potentiometric study of the SOD mimic system copper(II)/acetyl-L-histidylglycyl-L-histidylglycine.

Stoichiometry, stability constants and solution structures of the copper(II) complexes of the N-acetylated tetrapeptide HisGlyHisGly were determined in aqueous solution in the pH range 2-11. The potentiometric and spectroscopic data (UV-Vis, CD, EPR and Raman scattering) show that acetylation of the amino terminal group induces drastic changes in the coordination properties of AcHGHG compared to HGHG. The N3 atoms of the histidine side chains are the first anchoring sites of the copper(II) ion. At pH 4.7 and 5.6 both the imidazole rings cooperate in the formation of a 2N equatorial set, while, at higher pH values, 3N and 4N complexes are formed through the coordination of peptide N- atoms. The logbeta values of the copper complexes of AcHGHG are by far lower than those of the corresponding species in the parent CuII-HGHG system.

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 ] + .

Dioxygen uptake and transfer by Co(III), Rh(III) and Ir(III) catecholate complexes

Abstract A large number of five-coordinate metal catecholate complexes of the general formula [(triphos)M(Cat)]Y have been synthesized and characterized by chemical, spectroscopic and electrochemical techniques (MCo, Rh, Ir; Cat=9,10-phenathrenecatecholate, 1,2-naphthalencatecholate, 3,5-di-tert-butylcatecholate, 4-methylcatecholate, 4- carboxycatecholate-ethylester, tetrachlorocatecholate; YBPh4, PF6; triphos=MeC(CH2PPh2)3). All of the compounds undergo electron-transfer reactions that encompass the M(III), M(II) and M(I) oxidation states of the metal, and the catecholate, semiquinone and quinone oxidation levels of the quinoid ligand. Paramagnetic Ir(III) semiquinonate complexes, [(triphos)Ir(SQ)]2+, and Ir(II) catecholates, [(triphos)Ir(Cat)], have been characterized by X-band ESR spectroscopy. The reactions of the metal catecholates in non-aqueous media with dioxygen have been investigated. With very few exceptions, all of the compounds react with O2 to give adducts of the general formula [(triphos) M(O O)(S Q)]Y. An X-ray analysis has been carried out on [(triphos) Ir(O O)(P henSQ)]BPh4, (Phen=9, 10-phenanthrenesemiquinonate). In the complex cation, the metal is octahedrally coordinated by the three phosphorus atoms of triphos and by three oxygen atoms, one from O2 and the other two from the catecholate ligand that has attained a semiquinoid character. The electrochemical behavior of the dioxygen adducts has been studied in detail. Depending on the E°′ values relative to the MIII(SQ)/MIII(Cat) couples of the parent metal catecholates, the dioxygen adducts undergo either a one-electron oxidation to give o-quinone complexes [(triphos) M(Q)]3+ and superoxide ion (O2−) or a two-electron oxidation to give [(triphos)M(Q)]3+ and O2. Several factors have been found to affect the O2 uptake by metal catecholates. Of particular importance are: (i) the coordination number of the metal; (ii) the basicity of either the catecholate ligand or metal; (iii) the temperature; (iv) the pressure of dioxygen. The role of each factor has been analyzed and rationalized. The transport of dioxygen from one metal catecholate to another has been studied. A mechanistic interpretation for the formation of the [(triphos) M(O O)(S Q)]+ complexes is proposed in light of a large crop of experimental data and molecular orbital considerations.

Electrochemistry of acetylide complexes of iron

Abstract The synthesis of a symmetrical acetylide-bridged, diiron(II) complex, ClFe(DMPE) 2 (CCC 6 H 4 CC)-(DMPE) 2 FeCl ( 1 ) (DMPE = bis(dimethylphosphine)ethane) is reported. Electrochemistry and EPR spectroscopy are used to examine the redox properties of 1 as well as the mononuclear iron(II) complexes Fe(DMPE) 2 Cl 2 ( 2 ), ClFe(DMPE) 2 (CCPh) ( 3 ), and Fe(DMPE) 2 (CCPh) 2 ( 4 ). Evidence for the corresponding iron(III) and iron(IV) species is provided. The structural rearrangements accompanying redox changes are discussed on the basis of the electrochemical characteristics. The electrochemical behaviour of the bridged diiron species 1 provides evidence that the two metal centres interact electronically.

