Showing papers by "João Costa Pessoa published in 2013"

Vanadium complexes having [VO]2+, [VO]3+ and [VO2]+ cores with hydrazones of 2,6-diformyl-4-methylphenol: synthesis, characterization, reactivity, and catalytic potential

Abstract: The Schiff bases H3dfmp(L)2 obtained by the condensation of 2,6-diformyl-4-methylphenol and hydrazones [L = isonicotinoylhydrazide (inh), nicotinoylhydrazide (nah) and benzoylhydrazide (bhz)] are prepared and characterized. By reaction of [VIVO(acac)2] and the H3dfmp(L)2 in methanol the VIVO-complexes [VIVO{Hdfmp(inh)2}(H2O)] (1), [VIVO{Hdfmp(nah)2}(H2O)] (2) and [VIVO{Hdfmp(bhz)2}(H2O)] (3) were obtained. Upon their aerial oxidation in methanol [VVO(OMe)(MeOH){Hdfmp(inh)2}] (4), [VVO(OMe)(MeOH){Hdfmp(nah)2}] (5) and [VVO(OMe)(MeOH){Hdfmp(bhz)2}] (6) were isolated. In the presence of KOH, oxidation of 1–3 results in the formation of [VVO2{H2dfmp(inh)2}]n·5H2O (7), K[VVO2{Hdfmp(nah)2}] (8) and K[VVO2{Hdfmp(bhz)2}] (9). All compounds are characterized in the solid state and in solution, namely by spectroscopic techniques (IR, UV-Vis, EPR, 1H, 13C and 51V NMR), and DFT is also used to calculate the VIV hyperfine coupling constants of VIV-compounds and 51V NMR chemical shifts of several VV-species and assign them to those formed in solution. Single crystal X-ray analysis of [VVO(OMe)(MeOH){Hdfmp(bhz)2}] (6) and [VVO2{H2dfmp(inh)2}]n·5H2O (7) confirm the coordination of the ligand in the dianionic (ONO2−) enolate tautomeric form, one of the hydrazide moieties remaining non-coordinated. In the case of 7 the free N(pyridine) atom of the inh moiety coordinates to the other vanadium center yielding a polynuclear complex in the solid state. It is also demonstrated that the VVO2-complexes are catalyst precursors in the oxidative bromination of styrene by H2O2, therefore acting as functional models of vanadium dependent haloperoxidases. Plausible intermediates involved in the catalytic process are established by UV-Vis, 51V NMR and DFT studies.

Screening organometallic binuclear thiosemicarbazone ruthenium complexes as potential anti-tumour agents: cytotoxic activity and human serum albumin binding mechanism

Abstract: Four complexes combining the {Ru(p-cym)} moiety (p-cym = para-cymene) with thiosemicarbazone (TSC) ligands containing the 5-nitrofuryl pharmacophore were investigated in vitro for their properties as prospective anti-tumour agents. The compounds are dimeric structures of general formula [Ru2(p-cym)2(L)2]X2 where X = Cl−, PF6− and L = deprotonated 5-nitrofuraldehyde TSC (L1), and the N-methyl (L2), N-ethyl (L3) and N-phenyl (L4) derivatives. The precursor [RuCl2(p-cym)]2, all TSC ligands L1–L4 and their corresponding complexes 1–4 were screened in vitro for their cytotoxicity against a range of human cancer cell lines (HL-60 acute promyelocytic leukemia, A2780 ovarian adenocarcinoma, MCF7 breast adenocarcinoma and PC3 grade IV prostate carcinoma). While the precursor complex was found to be inactive and L4 exhibited moderate activity only in the MCF7 cell line, the coordination of L4 to the {Ru(p-cym)} moiety remarkably enhanced the activity of the whole complex. In fact, complex 4 [Ru2(p-cym)2(L4)2]Cl2 was found to be the most active agent of the whole series, and was studied further (as well as complex 1 for comparison). Concerning the mode of action, the mechanism of cell death for both 1 and 4 seemed to be related to apoptotic processes, and they strongly interacted with tubulin (involved in the cell cycle) and with integrin (involved in the cytoskeleton formation). As an approach to their pharmacokinetics, the interaction of 1 and 4 with human serum albumin (HSA) was assessed. A quantitative model for the binding of 4 to HSA is proposed from Circular Dichroism data, and validated by fluorescence results. Models of Forster resonance energy transfer and fluorescence quenching afforded the distance of 4 to the lone Trp214 residue. Importantly, HSA binding enhanced the cytotoxicity of 4 and correlated well with the HSA binding data. Our results consistently indicate that [Ru2(p-cymene)2(L4)2]Cl2 is quite promising as a prospective metallodrug for cancer chemotherapy.

