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.

Copper(II) Complexes with Saccharinate and Glutamine as Antitumor Agents: Cytoand Genotoxicity in Human Osteosarcoma Cells.

BACKGROUND: Copper has shown to be useful in disorders with an inflammation origin such as cancer [1-3]. It has previously shown that Casiopeínas® interact with DNA and promote the disruption by a mechanism related to the increase in the level of free radicals [4-6] which confers antineoplastic potential. Objetive: The aim of the present work was to study the antitumor effects of a series of Cu(II) complexes with saccharinate (sac) and glutamate (gln): [Cu(sac)2(H2O)4].2H2O (Cu-sac), [Cu(gln)2] (Cu-gln) and Na2[Cu(sac)2 (gln)2].H2O (Cu-sac-gln). METHODS: We have investigated the action of these compounds on cell viability on human osteosarcoma cells MG-63. In particular, we pay special attention to the cyto and genotoxicity actions of these complexes and to the association to oxidative stress. RESULTS: The three complexes: Cu-sac, Cu-gln and Cu-sac-gln caused a decline in cell viability. The half-maximal inhibitory concentration in MG-63 cells for Cu-sac-gln is 170 µM, showing the strongest antiproliferative effect. Moreover, only Cu-sac-gln caused a decrease of the mitochondrial activity from 100 µM. Our results indicate that the copper(II) complexes studied here produce DNA damage and suggest that the rise of reactive oxygen species (ROS) is the central mechanism action. Genotoxicity studied by the Cytokinesis-block micronucleus (MN) assay and the Single cell gel electrophoresis (comet assay) could be observed in MG-63 cells treated with Cu-sac-gln from 100 and 50 µM, respectively. Cu-sac and Cu-gln also induced DNA damage; however their effect was definitively weaker. The generation of reactive oxygen species increased from 50 µM of Cu-sac-gln and Cu-sac and only from 250 µM of Cugln, as well as a reduction of the GSH/GSSG ratio from 50 µM. When cells were treated with several concentrations of the complexes in addition to a combination of 50 µM of vitamin C plus 50 µM of vitamin E, a total recovery in cell survival was obtained for Cu-gln in the whole range of tested concentrations while only a partial viability recovery was obtained from 250 µM of Cu-sac and Cu-sac-gln. CONCLUSION: Overall, our results point to a differential cyto- and genotoxicity of the three copper(II) complexes and demonstrate that the complexation with both ligands confers the most potent antitumor action in human osteosarcoma cells.

Biomonitoring of arsenic in woodworkers exposed to CCA and evaluation of other non-occupational sources in Uruguay.

In Uruguay wood-impregnation plants use chromated copper arsenate (CCA) as preservative applying good manufacture practices (GMP). This study aims a retrospective evaluation of toxicologically relevant species levels in CCA exposed woodworker's urine (As-U) and an assessment of the effects of work risk factors and non-occupational sources in As-U of workers from a selected plant. From 2014 to 2016, As-U in 212 urine samples (As-U) of 73 woodworkers from six CCA impregnation plants were determined. In one of these plants, 35 workers were interviewed to obtain individual data of work tasks, lifestyles, diet, habits, etc. that may contribute to their overall exposure to Arsenic. Responses were statistically evaluated. Out of the 212 urine samples from 73 woodworkers, 96% showed lower levels of As-U than those established by health regulations (<35µgL-1). According to their work tasks 34% of 35 surveyed workers showed high exposure risk to As and 29% moderate exposure risk. Although they have lower levels of As-U owing to their personal protective equipment, As-U significantly correlate to work risk factors. Consumption of bottled water could also contribute to As-U levels as a non-occupational source. These results confirm that efforts of Uruguayan authorities to promote GMP were successful and justify the importance and frequency of As-U systematic biomonitoring for occupational risk assessment. A significant accomplishment of this work is that non-occupational sources of As-like bottled water consumption should also be considered in future studies.

Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer.