Spectroscopic and potentiometric study of copper(II) complexes with l-histidyl-glycyl-l-histidyl-glycine in aqueous solution

Abstract The complex formation between copper(II) and the tetrapeptide l -histidyl-glycyl- l -histidyl-glycine (HL) has been studied in aqueous solution in the pH range 2–10.5, by potentiometric and spectroscopic methods (visible, CD, EPR, 1 H NMR and Raman scattering). Between pH 3 and 6 the species [CuHL] 2+ and [CuH −1 L] have been detected. The former complex co-ordinates through two nitrogen and two oxygen atoms in the equatorial plane while, for the latter, the spectroscopic data (particularly Raman spectra) suggests an unusual structure with the two imidazole rings and two peptide NH in the plane. The species at pH 7, [CuH −2 L] − , is involved in the co-ordination by the amino group, the His 1 imidazole and two peptide nitrogens, while, for the complex [CuH −3 L] 2− , which seems to be predominant in alkaline medium, a third deprotonated backbone NH, replaces the imidazole nucleus.

Tendamistat surface accessibility to the TEMPOL paramagnetic probe

TEMPOL, the soluble spin-label 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl, has been used to determine the surface characteristics of tendamistat, a small protein with a well-characterised structure both in solution and in the crystal. A good correlation has been found between predicted regions of exposed protein surface and the intensity attenuations induced by the probe on 2D NMR TOCSY cross peaks of tendamistat in the paramagnetic water solution. All the high paramagnetic effects have been interpreted in terms of more efficient competition of TEMPOL with water molecules at some surface positions. The active site of tendamistat coincides with the largest surface patch accessible to the probe. A strong hydration of protein N and C termini can also be suggested by this structural approach, as these locations exhibit reduced paramagnetic perturbations. Provided that the solution structure is known, the use of this paramagnetic probe seems to be well suited to delineate the dynamic behaviour of the protein surface and, more generally, to gain relevant information about the molecular presentation processes.

Supraicosahedral indenyl cobaltacarboranes

13-vertex indenyl cobaltacarboranes with 4,1,6-, 4,1,10- and 4,1,2-CoC(2)B(10) architectures have been synthesised by reduction of the corresponding closo carborane and metallation with an {(eta-C(9)H(7))Co} fragment. Variants of the 4,1,6-isomer were prepared with no, one and two methyl groups on cage C atoms, whilst 4,1,2-species were obtained both with two methyl groups and a trimethylene tether on the cage C atoms. Thermolysis of the 4,1,6-isomers yielded the corresponding 4,1,8-isomers, which in turn were converted to 4,1,12-isomers by thermolysis at higher temperatures. Alternatively relatively mild heating of the 4,1,10-isomer led to the 4,1,12-isomer directly. Products were characterised by mass spectrometry, (1)H and (11)B NMR spectroscopies and, in most cases, elemental analysis, and nine compounds were studied crystallographically. The 4,1,6-, 4,1,8-, 4,1,10- and 4,1,12- species have docosahedral cages whilst the 4,1,2-species are henicosahedral. In the structural studies attention focused on the orientation of the indenyl ligand with respect to the carborane ligand since this affords experimental information on the metal-cage bonding through the structural indenyl effect. There is a general tendency for the indenyl ligand to adopt orientations in which the ring junction C atoms lie trans to cage B atoms. In cases where the orientation is not compromised by the presence of a non-H substituent on the face of the carborane there is generally good agreement between the experimental orientation and that computed by DFT calculations for the related naphthalene ferracarboranes (eta-C(10)H(8))FeC(2)B(10)H(12). The presence of C-methyl substituents in the indenyl cobaltacarboranes tends to override this preference except in the case of 1,6-Me(2)-4-(eta-C(9)H(7))-4,1,6-closo-CoC(2)B(10)H(10) where the indenyl ligand instead is forced to incline away from the cage methyl groups. In DCM solution the 4,1,6-, 4,1,8-, 4,1,10- and 4,1,12- isomers of (eta-C(9)H(7))CoC(2)B(10)H(12) exhibit two, stepwise, 1-electron reductions assigned to Co(III)/Co(II)/Co(I) couples at less negative potentials than those of the corresponding Cp compounds. Moreover these reductions are easier for those isomers (4,1,6- and 4,1,10-) in which there are two cage C atoms in the carborane face to which the metal atom is bound. By spectroelectrochemical and EPR measurements it is concluded that the reductions of these indenyl cobaltacarboranes are largely metal-based.

