Pd(II)/diphosphine/curcumin complexes as potential anticancer agents.

Palladium(II) complexes have stimulated research interest mainly due to their in vitro cytotoxicity against various cancer cell lines and their low cytotoxicity in healthy cells. Thus, in this work, we combined Pd(II)/phosphine systems with the natural product curcumin as a ligand, obtaining a series of complexes, [Pd(cur)(PPh3)2]PF6 (A1), [Pd(cur)(dppe)]PF6 (A2), [Pd(cur)(dppp)]PF6 (A3), [Pd(cur)(dppb)]PF6 (A4) and [Pd(cur)(dppf)]PF6 (A5), where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, dppb = 1,4-bis(diphenylphosphino)butane, and dppf = 1,1'-bis(diphenylphosphino)ferrocene (P-P), which were characterized by elemental analysis, molar conductivity analysis, and mass, NMR (1H, 13C, 31P{1H}), UV-vis, and IR spectroscopies, and four of them (A1, A2, A4, and A5) by X-ray crystallography. The in vitro cell viability of the complexes A1-A5, cisplatin, and the free ligand curcumin against MDA-MB-231 (human triple-negative breast tumor cells), SK-BR-3 (human breast tumor cells), A549 (human lung tumor cells), MRC-5 (non-tumor human lung cells), A2780 (human ovarian carcinoma cells), and A2780cis (cisplatin-resistant human ovarian carcinoma cells), was evaluated by the MTT colorimetric assay. For the tumor cell lines tested, the complexes showed good anticancer activities. The results showed that in general the complexes had lower IC50 values than free curcumin and the precursors [PdCl2(P-P)]. IC50 results obtained for the A1-A5 complexes, in the MCF-7 cell line, are similar to those that had already been observed for some Pd/bipy/curcumin complexes. In the MDA-MB-231 cell line, complexes A1 and A5 stood out, with their lowest IC50 values, around 5 µmol L-1, and the complexes appeared to be more active (lower IC50 values) against the ovarian cell lines. Complex A1 was 23 and 22-fold more cytotoxic than cisplatin, against the A2780 and A2780cis cells, respectively. The complex A1 was studied on A2780cis cells and it was found that this complex inhibits colony formation and induces cell cycle arrest in the sub-G1 phase in a concentration-dependent manner and leads to cell death by apoptosis. The DCFDA assay revealed a potent ROS induction for complex A1.

Biomimetic catalysis of nitrite reductase enzyme using copper complexes in chemical and electrochemical reduction of nitrite.

Copper nitrite reductase mimetics were synthesized using three new tridentate ligands sharing the same N,N,N motif of coordination. The ligands were based on L-proline modifications, attaching a pyridine and a triazole to the pyrrolidine ring, and differ by a pendant group (R = phenyl, n-butyl and n-propan-1-ol). All complexes coordinate nitrite, as evidenced by cyclic voltammetry, UV-Vis, FTIR and electron paramagnetic resonance (EPR) spectroscopies. The coordination mode of nitrite was assigned by FTIR and EPR as κ2O chelate mode. Upon acidification, EPR experiments indicated a shift from chelate to monodentate κO mode, and 15N NMR experiments of a Zn2+ analogue, suggested that the related Cu(II) nitrous acid complex may be reasonably stable in solution, but in equilibrium with free HONO under non catalytic conditions. Reduction of nitrite to NO was performed both chemically and electrocatalytically, observing the highest catalytic activities for the complex with n-propan-1-ol as pendant group. These results support the hypothesis that a hydrogen bond moiety in the secondary coordination sphere may aid the protonation step.

Cytotoxic activity of Ru(II)/DPEPhos/N,S-mercapto complexes (DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether).

We report here on three new ruthenium(II) complexes, [Ru(DPEPhos)(mtz)(bipy)]PF6 (Ru1), [Ru(DPEPhos)(mmi)(bipy)]PF6 (Ru2) and [Ru(DPEPhos)(dmp)(bipy)]PF6 (Ru3). DPEPhos = bis-[(2-diphenylphosphino)phenyl]ether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2-mercaptopyrimidine and bipy = 2,2'-bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 - Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC50 values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC50 value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 - Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies.