In the search for new cytotoxic drugs, two copper complexes with isomeric dipeptides (Ala-Phe and Phe-Ala) were developed in order to determine the influence of their different structures in the modulation of the chemical, biochemical and biological properties. Spectroscopic, voltammetric and equilibrium studies were performed providing information about the chemical properties. The superoxide dismutase (SOD) activity was studied and showed differences of IC50 for both Cu-Ala-Phe (IC50=4.5) and Cu-Phe-Ala (IC50=45). The computational results permitted to explain this behavior proposing that it is feasible that the O2- anion is attracted straight to the positive zone in Cu-Ala-Phe whereas for Cu-Phe-Ala this phenomenon would happen to a smaller extent. Confirming our previous studies, both complexes interacted with DNA. Molecular docking studies showed that the position of the phenyl ring modulates the complex-DNA affinity and in Cu-Ala-Phe the docked conformation allows the copper ion to face the DNA basis, giving rise to a more stable complex-DNA adduct than for Cu-Phe-Ala. In spite of the fact that Atomic Force Microscopy showed plasmid compactation and aggregation for both complexes, the image showed softer changes in the case of Cu-Ala-Phe in comparison with those produced by Cu-Phe-Ala. In order to evaluate the effect of Cu-Ala-Phe and Cu-Phe-Ala complexes against tumor cells, we have employed three aggressive metastatic breast adenocarcinoma cellular models, derived from human (MDA-MB-231 and MCF-7) and mouse (4T1) spontaneous tumors. These experiments showed that both Cu-dipeptide complexes have a similar cytotoxic effect against breast cancer cells, and lower toxicity against BJ non-tumor cells in comparison to Cisplatin.

Synthesis, characterization, microbiological evaluation, genotoxicity and synergism tests of new nano silver complexes with sulfamoxole: X-ray diffraction of [Ag2(SMX)2]·DMSO.

The synthesis and microbiological evaluation of two new Ag(I) complexes with sulfamoxole (SMX), [Ag2(SMX)2]·H2O and [Ag4(SCN)3(SMX)]·H2O are described. Both were characterized by elemental analysis, thermogravimetry, powder and single crystal X-ray diffraction, NMR, Raman and experimental and theoretical IR spectroscopies. Their antibacterial and antifungal properties were evaluated by agar and broth dilution assays, respectively. In addition, synergism tests for Pseudomonas aeruginosa were performed, and genotoxicity studies were carried out employing the Allium cepa test. Both complexes displayed good activity against Escherichia coli, Staphylococcus aureus, P. aeruginosa, and 10 fungi strains, with lower minimum inhibitory concentrations (MICs) than that of free SMX in all cases. The nanometrical crystallite particle size determined from XRPD, DLS and TEM might explain the good microbiological activity in spite of the low solubility of both complexes. The fractional inhibitory concentration (FIC) calculated from the P. aeruginosa test data indicated that the activity of the complexes is not due to synergism of the free components in the concentration ratios studied. Moreover, none of the complexes displayed cytotoxic effects on onions in the concentration range tested, and chromosome aberrations were not observed.

Synthesis, structural characterization and cytotoxic activity of ternary copper(II)-dipeptide-phenanthroline complexes. A step towards the development of new copper compounds for the treatment of cancer.

In the search for new compounds with antitumor activity, coordination complexes with different metals are being studied by our group. This work presents the synthesis and characterization of six copper complexes with general stoichiometry [Cu(L-dipeptide)(phen)]·nH2O (were phen=1,10-phenanthroline) and their cytotoxic activities against tumor cell lines. To characterize these systems, analytical and spectroscopic studies were performed in solid state (by UV-visible, IR, X-ray diffraction) including the crystal structure of four new complexes (of the six complexes studied): [Cu(Ala-Phe)(phen)]·4H2O, [Cu(Phe-Ala)(phen)]·4H2O, [Cu(Phe-Val)(phen)]·4.5H2O and [Cu(Phe-Phe)(phen)]·3H2O. In all of them, the copper ion is situated in a distorted squared pyramidal environment. The phen ligand is perpendicular to the dipeptide, therefore exposed and potentially available for interaction with biological molecules. In addition, for all the studied complexes, structural information in solution using EPR and UV-visible spectroscopies were obtained, showing that the coordination observed in solid state is maintained. The lipophilicity, DNA binding and albumin interaction were also studied. Biological experiments showed that all the complexes induce cell death in the cell lines: HeLa (human cervical adenocarcinoma), MCF-7 (human metastatic breast adenocarcinoma) and A549 (human lung epithelial carcinoma). Among the six complexes, [Cu(Ala-Phe)(phen)] presents the lowest IC50 values. Taken together all these data we hypothesize that [Cu(Ala-Phe)(phen)] may be a good candidate for further studies in vivo.