Synthesis, structure, magnetic properties and biological activity of supramolecular copper(II) and nickel(II) complexes with a Schiff base ligand derived from vitamin B6.

Abstract: Three new complexes of CuII and NiII, [CuII(H2pydmedpt)]2+·2Cl− (1), [NiII(H2pydmedpt)]2+·2Cl− (2) and [NiII(pydmedpt)(OH)]−·K+ (3) of the Schiff base ligand [H2pydmedpt]2+·2Cl− were synthesized by the in situ reaction of pyridoxal (pyd), a vitamer of vitamin B6, N,N-bis[3-aminopropyl]methylamine (medpt) and copper(II) acetate or nickel(II) acetate, respectively. The molecular structures of 1 and 2 were determined by single crystal X-ray diffraction studies. The structure of 3 in the solid state was inferred by elemental analysis, diffuse reflectance spectrum, variable temperature magnetic moment studies and DFT calculations. The binding of the Schiff base ligand to the metal centers involves two phenolato oxygens, two imine nitrogens and one amine nitrogen. The coordination geometry around Cu in 1 is distorted square pyramidal and that around the Ni atom in 2 is intermediate between square-pyramidal and trigonal-bipyramidal. In the crystals the compounds form supramolecular one dimensional chain structures stabilized by hydrogen bonding and π–π stacking interactions. Variable temperature magnetic moment data of 2 indicate the presence of a momomeric high spin NiII centre in the complex. The solid state diffuse reflectance spectrum, conductance and elemental analysis suggest that 3 is a NiII complex with a tetragonally distorted octahedral field, the sixth position being occupied by the oxygen atom of a hydroxyl group. The variable temperature magnetic moment of 3 indicates the presence of a ferromagnetic dinuclear species (29.2%) along with the major monomeric species, the intra-dimer exchange term J value being 14.3 cm−1. The competitive binding of 1 and 2 with DNA was studied in the concentration range 40 to 400 μM, the apparent binding constants being K = 2.9 × 103 and 6.7 × 103 M−1, respectively. Human Serum Albumin (HSA) binding studies were carried out at concentrations of 800–1000 μM and 400–500 μM for the complexes and HSA, respectively, in PBS buffer at pH 7.4. Complex 1 binds to HSA, while no binding is observed in case of 2, instead, the complex hydrolyses under the experimental conditions used and the resulting Ni2+ ions bind with HSA.

A new series of heteroleptic oxidovanadium(IV) compounds with phenanthroline-derived co-ligands: selective Trypanosoma cruzi growth inhibitors

Abstract: Searching for prospective metal-based drugs for the treatment of Chagas disease, a new series of ten mixed-ligand oxidovanadium(IV) complexes, [VIVO(L-2H)(NN)], where L is a tridentate salicylaldehyde semicarbazone derivative (L1–L5) and NN is either 5-amine-1,10-phenanthroline (aminophen) or 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), were synthesized. The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate through both nitrogen donor atoms in an axial–equatorial mode. The stability of the complexes in solution was investigated by EPR and 51V-nuclear magnetic resonance spectroscopies. The complexes were evaluated in vitro for their activities against Trypanosoma cruzi (T. cruzi), the parasite responsible for the disease, and their selectivity was analyzed using J-774 murine macrophages, as a mammalian model. All the complexes are more active than both the reference drug Nifurtimox and the previously reported [VIVO(L-2H)(NN)] complexes. In general they are more active than the corresponding free NN ligands. Complexation led to highly increased selectivities towards the parasite. In addition, the lipophilicity of the compounds was determined and correlated with the observed activity in order to perform a QSAR (quantitative structure–activity relationship) study. A clear quadratic correlation is found. This study also confirms the influence of the structure of the co-ligand on the anti-T. cruzi effect. To get insight into the mechanism of action of the compounds, the changes in biochemical pathways promoted by two of the most active and most selective complexes are studied by analyzing a few of the parasite excreted metabolites by 1H NMR spectroscopy. The combined information suggests that the mitochondrion could be a target for these complexes. Furthermore, DNA was preliminarily evaluated as a potential target by using atomic force microscopy (AFM), which showed that the complexes display an ability to interact with this biomolecule.