Ruthenium(II)-diphosphine complexes containing acylthiourea ligands are effective against lung and breast cancers.

We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N,N-dimethyl-N'-(benzoyl)thiourea (1), N,N-dimethyl-N'-(furoyl)thiourea (2), and N,N-dimethyl-N'-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07-0.70 µM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment.

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds.

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu3(AlaLeu)3(H2O)3(CO3)]·PF6·H2O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H2O2 produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu-amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu-dipeptide-phen complexes are good SOD mimics but poor ROS producers. The activity of Cu-dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra.

New AlIIIZnII and AlIIICuII dinuclear complexes: Phosphatase-like activity and cytotoxicity.

Herein, we report the synthesis and characterization of the first two AlIII(µ-OH)MII (M = Zn (1) and Cu (2)) complexes with the unsymmetrical ligand H2L{2-[[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl]-6-bis(pyridylmethyl)aminomethyl}-4-methylphenol. The complexes were characterized through elemental analysis, X-ray crystallography, IR spectroscopy, mass spectrometry and potentiometric titration. In addition, complex 2 was characterized by electronic spectroscopy. Kinetics studies on the hydrolysis of the model substrate bis(2,4-dinitrophenyl)phosphate by 1 and 2 show Michaelis-Menten behavior, with 1 being slightly more active (8.31%) than 2 (at pH 7.0). The antimicrobial effect of the compounds was studied using four bacterial strains (Staphylococcus aureus, Pseudomonas aeuruginosa, Shigella sonnei and Shigella dysenteriae) and for both complexes the inhibition of bacterial growth was superior to that caused by sulfapyridine, but inferior to that of tetracycline. The dark cytotoxicity and photocytotoxicity (under UV-A light) of the complexes in a chronic myelogenous leukemia cell line were investigated. Complexes 1 and 2 exhibited significant cytotoxic activity against K562 cells, which undergoes a 2-fold increase on applying 5 min of irradiation with UV-A light. Complex 2 was more effective and a good correlation between cytotoxicity and intracellular concentration was observed, the intracellular copper concentration required to inhibit 50% of cell growth being 3.5 × 10-15 mol cell-1.

Ruthenium(II) Phosphine/Mercapto Complexes: Their in Vitro Cytotoxicity Evaluation and Actions as Inhibitors of Topoisomerase and Proteasome Acting as Possible Triggers of Cell Death Induction.

In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF6 (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by 1H-31P HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent.

Selective Coordination Mode of Acylthiourea Ligands in Half-Sandwich Ru(II) Complexes and Their Cytotoxic Evaluation.

In this study, half-sandwich Ru(II) complexes containing acylthiourea ligands of the general type [Ru(η6-p-cymene)(PPh3)(S)Cl]PF6 (1m-6m) and [Ru(η6-p-cymene)(PPh3)(S-O)]PF6 (1b-6b) where S/S-O = N',N'-disubstituted acylthiourea were synthesized and characterized (via elemental analyses, IR spectroscopy, 1H NMR spectroscopy, 13C{1H} NMR spectroscopy, and X-ray diffractometry), and their cytotoxic activity was evaluated. The different coordination modes of the acylthiourea ligands, monodentately via S (1m-6m) and bidentately via S,O (1b-6b), to ruthenium were modulated from different synthetic routes. The cytotoxicity of the complexes was evaluated in five human cell lines (DU-145, A549, MDA-MB-231, MRC-5, and MCF-10A) by MTT assay. The IC50 values for prostate cancer cells (2.89-7.47 µM) indicated that the complexes inhibited cell growth, but that they were less cytotoxic than cisplatin (2.00 µM). Unlike for breast cancer cells (IC50 = 0.28-0.74 µM) and lung cancer cells (IC50 = 0.51-1.83 µM), the complexes were notably more active than the reference drug, and a remarkable selectivity index (SI 4.66-19.34) was observed for breast cancer cells. Based on both the activity and selectivity, complexes 5b and 6b, as well as their respective analogous complexes in the monodentate coordination 5m and 6m, were chosen for further investigation in the MDA-MB-231 cell line. These complexes not only induced morphology changes but also were able to inhibit colony formation and migration. In addition, the complexes promoted cell cycle arrest at the sub-G1 phase inducing apoptosis. Interaction studies by viscosity measurements, gel electrophoresis, and fluorescence spectroscopy indicated that the complexes interact with the DNA minor groove and exhibit an HSA binding affinity.

Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution.

1-Acyl thioureas [R1C(O)NHC(S)NR2R3] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R1=2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, 1H and 13C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans-cis geometry of the almost planar thiourea unit is stabilized by intramolecular NH⋯OC hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31+G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular NH⋯SC hydrogen bond forming R22(8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S⋯H, O⋯H and H⋯H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.

Synthesis, characterization, hydrolase and catecholase activity of a dinuclear iron(III) complex: Catalytic promiscuity.

Herein, we report the synthesis and characterization of the new di-iron(III) complex [(bbpmp)(H2O)(Cl)Fe(III)(µ-Ophenoxo)Fe(III)(H2O)Cl)]Cl (1), with the symmetrical ligand 2,6-bis{[(2-hydroxybenzyl)(pyridin-2-yl)methylamino]methyl}-4-methylphenol (H3bbpmp). Complexes 2 with the unsymmetrical ligand H2bpbpmp - {2-[[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl]-6-bis(pyridylmethyl) aminomethyl}-4-methylphenol and 3 with the ligand L(1)=4,11-dimethyl-1,8-bis{2-[N-(di-2-pyridylmethyl)amino]ethyl}cyclam were included for comparison purposes. Complex 1 was characterized through elemental analysis, X-ray crystallography, magnetochemistry, electronic spectroscopy, electrochemistry, mass spectrometry and potentiometric titration. The magnetic data show a very weak antiferromagnetic coupling between the two iron centers of the dinuclear complex 1 (J=-0.29cm(-1)). Due to the presence of labile coordination sites in both iron centers the hydrolysis of both the diester model substrate 2,4-BDNPP and DNA was studied in detail. Complex 1 was also able to catalyze the oxidation of the substrate 3,5-di-tert-butylcatechol (3,5-DTBC) to give the corresponding quinone, and thus it can be considered as a catalytically promiscuous system.

Secondary coordination sphere effects in ruthenium(III) tetraammine complexes: role of the coordinated water molecule.

The complexes trans-[Ru(III)(NH3)4(4-pic)(H2O)](CF3SO3)3 (1) and [Ru(III)(NH3)5(4-pic)](CF3SO3)3 (2) were isolated and studied experimentally by electron paramagnetic resonance (EPR) and UV-vis spectroscopies, cyclic voltammetry, and X-ray crystallography and theoretically by ligand-field theory (LFT) and density functional theory (DFT) calculations. Complex 1 is reported in two different crystal forms, 1a (100 K) and 1b (room temperature). EPR and UV-vis spectroscopies suggest that aqua ligand interaction in this low-spin ruthenium(III) complex changes as a function of hydrogen bonding with solvent molecules. This explicit water solvent effect was explained theoretically by DFT calculations, which demonstrated the effect of rotation of the aqua ligand about the Npic-Ru-Oaq axis. The UV-vis spectrum of 1 shows in an aqueous acid solution a broad- and low-intensity absorption band around 28,500 cm(-1) (ε ≈ 500 M(-1) cm(-1)) that is assigned mainly to a charge-transfer (CT) transition from the equatorial ligands to the Ru ß-4dxy orbital (ß-LUMO) using DFT calculations. The electronic reflectance spectrum of 1 shows a broad and intense absorption band around 25,500 cm(-1) that is assigned to a CT transition from 4-picoline to the Ru ß-4dxz orbital (ß-LUMO) using DFT calculations. The t2g(5) set of orbitals had its energy splitting investigated by LFT. LFT analysis shows that a rhombic component arises from C2v symmetry by a simple π-bonding ligand (H2O in our case) twisting about the trans (C2) axis. This twist was manifested in the EPR spectra, which were recorded for 1 as a function of the solvent in comparison with [Ru(NH3)5(4-pic)](3+) and [Ru(NH3)5(H2O)](3+). Only 1 shows an evident change in the g-tensor values, wherein an increased rhombic component is correlated with a higher nucleophilicity (donor) solvent feature, as parametrized by the Abraham system.