Antibacterial, antifungal, phytotoxic, and genotoxic properties of two complexes of Ag(I) with sulfachloropyridazine (SCP): X-ray diffraction of [Ag(SCP)]n.

We report the synthesis, characterization, antibacterial and antifungal activities, phytotoxicity, and genotoxicity of two new complexes of silver(I) with sulfachloropyridazine (SCP), one of which is heteroleptic with SCP and SCN(-) ligands (Ag-SCP-SCN), the other of which is homoleptic (Ag-SCP); furthermore, the crystal structure of the homoleptic complex is disclosed. The heterocyclic N atom nearest to the Cl atom and the N(sulfonamide) atom could be coordination sites for the silver ion in the Ag-SCP-SCN complex. The Ag-SCP complex is a polymeric compound with metal-metal bonds, and the heterocyclic and sulfonamide N atoms are points of coordination for Ag(I) . Both complexes showed activity against all the tested bacteria, and in the cases of Escherichia coli and Pseudomonas aeruginosa, the action was better than that of SCP. In all cases, both silver-SCP complexes showed better antifungal activity than SCP, which was inactive against the tested fungi. Notably, the activity against P. aeruginosa, a nosocomial multidrug-resistant pathogen, was better than that of the reference antibiotic cefotaxim. Both silver-sulfa complexes displayed moderate activity against the tested yeast, especially for C. neoformans, which is an important fact considering the incidence of cryptococcosis, mainly in immune-deficient patients. No chromosomal aberrations were observed with the Allium cepa test, which is auspicious for further study of these complexes as potential drugs.

High-dose selenium reduces ventilator-associated pneumonia and illness severity in critically ill patients with systemic inflammation.

PURPOSE: To confirm the pharmacodynamics and evaluate the efficacy of high-dose selenium (Se) administered by continuous infusion, following an initial loading bolus of selenite, on clinical outcome in critically ill patients with systemic inflammatory response syndrome (SIRS). METHODS: Prospective, placebo-controlled, randomized, single-blinded phase II study in a multidisciplinary university hospital intensive care unit (ICU). Two groups of patients with SIRS, age >18 years, and Acute Physiology and Chronic Health Evaluation (APACHE) II ≥15 (n = 35) were randomized to receive either placebo or intravenous selenite as a bolus-loading dose of 2,000 µg Se followed by continuous infusion of 1,600 µg Se per day for 10 days. Blood samples were analyzed before randomization (day 0) then at days 3, 7, and 10. Clinical outcome was assessed by Sequential Organ Failure Assessment (SOFA) score. Hospital-acquired pneumonia including ventilator-associated pneumonia (VAP), adverse events, and other safety parameters were monitored as secondary endpoints. RESULTS: SOFA score decreased significantly in the selenite group at day 10 (1.3 ± 1.2 versus 4.6 ± 2.0, p = 0.0001). Early VAP rate was lower in the selenite group (6.7% versus 37.5%, p = 0.04), and hospital-acquired pneumonia was lower after ICU discharge (p = 0.03). Glutathione peroxidase-3 (GPx-3) activity increased in both groups, reaching a maximum at day 7 (0.62 ± 0.24 versus 0.28 ± 0.14 U/mL, p = 0.001) in the selenite group. No adverse events attributable to selenite were observed. CONCLUSIONS: Daily infusion of 1,600 µg Se (as selenite), following an initial bolus of 2,000 µg, is novel and without short-term adverse events. High-dose parenteral selenite significantly increases Se status, improves illness severity, and lowers incidence of hospital-acquired pneumonia including early VAP for SIRS patients in ICU.

