M. Fernanda N. N. Carvalho

Copper(II) complexes with tridentate pyrazole-based ligands: synthesis, characterization, DNA cleavage activity and cytotoxicity.

Tridentate pyrazole-containing ligands of the Schiff base type, SalPz - HL(1), Cl(2)SalPz - HL(2) and I(2)SalPz - HL(3), were used to prepare a series of new Cu(II) complexes (CuSalPz - 1, CuCl(2)SalPz - 2 and CuI(2)SalPz - 3). These new complexes have been studied by different analytical techniques (electrospray ionization mass spectrometry (ESI-MS), elemental analysis, FT-IR and EPR). The spectroscopic properties of 1-3 are consistent with the formation of Cu(II) complexes coordinated by monoanionic and tridentate (N,N,O)-chelators, behaving as monomeric species in aqueous solution, as shown by EPR studies. Crystals of 2 and 3, obtained by slow concentration of methanolic solutions of the compounds, were also analyzed by X-ray diffraction analysis. The X-ray structural study has shown that 2 crystallized as a dinuclear compound, [Cu(2)(μ-Cl)(2)(Cl(2)SalPz)(2)], while the solid state structure determined for 3 is best described by monomeric units of [CuCl(I(2)SalPz)] displaying short Cu···Cl intermolecular contacts. The in vitro evaluation of 1-3 comprised the study of their DNA-cleaving ability using plasmid DNA and the assessment of their cytotoxic activity against several human cancer cell lines (PC-3 prostate, MCF-7 breast and A2780 and A2780cisR-ovary). The studies with plasmid DNA have shown that 2 and 3 induce extensive DNA cleavage in the presence of different additives. The cytotoxic activity of 2 and 3 is comparable to the one presented by cisplatin, with the exception of the A2780 cell line where cisplatin is more active. It has been found that the introduction of halogen substituents in the phenolate rings of the chelators enhanced the cytotoxicity of the respective Cu(II) complexes.

Benzene ring assembly promoted by a camphor derived palladium complex

Abstract Trans-[PdCl2L2] (1, L=3-NNMe2C10H14O), under mild reaction conditions, acts as a catalyst for the cyclic trimerization of alkynes. The best performance is achieved for the reaction with PhCCMe that affords 1,3,5-trimethyl-2,4,6-triphenyl benzene with high activity and selectivity (ca. 99%). As a general trend the catalytic activity is higher for internal (PhCCMe, PhCCPh) than for terminal alkynes (HCCPh, HCCtBu, HCCCO2Me). Under more drastic experimental conditions the reaction of 1 with PhCCPh yields trans-[PdCl2(PhCCPh)2] and no catalytic activity is observed. The molecular structure of 1,3,5-trimethyl-2,4,6-triphenyl benzene was confirmed by X-ray diffraction analysis. The molecules were characterized by 1H- and 13C-NMR spectroscopies, FAB-MS and, in some cases, elemental analyses.

Chemistry of Monomeric and Dinuclear Non-Oxido Vanadium(IV) and Oxidovanadium(V) Aroylazine Complexes: Exploring Solution Behavior

A series of mononuclear non-oxido vanadium(IV) [V(IV)(L(1-4))2] (1-4), oxidoethoxido vanadium(V) [V(V)O(L(1-4))(OEt)] (5-8), and dinuclear μ-oxidodioxidodivanadium(V) [V(V)2O3(L(1))2] (9) complexes with tridentate aroylazine ligands are reported [H2L(1) = 2-furoylazine of 2-hydroxy-1-acetonaphthone, H2L(2) = 2-thiophenoylazine of 2-hydroxy-1-acetonaphthone, H2L(3) = 1-naphthoylazine of 2-hydroxy-1-acetonaphthone, H2L(4) = 3-hydroxy-2-naphthoylazine of 2-hydroxy-1-acetonaphthone]. The complexes are characterized by elemental analysis, by various spectroscopic techniques, and by single-crystal X-ray diffraction (for 2, 3, 5, 6, 8, and 9). The non-oxido V(IV) complexes (1-4) are quite stable in open air as well as in solution, and DFT calculations allow predicting EPR and UV-vis spectra and the electronic structure. The solution behavior of the [V(V)O(L(1-4))(OEt)] compounds (5-8) is studied confirming the formation of at least two different types of V(V) species in solution, monomeric corresponding to 5-8, and μ-oxidodioxidodivanadium [V(V)2O3(L(1-4))2] compounds. The μ-oxidodioxidodivanadium compound [V(V)2O3(L(1))2] (9), generated from the corresponding mononuclear complex [V(V)O(L(1))(OEt)] (5), is characterized in solution and in the solid state. The single-crystal X-ray diffraction analyses of the non-oxido vanadium(IV) compounds (2 and 3) show a N2O4 binding set and a trigonal prismatic geometry, and those of the V(V)O complexes 5, 6, and 8 and the μ-oxidodioxidodivanadium(V) (9) reveal that the metal center is in a distorted square pyramidal geometry with O4N binding sets. For the μ-oxidodioxidodivanadium species in equilibrium with 5-8 in CH2Cl2, no mixed-valence complexes are detected by chronocoulometric and EPR studies. However, upon progressive transfer of two electrons, two distinct monomeric V(IV)O species are detected and characterized by EPR spectroscopy and DFT calculations.