New La(III) complex immobilized on 3-aminopropyl-functionalized silica as an efficient and reusable catalyst for hydrolysis of phosphate ester bonds.

Described herein is the synthesis, structure, and monoesterase and diesterase activities of a new mononuclear [La(III)(L(1))(NO3)2] (1) complex (H2L(1) = 2-bis[{(2-pyridylmethyl)-aminomethyl}-6-[N-(2-pyridylmethyl) aminomethyl)])-4-methyl-6-formylphenol) in the hydrolysis of 2,4-bis(dinitrophenyl)phosphate (2,4-BDNPP). When covalently linked to 3-aminopropyl-functionalized silica, 1 undergoes disproportionation to form a dinuclear species (APS-1), whose catalytic efficiency is increased when compared to the homogeneous reaction due to second coordination sphere effects which increase the substrate to complex association constant. The anchored catalyst APS-1 can be recovered and reused for subsequent hydrolysis reactions (five times) with only a slight loss in activity. In the presence of DNA, we suggest that 1 is also converted into the dinuclear active species as observed with APS-1, and both were shown to be efficient in DNA cleavage.

Second-coordination-sphere effects increase the catalytic efficiency of an extended model for Fe(III)M(II) purple acid phosphatases.

Herein we describe the synthesis of a new heterodinuclear Fe(III)Cu(II) model complex for the active site of purple acid phosphatases and its binding to a polyamine chain, a model for the amino acid residues around the active site. The properties of these systems and their catalytic activity in the hydrolysis of bis(2,4-dinitrophenyl)phosphate are compared, and conclusions regarding the effects of the second coordination sphere are drawn. The positive effect of the polymeric chain on DNA hydrolysis is also described and discussed.

Design of a dinuclear nickel(II) bioinspired hydrolase to bind covalently to silica surfaces: synthesis, magnetism, and reactivity studies.

Presented herein is the design of a dinuclear Ni(II) synthetic hydrolase [Ni(2)(HBPPAMFF)(µ-OAc)(2)(H(2)O)]BPh(4) (1) (H(2)BPPAMFF = 2-[(N-benzyl-N-2-pyridylmethylamine)]-4-methyl-6-[N-(2-pyridylmethyl)aminomethyl)])-4-methyl-6-formylphenol) to be covalently attached to silica surfaces, while maintaining its catalytic activity. An aldehyde-containing ligand (H(2)BPPAMFF) provides a reactive functional group that can serve as a cross-linking group to bind the complex to an organoalkoxysilane and later to the silica surfaces or directly to amino-modified surfaces. The dinuclear Ni(II) complex covalently attached to the silica surfaces was fully characterized by different techniques. The catalytic turnover number (k(cat)) of the immobilized Ni(II)Ni(II) catalyst in the hydrolysis of 2,4-bis(dinitrophenyl)phosphate is comparable to the homogeneous reaction; however, the catalyst interaction with the support enhanced the substrate to complex association constant, and consequently, the catalytic efficiency (E = k(cat)/K(M)) and the supported catalyst can be reused for subsequent diester hydrolysis reactions.

2-Acetylpyridine- and 2-benzoylpyridine-derived hydrazones and their gallium(III) complexes are highly cytotoxic to glioma cells.