Synthesis and characterization of heteroleptic copper and zinc complexes with saccharinate and aminoacids. Evaluation of SOD-like activity of the copper complexes.

Five new copper and zinc heteroleptic complexes with saccharin and aminoacids with general stoichiometry Na(2)[M(sac)(2)(aa)(2)].nH(2)O (M denotes Cu or Zn, sac the saccharinate ion, and aa the aminoacids) were synthesized and characterized by elemental and thermogravimetric analysis, conductimetric measurements and IR, Raman and UV-vis spectroscopies. In all the complexes, copper and zinc ions coordinated with the aminoacids through the terminal amine and carboxylate residues and with saccharin through the heterocyclic nitrogen atom. Besides, the superoxide dismutase-like activity of the heteroleptic copper complexes was evaluated and compared with the homoleptic copper amino acid complexes with the aim to observe the influence of the saccharin coordination.

Design of novel iron compounds as potential therapeutic agents against tuberculosis.

In the search for new therapeutic tools against tuberculosis two novel iron complexes, [Fe(L-H)(3)], with 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives (L) as ligands, were synthesized, characterized by a combination of techniques, and in vitro evaluated. Results were compared with those previously reported for two analogous iron complexes of other ligands of the same family of quinoxaline derivatives. In addition, the complexes were studied by cyclic voltammetry and EPR spectroscopy. Cyclic voltammograms of the iron compounds showed several cathodic processes which were attributed to the reduction of the metal center (Fe(III)/Fe(II)) and the coordinated ligand. EPR signals were characteristic of magnetically isolated high-spin Fe(III) in a rhombic environment and arise from transitions between m(S) = ± 1/2 (g(eff) ~ 9) or m(S) = ± 3/2 (g(eff) ~ 4.3) states. Mössbauer experiments showed hyperfine parameters that are typical of high-spin Fe(III) ions in a not too distorted environment. The novel complexes showed in vitro growth inhibitory activity on Mycobacterium tuberculosis H(37)Rv (ATCC 27294), together with very low unspecific cytotoxicity on eukaryotic cells (cultured murine cell line J774). Both complexes showed higher inhibitory effects on M. tuberculosis than the "second-line" therapeutic drugs.

High-dose selenium for critically ill patients with systemic inflammation: pharmacokinetics and pharmacodynamics of selenious acid: a pilot study.

OBJECTIVE: Systemic inflammatory response syndrome is characterized by increased urinary excretion of selenium and low serum concentration. Repletion by parenteral selenite is the most efficacious form of supplementation. However, the optimum safe dose and mode of administration remain controversial. We aimed to determine pharmacokinetic and pharmacodynamic profiles of selenite and estimate a safe dose to optimize selenium status. METHODS: A prospective, randomized, pilot study in 20 patients with systemic inflammatory response syndrome compared a high-dose (HD) group that received a loading dose of selenium as selenite 15.18 micromol over 2 h and thereafter 10.12 micromol/d as a continuous intravenous infusion (CIV) for 10 d with a very-high-dose (VHD) group that received a loading dose of 25.30 micromol over 2 h and thereafter 20.24 micromol as a CIV for 10 d. Clinical outcome was evaluated by length of stay in the intensive care unit, incidence of ventilator-associated pneumonia, and Sequential Organ Failure Assessment score. RESULTS: Patients in group HD (n = 10, age 54 +/- 23 y) had an Acute Physiology and Chronic Health Evaluation II score of 23 +/- 5 and a Sequential Organ Function Assessment score of 10 +/- 2. Those in group VHD (n = 10, age 41 +/- 19 y) had scores of 21 +/- 7 and 8 +/- 3, respectively. Pharmacokinetic concentration/time curves for serum selenium overlapped but were independent of dose, whereas the pharmacodynamics were different, showing maximum glutathione peroxidase activity only with VHD. Glutathione peroxidase decreased after day 7 independently of the selenium dose. Clinical outcomes were similar in both groups. CONCLUSION: A bolus loading dose of selenite providing 2000 microg of selenium (25.30 micromol) followed by a CIV of 1600 microg/d (20.24 micromol/d) for 10 d is most effective at returning serum selenium to physiologic levels and safely maximizing glutathione peroxidase activity.