A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding

Abstract: The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3-dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5-hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid–base properties of 1 are studied by potentiometric and spectrophotometric methods, the pKa values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L+, HL and L− forms (HL = mhcpe) and assign the groups involved in the protonation–deprotonation processes. The mhcpe− ligand forms stable complexes with VIVO2+ in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the VIVO–mhcpe species formed. The results are consistent with the formation of VIVO, (VIVO)L, (VIVO)L2, (VIVO)2L2H−2, (VIVO)L2H−1, (VIVO)2L2H−3, (VIVO)LH−2 species and VIVO-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards VIVO2+ is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdhp). The interaction of VIVO-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and 51V NMR spectroscopy. VIVO–mhcpe–protein ternary complexes are formed in both cases. The binding of VIVO2+ to transferrin (hTF) in the presence of mhcpe involves mainly (VIVO)1(hTF)(mhcpe)1, (VIVO)2(hTF)(mhcpe)1 and (VIVO)2(hTF)(mhcpe)2 species, bound at the FeIII binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the VIVO–mhcpe complexes mainly bind to hTF; the formation of VIVO–hTF–mhcpe complexes occurs in the presence of FeIII as well, distinct EPR signals being clearly obtained for FeIII–hTF and to VIVO–hTF–mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of VIVO–mhcpe complexes under blood plasma conditions in the form of ternary VIV–ligand–protein complexes.

Binding of VIVO2+ to the Fe binding sites of human serum transferrin. A theoretical study

Abstract: The binding of VIVO2+ to human serum transferrin (hTF) at the FeIII binding sites is addressed. Geometry optimization calculations were performed for the binding of VIVO2+ to the N-terminal lobe of hTF (hTFN), and indicate that in the presence of CO3 2− or HCO3 −, VIV is bound to five atoms in a distorted geometry. The structures of VIVO–hTFN species optimized at the semiempirical level were also used to calculate the 51V and 14N A tensors by density functional theory methods, and were compared with the reported experimental values. Globally, of all the calculated VIVO–hTF structures, the one that yields the lowest calculated heats of formation and minimum deviations from the experimental values of the 51V and 14N A tensor components is the structure that includes CO3 2− as a synergistic anion. In this structure the V=O bond length is approximately 1.6 A, and the vanadium atom is also coordinated to the phenolate oxygen atom of Tyr188 (at approximately 1.9 A), the aspartate oxygen atom of Asp63 (at approximately 1.9 A), the His249 Nτ atom (at approximately 2.1 A), and a carbonate oxygen atom (at approximately 1.8 A). The Tyr95 phenolic ocygen atom is approximately 3.3 A from the metal center, and thus is very weakly bound to VIV. All of these oxygen atoms are able to establish dipolar interactions with groups of the protein.

Searching for Vanadium-Based Prospective Agents against Trypanosoma cruzi: Oxidovanadium(IV) Compounds with Phenanthroline Derivatives as Ligands†

Abstract: Searching for new promising metal-based drugs for the treatment of parasitic diseases against Trypanosoma cruzi, three related oxidovanadium(IV) complexes, [VIVO(SO4)(H2O)2(NN)], with the phenanthroline derivatives (NN) 1,2,5thiadiazolo[3,4-f]1,10phenanthroline (tdzp), 1,10-phenanthroline-5, 6-dione (phendione), and 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen) are synthesized, characterized, and evaluated in vitro as anti-T. cruzi agents. The compounds are characterized in the solid state and in solution by elemental analysis, electrospray ionization mass spectrometry (ESI-MS), conductimetric measurements, and infrared (FTIR), UV/Vis, and electronic paramagnetic resonance (EPR) spectroscopy. EPR spectroscopy suggests that the ligands act as bidentate, binding through both nitrogen donor atoms in an axial-equatorial mode. DFT calculations corroborate the structural assignments. The stability of the complexes in solution is evaluated by EPR and 51V- NMR spectroscopy and all complexes show reasonable stability. The anti-T. cruzi activity of the complexes was tested by measuring the growth inhibitory effect on the epimastigote life cycle form of the parasite (Dm28c strain). All complexes show IC50 values in the micromolar range against T. cruzi and display activities of the same order of that of Nifurtimox, but lower than that of the previously reported analogue [VIVO(SO4)(H2O)2(dppz)] (dppz = dipyrido[3, 2-a:2′,3′-c]phenazine). Furthermore, DNA was evaluated as a potential target by using atomic force microscopy (AFM), showing that the complexes display ability to interact with this biomolecule.