2-Acetylpyridine-phenylhydrazone (H2AcPh), its para-chlorophenylhydrazone (H2AcpClPh) and para-nitrophenylhydrazone (H2AcpNO(2)Ph) analogues, the corresponding 2-benzoylpyridine-derived hydrazones (H2BzPh, H2BzpClPh and H2BzpNO(2)Ph) and their gallium(III) complexes were assayed for their cytotoxic activity against U87 (expressing wild-type p53 protein) and T98 (expressing mutant p53 protein) glioma cells. IC(50) values against both glioma cells and against the MRC5 (human fetal lung fibroblast) lineage were obtained for the hydrazones, but not for their gallium(III) complexes, due to their low solubility. Hydrazones were highly cytotoxic at nanomolar doses against U87 and T98 cells. The therapeutic indexes (TI = IC(50MRC5)/IC(50glioma)) were 2-660 for T98 cells and 28-5000 for U87 cells, indicating that the studied hydrazones could be good antitumor drug candidates to treat brain tumors.

Bioinspired FeIIICdII and FeIIIHgII complexes: synthesis, characterization and promiscuous catalytic activity evaluation.

In this work we report on the synthesis, crystal structure, and physicochemical characterization of the novel dinuclear [Fe(III)Cd(II)(L)(µ-OAc)(2)]ClO(4)·0.5H(2)O (1) complex containing the unsymmetrical ligand H(2)L=2-bis[{(2-pyridyl-methyl)-aminomethyl}-6-{(2-hydroxy-benzyl)-(2-pyridyl-methyl)}-aminomethyl]-4-methylphenol. Also, with this ligand, the tetranuclear [Fe(2)(III)Hg(2)(II)(L)(2)(OH)(2)](ClO(4))(2)·2CH(3)OH (2) and [Fe(III)Hg(II)(L)(µ-CO(3))Fe(III)Hg(II)(L)](ClO(4))(2)·H(2)O (3) complexes were synthesized and fully characterized. It is demonstrated that the precursor [Fe(III)(2)Hg(II)(2)(L)(2)(OH)(2)](ClO(4))(2)·2CH(3)OH (2) can be converted to (3) by the fixation of atmospheric CO(2) since the crystal structure of the tetranuclear organometallic complex [Fe(III)Hg(II)(L)(µ-CO(3))Fe(III)Hg(II)(L)](ClO(4))(2)·H(2)O (3) with an unprecedented {Fe(III)(µ-O(phenoxo))(2)(µ-CO(3))Fe(III)} core was obtained through X-ray crystallography. In the reaction 2→3 a nucleophilic attack of a Fe(III)-bound hydroxo group on the CO(2) molecule is proposed. In addition, it is also demonstrated that complex (3) can regenerate complex (2) in aqueous/MeOH/NaOH solution. Magnetochemical studies reveal that the Fe(III) centers in 3 are antiferromagnetically coupled (J=-7.2cm(-1)) and that the Fe(III)-OR-Fe(III) angle has no noticeable influence in the exchange coupling. Phosphatase-like activity studies in the hydrolysis of the model substrate bis(2,4-dinitrophenyl) phosphate (2,4-bdnpp) by 1 and 2 show Michaelis-Menten behavior with 1 being ~2.5 times more active than 2. In combination with k(H)/k(D) isotope effects, the kinetic studies suggest a mechanism in which a terminal Fe(III)-bound hydroxide is the hydrolysis-initiating nucleophilic catalyst for 1 and 2. Based on the crystal structures of 1 and 3, it is assumed that the relatively long Fe(III···)Hg(II) distance could be responsible for the lower catalytic effectiveness of 2.

Analgesic and anti-inflammatory activities of salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their zinc(II) complexes.

Salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their complexes [Zn(LASSBio-466)H(2)O](2) (1) and [Zn(HLASSBio-1064)Cl](2) (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the anti-nociceptive activity was favored in the complex 1. H(2)LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H(2)LASSBio-466. H(2)LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile.

A new nitrosyl ruthenium complex: synthesis, chemical characterization, in vitro and in vivo antitumor activities and probable mechanism of action.