Cytotoxic palladium complexes of bioreductive quinoxaline N1,N4-dioxide prodrugs.

Four new palladium(II) complexes with the formula Pd(L)(2), where L are quinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, were synthesized as a contribution to the chemistry and pharmacology of metal compounds with this class of pharmacologically interesting bioreductive prodrugs. Compounds were characterized by elemental, conductometric and thermogravimetric analyses, fast atom bombardment mass spectrometry (FAB-MS) and electronic, Fourier transform infrared (FTIR) and (1)H-nuclear magnetic resonance spectroscopies. The complexes were subjected to cytotoxic evaluation on V79 cells in hypoxic and aerobic conditions. In addition, a preliminary study on interaction with plasmid DNA in normoxia was performed. Complexes showed different in vitro biological behavior depending on the nature of the substituent on the quinoxaline ring. Pd(L1)(2) and Pd(L2)(2), where L1 is 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide and L2 is 3-amino-6(7)-methylquinoxaline-2-carbonitrile N(1),N(4)-dioxide, showed non selective cytotoxicity, being cytotoxic either in hypoxic or in aerobic conditions. On the other hand, Pd(L3)(2), where L3 is 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1),N(4)-dioxide, resulted in vitro more potent cytotoxin in hypoxia (P=5.0 microM) than the corresponding free ligand (P=9.0 microM) and tirapazamine (P=30.0 microM), the first bioreductive cytotoxic drug introduced into clinical trials. In addition, it showed a very good selective cytotoxicity in hypoxic conditions, being non-cytotoxic in normoxia. Its hypoxic cytotoxicity relationship value, HCR, was of the same order than those of other hypoxia selective cytotoxins (i.e., Mitomycine C, Misonidazole and the N-oxide RB90740). Interaction of the complexes with plasmid DNA in normoxia showed dose dependent ability to relax the negative supercoiled forms via different mechanisms. Pd(L2)(2) introduced a scission event in supercoiled DNA yielding the circular relaxed form. Meanwhile, both Pd(L1)(2) and Pd(L3)(2) produced the loss of negative supercoils rendering a family of topoisomers with reduced electrophoretic mobility. Pd(L3)(2) showed a more marked effect than Pd(L1)(2). Indeed, for the highest doses assayed, Pd(L3)(2) was even able to introduce positive supercoils on the plasmid DNA.

Serum selenium and glutathione peroxidase-3 activity: biomarkers of systemic inflammation in the critically ill?

OBJECTIVES: To confirm the influence of systemic inflammatory response syndrome (SIRS) on selenium (Se) levels and prospectively evaluate the relationship between serum Se concentration [Se], glutathione peroxidase activity [GPx-3] and injury severity in patients at the time of intensive care unit (ICU) admission. DESIGN: Prospective, observational study. SETTING: Multidisciplinary University Hospital ICU. PATIENTS AND PARTICIPANTS: A total of 36 ICU patients and 23 healthy volunteer subjects (HVS). MEASUREMENTS AND RESULTS: Healthy volunteer subjects were designated as controls (Group 1). ICU patients were divided into three groups: without SIRS (Group 2); with SIRS (Group 3); with SIRS and multiple organ dysfunction syndrome (MODS) (Group 4). The latter groups had APACHE II scores >15. [GPx-3] and [Se] were determined by standard methods within the first 48 h of admission to ICU. Kruskal-Wallis and Mann-Whitney U test were used for analysis of non-parametric continuous variables. The predictive value of [Se] and [GPx-3] for SIRS was calculated using a receiver operating characteristics (ROC) analysis. In SIRS and MODS patients [GPx-3] and [Se] decreased significantly (P = 0.0001 and P = 0.002, respectively). After ICU admission [GPx-3] and [Se] had a predictive value for SIRS ([GPx-3] sensitivity: 90%, specificity: 86.2% (cut-off value: 0.5 U/mL); [Se]: sensitivity 90%, specificity 72.4% (cut-off value: 60 microg/L). [Se] had predictive value for ICU mortality (P = 0.034). CONCLUSIONS: Systemic inflammatory response syndrome and MODS were associated with early decreases in [Se] and [GPx-3]. Low [Se] and [GPx-3] after ICU admission had a predictive value for SIRS, which may aid future selection of patients who could benefit from Se supplementation.