Anodically-induced metal deprotonation of the hydrido complexes [{PCH2CH2PPh2)3}M (H) Cl ] (M = Fe, Ru, Os) : the first step to the electrogeneration of Fe(I),u(I) and Os(I) five-coordinate complexes

Abstract The electrochemical behaviour of the (hydride) chloride complexes [(PP3)M(H)Cl] (M = Fe, Ru, Os) has been studied by cyclic voltammetry and controlled-potential electrolysis in tetrahydrofuran (PP3 = P(CH2CH2PPh2)3). All compounds undergo anodically-induced deprotonation to give the corresponding M(II) chlorides [(PP3)MCl]+. All the oxidation processes correspond to an EEC reaction pathway. The two-electron oxidation processes occur at coincident potentials for M = Ru, at slightly different potentials for M = Os, and at largely different potentials for M = Fe. The M(II) complexes [(PP3)MCl)+ are reversibly reduced to the corresponding M(I) derivatives [(PP3)MCl), which can be generated in solution by exhaustive macroelectrolysis. The paramagnetic Fe(I), Ru(I) and Os(I) chloride complexes have been characterised by X-band ESR spectroscopy in glassy and fluid solutions.

The redox behaviour of the cluster anion [Fe4N(CO)12]−. Electron transfer chain catalytic substitution reactions. Crystal structure of [Fe4N(CO)11PPh3)]−

Abstract The electrochemical investigation of the redox properties of the monoanion [Fe4N(CO)12]− points out its ability to undergo sequentially two one-electron reductions. The first step leads to the quite stable dianion [Fe4N(CO)12]:2−; the EPR results indicate that in frozen solution an equilibrium exists between two different molecular geometries of such a dianion. The second electron addition produces the relatively short-lived trianion [Fe4N(CO)12]3−. In the presence of monodentate phosphines, the redox change [Fe4N(CO)12]−/2− triggers the electrocatalytic substitution of one CO group to afford the substituted monoanions [Fe4N(CO)11(PR3)]−. As a matter of fact, sub-stoichiometric amounts of Ph2CO − produce [Fe4N(CO)11(PPh3)]−, the crystal structure of which has been solved. Crystal data for [N(PPh3)2][Fe4N(CO)11(PPh3)]: triclinic, space group P 1 (No. 2), a=11.009(6), b=17.285(4), c=17.380(2) A, α=103.11(3), β=91.18(2), γ=105.26(3)°, Z=2, Dc=1.444 g cm−3, Mo Kα radiation (λ=0.71073 A), μ(Mo Kα)=10.5 cm−1, R=0.048 (Rw=0.054) for 5010 independent reflections having I > 3σ(I). Preliminary evidence is given that in the presence of bidentate phosphines one CO ligand substitution occurs at room temperature, whereas two CO groups are replaced at higher temperatures.