This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl(2)NO(BPA)] [BPA = (2-hydroxybenzyl)(2-methylpyridyl)amine ion], which was synthesized and characterized by spectroscopy, cyclic voltammetry, X-ray crystallography, and theoretical calculation data. The biological studies of this complex included in vitro cytotoxic assays, which revealed its activity against two different tumor cell lines (HeLa and Tm5), with efficacy comparable to that of cisplatin, a metal-based drug that is administered in clinical treatment. The in vivo studies showed that [RuCl(2)NO(BPA)]is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl(2)NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis.

Electronic structure and spectro-structural correlations of Fe(III)Zn(II) biomimetics for purple acid phosphatases: relevance to DNA cleavage and cytotoxic activity.

Purple acid phosphatases (PAPs) are a group of metallohydrolases that contain a dinuclear Fe(III)M(II) center (M(II) = Fe, Mn, Zn) in the active site and are able to catalyze the hydrolysis of a variety of phosphoric acid esters. The dinuclear complex [(H(2)O)Fe(III)(µ-OH)Zn(II)(L-H)](ClO(4))(2) (2) with the ligand 2-[N-bis(2-pyridylmethyl)aminomethyl]-4-methyl-6-[N'-(2-pyridylmethyl)(2-hydroxybenzyl) aminomethyl]phenol (H(2)L-H) has recently been prepared and is found to closely mimic the coordination environment of the Fe(III)Zn(II) active site found in red kidney bean PAP (Neves et al. J. Am. Chem. Soc. 2007, 129, 7486). The biomimetic shows significant catalytic activity in hydrolytic reactions. By using a variety of structural, spectroscopic, and computational techniques the electronic structure of the Fe(III) center of this biomimetic complex was determined. In the solid state the electronic ground state reflects the rhombically distorted Fe(III)N(2)O(4) octahedron with a dominant tetragonal compression aligned along the µ-OH-Fe-O(phenolate) direction. To probe the role of the Fe-O(phenolate) bond, the phenolate moiety was modified to contain electron-donating or -withdrawing groups (-CH(3), -H, -Br, -NO(2)) in the 5-position. The effects of the substituents on the electronic properties of the biomimetic complexes were studied with a range of experimental and computational techniques. This study establishes benchmarks against accurate crystallographic structural information using spectroscopic techniques that are not restricted to single crystals. Kinetic studies on the hydrolysis reaction revealed that the phosphodiesterase activity increases in the order -NO(2) ←Br ←H ←CH(3) when 2,4-bis(dinitrophenyl)phosphate (2,4-bdnpp) was used as substrate, and a linear free energy relationship is found when log(k(cat)/k(0)) is plotted against the Hammett parameter σ. However, nuclease activity measurements in the cleavage of double stranded DNA showed that the complexes containing the electron-withdrawing -NO(2) and electron-donating -CH(3) groups are the most active while the cytotoxic activity of the biomimetics on leukemia and lung tumoral cells is highest for complexes with electron-donating groups.

Antimycobacterial and antitumor activities of palladium(II) complexes containing isonicotinamide (isn): X-ray structure of trans-[Pd(N3)2(isn)(2)].

Complexes of the type trans-[PdX(2)(isn)(2)] {X = Cl (1), N(3) (2), SCN (3), NCO (4); isn = isonicotinamide} were synthesized and evaluated for in vitro antimycobacterial and antitumor activities. The coordination mode of the isonicotinamide and the pseudohalide ligands was inferred by IR spectroscopy. Single crystal X-ray diffraction determination on 2 showed that coordination geometry around Pd(II) is nearly square planar, with the ligands in a trans configuration. All the compounds demonstrated better in vitro activity against Mycobacterium tuberculosis than isonicotinamide and pyrazinamide. Among the complexes, compound 2 was found to be the most active with MIC of 35.89 µM. Complexes 1-4 were also screened for their in vitro antitumor activity towards LM3 and LP07 murine cancer cell lines.