New Ni(II)-sulfonamide complexes: synthesis, structural characterization and antibacterial properties. X-ray diffraction of [Ni(sulfisoxazole)2(H2O)4].2H2O and [Ni(sulfapyridine)2].

The synthesis, structural characterization, voltammetric experiments and antibacterial activity of [Ni(sulfisoxazole)(2)(H(2)O)(4)].2H(2)O and [Ni(sulfapyridine)(2)] were studied and compared with similar previously reported copper complexes. [Ni(sulfisoxazole)(2)(H(2)O)(4)].2H(2)O crystallized in a monoclinic system, space group C2/c where the nickel ion was in a slightly distorted octahedral environment, coordinated with two sulfisoxazole molecules through the heterocyclic nitrogen and four water molecules. [Ni(sulfapyridine)(2)] crystallized in a orthorhombic crystal system, space group Pnab. The nickel ion was in a distorted octahedral environment, coordinated by two aryl amine N from two sulfonamides acting as monodentate ligands and four N atoms (two sulfonamidic N and two heterocyclic N) from two different sulfonamide molecules acting as bidentate ligands. Differential pulse voltammograms were recorded showing irreversible peaks at 1040 and 1070 mV, respectively, attributed to Ni(II)/Ni(III) process. [Ni(sulfisoxazole)(2)(H(2)O)(4)].2H(2)O and [Ni(sulfapyridine)(2)] presented different antibacterial behavior against Staphylococcus aureus and Escherichia coli from the similar copper complexes and they were inactive against Mycobacterium tuberculosis.

New copper-based complexes with quinoxaline N1,N4-dioxide derivatives, potential antitumoral agents.

Taking into account our previous studies on cytotoxic metal compounds, new copper complexes with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands were synthesized and characterized by different spectroscopic methods. The hypoxic selective cytotoxicity towards V79 cells and the superoxide dismutase-like activity of the complexes were determined and related to physicochemical properties of the compounds. In particular, the copper(II) complex with 3-amino-6-chloro-7-fluoroquinoxaline-2-carbonitrile N1,N4-dioxide showed cytotoxic selectivity in hypoxia being the most lipophilic compound of the series. On the contrary, the complex with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide was cytotoxic but not selective and that with 3-amino-7-chloro-6-methoxy-quinoxaline-2-carbonitrile N1,N4-dioxide was not cytotoxic towards V79 cells neither in oxia nor in hypoxia in the assayed conditions. The sigmam Hammett substituent electronic descriptor was related to the effect in hypoxic conditions and the SOD-like activity was correlated to the effect in normoxia.

Vibrational spectra of the Cu(II) complexes of L-asparagine and L-glutamine.

The infrared and Raman spectra of the copper(II) complexes [Cu(L-asn)2] and [Cu(L-gln)2] (L-asn=L-asparagine; L-gln=L-glutamine), were recorded and analyzed in relation to its structural peculiarities. Some comparisons between the spectra of these complexes and with those of related systems are made. The characteristics of the carboxylate and amide groups of the bonded ligands are discussed in detail.

Improving anti-trypanosomal activity of 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives by complexation with vanadium.

New vanadium complexes of the type [V(IV)O(L)(2)], where L are 3-aminoquinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, were prepared as an effort to obtain new anti-trypanosomal agents improving the bioactivity of the free ligands. Complexation to vanadium of the quinoxaline ligands leads to excellent antiprotozoal activity, similar to that of the reference drugs nifurtimox and benznidazole and in all cases higher than that of the corresponding free ligands. In addition, it is for the first time that the V((IV))O-quinoxaline complexes are reported as a family of anti-Trypanosoma cruzi agents. Finally, the anti-trypanosomal activity of these vanadium complexes could be explained on the basis of their lipophilicity and the electronic characteristics of the quinoxaline substituents.

