Maddalena Corsini

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).

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)

Dinuclear Pt(II)-bisphosphonate complexes: a scaffold for multinuclear or different oxidation state platinum drugs†

Geminal bisphosphonates (BPs), used in the clinic for the treatment of hypercalcaemia and skeletal metastases, have been also exploited for promoting the specific accumulation of platinum antitumor drugs in bone tissue. In this work, the platinum dinuclear complex [{Pt(en)}(2)(μ-AHBP-H(2))](+) (1) (the carbon atom bridging the two phosphorous atoms carrying a 2-ammonioethyl and a hydroxyl group, AHBP-H(2)) has been used as scaffold for the synthesis of a Pt(II) trinuclear complex, [{Pt(en)}(3)(μ-AHBP)](+) (2), and a Pt(IV) adamantane-shaped dinuclear complex featuring an oxo-bridge, [{Pt(IV)(en)Cl}(2)(μ-O)(μ-AHBP-H(2))](+) (3) (X-ray structure). Compound 2 undergoes a reversible, pH dependent, rearrangement with a neat switch point around pH = 5.4. Compound 3 undergoes a one-step electrochemical reduction at E(pc) = -0.84 V affording compound 1. Such a potential is far lower than that of glutathione (-0.24 V), nevertheless compound 3 can undergo chemical reduction to 1 by GSH, most probably through a different (inner-sphere) mechanism. In vitro cytotoxicity of the new compounds, tested against murine glioma (C6) and human cervix (HeLa) and hepatoma (HepG2) cell lines, has shown that, while the Pt(IV) dimer 3 is inactive up to a concentration of 50 μM, the two Pt(II) polynuclear compounds 1 and 2 have a cytotoxicity comparable to that of cisplatin with the trinuclear complex 2 generally more active than the dinuclear complex 1.

Ru(III)-based compounds with sulfur donor ligands: synthesis, characterization, electrochemical behaviour and anticancer activity

In recent years, Ru(iii) complexes have emerged as a new class of effective anticancer agents against tumors that proved to be resistant to all other chemotherapeutic drugs currently in clinical use. To extend our previous studies on metal complexes containing sulfur-donor ligands, we report here on the synthesis and characterization, by means of several spectroscopic and analytical techniques, some [Ru(RSDT)(3)] and [Ru(2)(RSDT)(5)]Cl complexes with dithiocarbamato ligands derived from methyl/ethyl/tert-butyl esters of sarcosine. Their electrochemical behaviour was also studied by cyclic voltammetry. All the complexes were tested for their cytotoxicity on a panel of human tumor cell lines showing highly significant antitumor activity. The chemical and biological properties of the newly synthesized complexes, were compared with those of [Ru(DMDT)(3)] and [Ru(2)(DMDT)(5)]Cl species (DMDT = N,N-dimethyldithiocarbamate) whose chemical (not biological) characterization has been already reported in literature.

3,3-Diethyl-and 3,3-dibenzyl-1,2-diferrocenylcyclopropenes.

Reactions of 2,3-diferrocenylcyclopropenone 1 with ethyl- and benzylmagnesium chlorides afford 3,3-diethyl-and 3,3-dibenzyl- 1,2-diferrocenylcyclopropenes 2 and 3, respectively, and products of nucleophilic opening of the three-membered ring resulting from the addition of RMgCl to the carbonyl group, viz., saturated ketones(4,5-diferrocenylheptan-3-ones 4a,b and 3,4-diferrocenyl-1,5-diphenylpentan-2-ones 5a,b as ca. 3: 1 mixtures of two diastereomers) and other products. The spatial structures of compounds 2 and 4a were established by X-ray diffraction analysis of single crystals. Protonation of the cyclopropenes 2 and 3 with tetrafluoroboric acid at -40 degrees C yields the corresponding 3,3-dialkyl-1 ,2-diferrocenylcyclopropylium tetrafluoroborates. Transformation of the latter into diferrocenylallylic cations upon increasing the temperature to 20 degrees C and their eprotonation under the action of N,N-dimethylaniline were studied. Electrochemical investigation of 1 and 2 shows that in both complexes the cyclopropene spacer allows electronic communication between the two outer ferrocenyl groups, this being notably greater for 2 than for 1.

Parallel and perpendicular stacking of ferrocene rings. Syntheses, X-ray structures, and electrochemistry of 1,8-bis-[1-(1'-phenylthio)ferrocenyl]naphthalene and 8,8'-bis-[1-(1'-phenylthio)ferrocenyl]-1,1'-binaphthyl

Abstract The parallel and perpendicular stacking of ferrocene rings in 1,8-bis-[1-(1′-phenylthio)ferrocenyl]naphthalene (1) and 8,8′-bis-[1-(1′-phenylthio)ferrocenyl]-1,1′-binaphthyl (2), respectively, were investigated. They were synthesized from the Suzuki coupling of 2,4,6-tris(1′-phenylthio-1-ferrocenyl)boroxin (3) with 1,8-diiodonaphthalene and 1,8-diiodo-1,1’-binaphthyl, respectively. Their structures were confirmed by single-crystal X-ray analyses. The two cyclopentadienyl (Cp) rings (C9C13 and C19C23) of the two respective ferrocenes Fe(1) and Fe(2) of 1 are not parallel, but are 21.3° away from parallel. The distance between the centroids of these two Cp rings is 3.336 A. The two Cp rings (C9C13 and C9′C13′) of the two respective ferrocenes Fe(1) and Fe(2) of 2 are not perpendicular, but have a dihedral angle of 49.9°, and the distance between two centroids of these two Cp rings is 5.255 A. The electrochemical behaviour of 1 and 2 in dichloromethane solution shows that they undergo reversibly two ferrocene-centred one-electron oxidations to the corresponding dications. The separation between the two anodic processes is greater for 1 with respect to 2, but the absolute value of the separation significantly depends upon the nature of the supporting electrolyte. In the presence of the classical [NBu4][PF6] the ΔE°′ value is 0.15 V for 1 and 0.07 V for 2. In the presence of the new [NBu4][B(C6F5)4] the ΔE°′ value increases to 0.45 V for 1 and 0.13 V for 2. In view of the low ion-pairing ability of the [B(C6F5)4]− counteranion, it is conceivable that the increased intramolecular electronic communication might essentially arise from the increased electrostatic repulsion (or through-space interaction) following the 0/+/2+ redox changes rather than from through-bond electron delocalization.