Kinetic study of the alkylation of cyanide at [NBu4][trans-Re(CN)2(dppe)2]. Crystal structures of [NBu4][trans-Re(CN)2(dppe)2] and trans-[Re(CN)2(dppe)2]

Abstract The mechanism of alkylation of [NBu 4 ][ trans -Re(CN) 2 (dppe) 2 ] ( 1 ) by alkyl iodides (RI; R=Me, Et or Pr) or EtBr was studied by stopped-flow techniques, which indicate that it involves a fast first alkylation to give trans -[Re(CN)(CNR)(dppe) 2 ] that undergoes a subsequent relatively slow alkylation at the cyano-ligand with a rate constant that decreases with the increase of the carbon chain length of the R group and with the replacement of iodide by bromide in the organohalide. Sodium iodide inhibits the rates of alkylation, probably by forming ion pairs with trans -[Re(CN) 2 (dppe) 2 ] − as confirmed by the formation of the adducts [Re(CN)(CNM)(dppe) 2 ] (M=Li, Na, Tl or Ag) by reaction of 1 with convenient metal salts and by the kinetics of the reaction between MeI and [Re(CN)(CNNa)(dppe) 2 ]. The X-ray molecular structures of [NBu 4 ][ trans -Re(CN) 2 (dppe) 2 ] and trans -[Re(CN) 2 (dppe) 2 ] confirm they have pseudo octahedral geometries and indicate that the former crystallizes in the triclinic P 1 space group with a =17.938(2), b =18.473(3), c =20.061(3) A and the latter in the monoclinic space group P 2 1 / c with a =11.673(2), b =13.302(3), c =17.166(4) A.

New ternary bipyridine–terpyridine copper(II) complexes as self-activating chemical nucleases

Seeking self-activating chemical nucleases with potential applications as therapeutic agents, new ternary terpyridine–bipyridine–Cu(II) complexes carrying pendant cyclic amines were developed. After detailed characterization, the nuclease activity of the synthesized compounds was evaluated by using circular plasmid DNA as substrate and analyzing the products by agarose-gel electrophoresis. The new complexes present an impressive plasmid DNA cleaving ability, which triggers double-strand DNA breaks in the absence of any exogenous agents, via an oxidative mechanism. The binding affinity towards duplex DNA was determined using UV-Vis and fluorescence spectroscopic titrations. These studies showed that the tested complexes bind moderately (in the order of 104 M−1) to duplex DNA. The copper complexes displayed high cytotoxicity against ovarian carcinoma A2780 cells (4-fold cisplatin activity), surpassing the resistance on the cisplatin-resistant cell line (A2780cisR) with lower resistance factors. Cellular uptake studies showed that the ternary complexes were able to enter the cell with a significant localization in the cytoskeleton.

Activation of a coordinated alkyne by electron transfer: crystal structures of [Ph2}{C(CO2Me)CH(CO2Me)}] and [PPh2}{C(CO2Me)C(CO2Me)}]

Abstract A new zerovalent complex [ Pd{PPh 2 CH 2 C(Bu t )NNC(Bu t )CH 2 P Ph2}{C(CO2Me)C(CO2Me)}] (1) was prepared and its crystal structure was determined by X-ray diffraction analysis, which shows it crystallises in the C2/C monoclinic space group with a=10.940(1) A, b=22.086(1) A, c=19.042(2) A and β=92.692(9)°. The azine diphosphine ligand chelates the metal in a (Z,Z) configuration with a PPdP bite angle of 114.63(4)°. The alkyne carbon atoms lie essentially in the PPdP plane. The electrochemical reduction of 1 promoted the conversion of the alkyne ligand to a vinyl species, and of the azine diphosphine to ene-hydrazone diphosphine, with formation of [ Pd{PPh 2 CHC(Bu t )NNC(Bu t )CH 2 P Ph2}{C(CO2Me)CH(CO2Me)}] (2). X-ray diffraction analysis of complex 2 shows it crystallises in the triclinic space group P1 with a=11.302(1) A, b=12.528(1) A, c=16.028(2) A, α=107.64(2)°, β=92.27(1)° and γ=111.79(2)°. It displays a square-planar geometry with the two phosphorus atoms in trans position. Extended Huckel MO calculations were performed in order to elucidate the redox process.A new zerovalent complex [Ph2}{C(CO2Me)C(CO2Me)}] (1) was prepared and its crystal structure was determined by X-ray diffraction analysis, which shows it crystallises in the C2/C monoclinic space group with a=10.940(1) A, b=22.086(1) A, c=19.042(2) A and β=92.692(9)°. The azine diphosphine ligand chelates the metal in a (Z,Z) configuration with a PPdP bite angle of 114.63(4)°. The alkyne carbon atoms lie essentially in the PPdP plane. The electrochemical reduction of 1 promoted the conversion of the alkyne ligand to a vinyl species, and of the azine diphosphine to ene-hydrazone diphosphine, with formation of [Ph2}{C(CO2Me)CH(CO2Me)}] (2). X-ray diffraction analysis of complex 2 shows it crystallises in the triclinic space group P1 with a=11.302(1) A, b=12.528(1) A, c=16.028(2) A, α=107.64(2)°, β=92.27(1)° and γ=111.79(2)°. It displays a square-planar geometry with the two phosphorus atoms in trans position. Extended Huckel MO calculations were performed in order to elucidate the redox process.