Selective hypoxia-cytotoxins based on vanadyl complexes with 3-aminoquinoxaline-2-carbonitrile-N1,N4-dioxide derivatives.

A new vanadyl complex with the formula VO(L1)2, where L1=3-amino-6(7)-chloroquinoxaline-2-carbonitrile N(1), N(4)-dioxide, has been synthesized and characterized by elemental analyses, conductometry, fast atom bombardment mass spectroscopy (FAB-MS) and electronic, Fourier transform infrared (FTIR), Raman, nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopies. Results were compared with those previously reported for analogous vanadium complexes with other 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands. As an effort to develop novel metal-based selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of aminoquinoxaline carbonitrile N-dioxides bioreductive prodrugs, the new complex and VO(L)2 complexes, with L=3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide (L2) and 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide (L3), were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes resulted in vitro more potent cytotoxins than the free ligands (i.e. potencies P(VO(L1)2)=3.0, P(L1)=9.0 microM) and Tirapazamine (P=30.0 microM) and showed excellent selective cytotoxicity in hypoxia, being no cytotoxic in oxia. In addition, the solubility in hydrophilic solvents resulted significantly higher for the vanadyl complexes than for the free ligands. These results could be indicative that complexation of the quinoxaline-2-carbonitrile N1,N4-dioxide derivatives with vanadium could improve their bioavailability. In addition, a new aspect of the series has been investigated. A detailed comparison of the electrochemical behavior of the free ligands and the complexes has been performed searching for a correlation between reduction potentials of the complexes and their activities and hypoxia selectivities.

Weak exchange interaction supported by a biologically relevant long chemical bridge in a Cu-peptide model compound.

The copper complex of the dipeptide L-alanyl-L-phenylalanine, catena-(L-alaninate-L-phenylalaninate-copper(II) monohydrate), identified as Cu(II)Ala-Phe, provides a convenient system to study a weak exchange interaction between unpaired spins transmitted through a biologically relevant long chemical bridge (18.34 A). In this complex, the copper ions are arranged in two symmetry-related anisotropic layers parallel to the ab plane at 13.17 A, separated by a double layer of water molecules. The equatorial-equatorial bridge considered as the most relevant path for exchange interactions between copper ions in neighbor layers contains 11 diamagnetic atoms (including three hydrogens), with two covalent amidate bridges plus three weak and moderate H bonds that go across the water layer. This interaction was studied using electron paramagnetic resonance in single-crystal samples, at 9.5 and 34.5 GHz. The measured magnitude of the interlayer interaction, |J3|/kB = 1.7(2) x 10(-3) K, is discussed in terms of values obtained for similar paths in other model compounds and in proteins. These results in model systems provide information that may be important in understanding biological functions at the molecular level.

Novel vanadyl complexes with quinoxaline N(1),N(4)-dioxide derivatives as potent in vitro insulin-mimetic compounds.

As a contribution to the development of novel vanadyl complexes with potential insulin-mimetic activity, three new oxovanadium(IV) complexes with the formula VO(L)(2), where L are 3-amino-quinoxaline-2-carbonitrile N(1),N(4)-dioxide derivatives, have been synthesized. Complexes have been characterized by elemental and thermal analyses, fast atom bombardment mass spectroscopy (FAB-MS), conductivity measurements and electronic, Fourier transform infrared (FTIR) and electron paramagnetic resonance (EPR) spectroscopies. The in vitro insulin-mimetic activity of the vanadyl complexes has been estimated by lipolysis inhibition tests, in which the inhibition of the release of free fatty acid from isolated rat adipocytes treated with epinephrine was determined. All the complexes showed inhibitory effects on free fatty acid release. [V(IV)O(3-amino-6(7)-bromoquinoxaline-2-carbonitrile N(1),N(4)-dioxide)(2)] exhibited higher in vitro insulin-mimetic activity than the very active bis(6-methylpicolinato)oxovanadium(IV), VO(6mpa)(2). This new vanadyl complex is expected to exhibit a higher blood glucose lowering activity than VO(6mpa)(2) in diabetic animals.