Synthesis and properties of styryl-substituted tetrapyrazinoporphyrazines [St8PyzPzM], M = 2NaI, MgII(H2O) and ZnII

New styryl-substituted tetrapyrazinoporphyrazines [St8PyzPzM] (M = 2NaI, MgII(H2O) and ZnII; St = -CH=CHAr, where Ar = phenyl or cumyl) were prepared by template cyclotetramerization of 5,6-distyrylpyrazine-2,3-dicarbonitriles available from condensation of diaminomaleodinitrile with the substituted cinnamils (StCO)2 obtained from biacetyl and arylaldehydes ArCHO. The new porphyrazine macrocycles were characterized by electronic absorption and emission spectra, which provide evidence of efficient π-interaction of the peripheral styryl moieties with the central pyrazinoporphyrazine framework. The electronic excitation of the stylbenoid chromophore in the near UV-region (400 nm) leads to strong emission of the porphyrazine chromophore near 700 nm, allowing to consider the styryl-substituted porphyrazines as efficient light-harvesting species. Their spectral properties and electrochemical behavior are compared with those of stylbenoid phthalocyanines and peripherally substituted tetrapyrazinoporphyrazines.

X-ray structure and density functional theory studies of an unexpected product: trans-bis{2-[(2-cyanoethyl)iminomethyl]phenolato}copper(II).

The title compound, [Cu(C(10)H(9)N(2)O)(2)] or [Cu(II)(CYMB)(2)], (I), was obtained in an attempt to reduce trans-bis(2-{[3,5-bis(trifluoromethyl)phenyl]iminomethyl}phenolato)copper(II), [Cu(TIMB)(2)], (II), with bis(pentamethylcyclopentadienyl)cobalt(II) [decamethylcobaltocene, Cp*(2)Co, (III)]. The molecular structure of (I) has the Cu(II) centre located on an inversion centre of the C2/c space group. A density functional theory (DFT) analysis at the B3LYP/Lanl2dz(CuF);6-31G**(CHNO) level performed in order to optimize the structures of the free ligands CYMB(-) and TIMB(-), and the metal complexes [Cu(I/II)(CYMB)(2)](-/0) and [Cu(I/II)(TIMB)(2)](-/0), reproduced well the X-ray diffraction structure and allowed us to infer the insertion of the cyanomethide anion on the 3,5-bis(trifluoromethyl)phenyl system from an evaluation of the Mulliken atomic charges and the electronic energies.

Prebiotic iron–sulfur peptide catalysts generate a pH gradient across model membranes of late protocells

Prebiotic chemistry was likely mediated by metals, but how such prebiotic chemistry progressed into the metabolic-like networks needed to sustain life remains unclear. Here we experimentally delineate a potential path from prebiotically plausible iron–sulfur peptide catalysts to the types of pH gradients exploited by all known living organisms. Iron–sulfur peptides cooperatively accept electrons from NADH in a manner that is only partially mediated by ionic interactions. The electrons are then either passed to a terminal electron acceptor, such as hydrogen peroxide, or to an intermediate carrier, such as ubiquinone. The reduction of hydrogen peroxide leads to the production of hydroxide, which then contributes to the formation of a pH gradient across late protocell membranes. The data are consistent with the activity of prebiotic iron–sulfur peptide catalysts providing a selective advantage by equipping protocells with a pathway that connects catabolism to anabolism.The bioenergetic metabolism of all life today depends on proton gradients; however, it remains unclear how such gradients developed in early life. Here, Mansy and co-workers establish a possible prebiotic mechanism in which iron–sulfur peptide redox networks generate a trans-membrane pH gradient.

The first triple-decker complex with a carbenium center, [CpCo(µ-C3B2Me5)RuC5Me4CH2]+: synthesis, reactivity, X-ray structure and bonding.

The first derivative of the methylium cation with the triple-decker substituent, [CpCo(C3 B2 Me5 )RuC5 Me4 CH2 ]PF6 (2PF6 ), was synthesized from the reaction of the triple-decker complex CpCo(C3 B2 Me5 )RuCp* (1) with the salt of the trityl cation [CPh3 ]+ . The X-ray crystal structure of 2PF6 reveals that the methylium carbon is bound to the ruthenium with Ru-C bond length of 2.259 Å and corresponds to the description of its structure as η6 -fulvene-ruthenium. Reactions of 2PF6 with nucleophiles OH- , Ph3 P, Et3 N led to the corresponding derivatives of 1 in high yields. Aromatic amines PhNEt2 and 4-MeC6 H4 NH2 react with 2PF6 to give the electrophilic aromatic substitution products quantitatively. Chemical reduction of 2PF6 with Zn powder in tetrahydrofuran leads to the formation of the bis(triple-decker) derivative (CpCo(C3 B2 Me5 )RuC5 Me4 CH2 )2 (10) with a CH2 CH2 -bridge. The structures of complexes 4, 7-10 were determined by X-ray diffraction. Density functional calculations support the crystallographically determined geometry of 2 and allow rationalization of some characteristics of its structure, spectroscopy, and reactivity.