Alkylation of cyanide at [NBu4]trans-[Re(CN)2(Ph2PCH2CH2PPh2)2]. Syntheses and properties of derived isocyanide complexes and X-ray structure of trans-[Re(CNEt)2(Ph2PCH2CH2PPh22][PF6]

Abstract The reaction of RI (R = Me, Et or Pr) or [Et 3 O][PF 6 ] with [NBU 4 ] trans -[Re(CN) 2 (dppe) 2 ] (dppe = Ph 2 PCH 2 CH 2 PPh 2 ) affords the diisocyanide complexes trans -[Re(CNR) 2 (dppe) 2 ]A (R = Me, A = I; R = Pr, A =I 3 ; R = Et, A = PF 6 , whereas trans -[Re(CNH)(CNSiMe 3 )(dppe) 2 ]CF 3 SO 3 is obtained from the reaction with Me 3 SiO 3 SCF 3 . The X-ray crystal structure of trans -[Re(CNEt) 2 )(dppe) 2 ]CF 6 was determined. The redox properties of the compounds were studied by cyclic voltammetry and controlled potential electrolysis, and are discussed in terms of the electronic properties of the metal centres and ligands.

Synthesis of Ag(I) camphor sulphonylimine complexes and assessment of their cytotoxic properties against cisplatin-resistant A2780cisR and A2780 cell lines.

Camphorsulphonylimine complexes [Ag(NO3)(IL)2] (IL=C12H19N3SO2, 1) and [(AgNO3)2(IIL)] (IIL=C22H23N3SO2, 2) were synthesized and characterized by elemental analysis, spectroscopy (IR, NMR) and cyclic voltammetry. [Ag(NO3)(IL)2] crystalizes in the monoclinic C2 space group with a triangular geometry assuming a chalice-type shape. The anti-proliferative properties of the new complexes 1 and 2 and those of the previously reported [Ag(NO3)(IIIL)] (IIIL=C16H18N3SO2, 3) were assessed against the human ovarian cancer cells (cisplatin-sensitive A2780, cisplatin-resistant A2780cisR) and the non-tumoral human HEK 293 cell line, using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The NR (3-amino-7-dimethylamino-2-methylphenazine hydrochloride) assay was alternatively used to assess the cytotoxicity on the A2780 cells. Results from the MTT assay (48h exposure) show that the complexes display IC50 values lower (by at least one order of magnitude) than cisplatin, while the cytotoxicity of AgNO3 is of the same order of cisplatin. The camphorsulphonylimine ligands display irrelevant (IL, IIIL) or no cytotoxicity (IIL). The highest cytotoxicity (lower IC50) was found for [(AgNO3)2(IIL)]. The binding ability of the complexes to calf thymus-deoxyribonucleic acid (CT-DNA) was studied by fluorescence. Constants (Ksv, Ka) and the number (n) of binding centres to DNA were calculated showing that DNA intercalation possibly occurs in the cases of complexes 2 and 3, while a more complicated process operates for 1. As expected from the cytotoxicity, [(AgNO3)2(IIL)] displays the highest binding affinity (Ka=1.61×105 M-1). No binding to DNA was detected for AgNO3 or IIL under the experimental conditions used. The binding trend to CT-DNA found by fluorescence was corroborated by cyclic voltammetry.

Mechanism of alkylidyne complex formation by protonation of the vinylidene complex trans-[ReCl(CCHPh)(Ph2PCH2CH2PPh2)2]

Stopped-flow kinetic studies have demonstrated that in tetrahydrofuran the protonation of trans-[ReCl(CCHPh)(Ph2PCH2CH2PPh2)2] to form trans-[ReCl(CCH2Ph)(Ph2PCH2CH2PPh2)2]+ can occur by three pathways.

Electronic communication in linear oligo(azobenzene) radical anions.

The radical anions of five bis(azobenzene) and one tris(azobenzene) compounds were studied by optical and electron paramagnetic resonance (EPR) spectroscopies in polar aprotic solvents. The radicals with planar or almost-planar bridges are charge-delocalized mixed-valence species. Localization of charge occurs only on radicals with highly twisted biphenyl bridges. The electronic coupling between the azobenzene charge-bearing units, calculated as half the energy of the intervalence band for the charge-delocalized and by the Hush equation for the charge-localized radicals, decreases with the distance and torsion angle between azobenzene units. These radicals have smaller electronic couplings between charge-bearing units than other mixed-valence organic radicals with similar bridges. However, the application of a three-stage model to the tris(azobenzene) radical anion intervalence band yields an electronic coupling between consecutive azobenzenes that is higher than in any of the bis(azobenzene) radicals studied.