Relationship between the antiproliferative properties of Cu(II) complexes with the Schiff base derived from pyridine-2-carboxaldehyde and 5,6-diamino-1,3-dimethyluracil and the redox status mediated by antioxidant defense systems on glioma tumoral cells.

A set of new copper(II) complexes containing the Schiff base ligand derived from pyridine-2-carboxaldehyde and 5,6-diamino-1,3-dimethyluracil (6-amino-1,3-dimethyl-5-[(pyridin-2-ylmethylidene)-amino]-pyrimidine-2,4(1H,3H)-dione) with several anions (Cl-, Br-, I-, ClO4-, NO3-) and, two of them with 1,10-phenanthroline, were synthesized and characterized by means of elemental analysis, FT-IR, and single-crystal X-ray diffraction methods. Their ability to act as antitumor agents against C6 glioma cells has been also explored. These complexes contain copper a redox active metal essential for the regulation of cellular pathways that are fundamental for brain function. The antiproliferative activity of the complexes and their effect on cell cycle, apoptosis profile, bioenergetic behavior, intracellular reactive oxygen species (ROS) production, autophagy and enzyme antioxidant defense systems (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities) were analyzed in C6 glioma cells. Although the compounds show limited antiproliferative activity, they are able to modify S-phase of cell cycle and induce G2/M phase arrest. Also, copper(II) complexes promote apoptosis and, in a lesser extent, autophagy, being both processes modulated by ROS generation, due to their property to affect the enzyme antioxidant defense systems, mainly SOD and CAT but not GPx.

Effects on estrogen-dependent and triple negative breast cancer cells growth of Ni(II), Zn(II) and Cd(II) complexes with the Schiff base derived from pyridine-2-carboxaldehyde and 5,6-diamino-1,3-dimethyluracil explored through the renin-angiotensin system (RAS)-regulating aminopeptidases.

A series of Ni(II), Zn(II) and Cd(II) complexes with the Schiff base derived from the condensation 1:1 from pyridine-2-carboxaldehyde and 5,6-diamino-1,3-dimethyluracil (6-amino-1,3-dimethyl-5-[(pyridin-2-ylmethylidene)-amino]pyrimidine-2,4(1H,3H)-dione, DAAUPic) were synthesized and subsequently characterized by means of elemental analysis, FT-IR, NMR and nine of them by X-ray diffraction. Except the [Zn(µ-O,O'-AcO)(N5,N6,N1F-DAAUPicH-1)]2 and [Cd(O,O'-NO3)(µ-O4,(N5,N6,N1F)-DAAUPicH-1)(H2O)]2·2H2O dimers and the [Cd(µ-S,N-SCN)(N5,N6,N1F-DAAUPicH-1)]n chain-like polymer, all of them display monomeric molecular structures. The anticancer activity of compounds was also explored studying their effects on renin-angiotensin system (RAS)-regulating aminopeptidases on estrogen-dependent and triple negative breast cancer cell lines. At the concentrations used, some of the complexes showed different effects on (RAS) peptidases, which support the idea that their effects on cell growth/proliferation could be related to autocrine/paracrine regulatory functions of their corresponding peptide substrates.

A combined experimental and DFT investigation on the structure and CO-releasing properties of mono and binuclear fac-ReI(CO)3 complexes with 5-pyridin-2-ylmethylene-amino uracils.

The synthesis, structure and CO-releasing properties of a number of new tricarbonyl rhenium(i) complexes with 5-substituted-6-amino-1,3-dimethyluracils are reported and their structural features discussed on the basis of both spectral and X-ray crystallographic analyses. The 5-substituent library includes -N[double bond, length as m-dash]CH-2py (DAAUPic) and -CH[double bond, length as m-dash]N-N[double bond, length as m-dash]CH-2py (FDUHzPic) as additional metal binding components and chloride, acetonitrile or pyridine acting as ancillary ligands. The compounds have been identified by elemental analysis, NMR, MS and IR spectroscopy. In addition, [ReCl(CO)3(DAAUPic)], [Re(CO)3(FDUHzPic)py]ClO4, [Re(CO)3(FDUHzPic)py]PF6, [Re2Cl2(CO)6(FDUHzPic)] and [Re2Cl(CO)6(FDUHzPicH-1)(H2O)] structures have been solved by X-ray diffraction methods. These studies have clearly shown that the preferred coordination mode to rhenium takes place through the (N1F,N52)-pyridin-2-yl-methyleneamine moiety, the uracil coordinative availability (O4-N51 or N6-N51) being used only to bind the second metal center. The CO-releasing ability of these rhenium compounds has been investigated by the reaction with myoglobin; the corresponding studies have revealed that two of the mononuclear complexes and their related binuclear analogues are able to release CO to a moderate extent. This ability has also been theoretically assessed through a QTAIM analysis. The results, although non-conclusive, may explain somehow possible different preferences in CO releasing power after a comparison between the nature of Re-CO links in mononuclear and binuclear compounds.

Interactions between 2,4-bis-pteridine-1,5-benzodiazepine and group 12 dihalides: synthesis, spectral and XRD structural studies and theoretical calculations.

2,4-Bis(1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione-6-yl)-2,3-dihydro-2-methyl-1H-1,5-benzodiazepine (DLMBZD) has been prepared and its molecular and crystal structures have been determined from spectral and XRD data. The benzodiazepine ligand was reacted with zinc(ii), cadmium(ii) and mercury(ii) chloride, bromide and iodide to give complexes with general formula [M(DLMBZD)X2]. The complexes have been synthesized and characterized by IR, NMR and elemental analysis. The structure of seven complexes has been obtained by single crystal X-ray diffraction. In all the cases, the metal is (2 + 2 + 1)-five-coordinated by two halide ligands, two nitrogen atoms from pyrazine and diazepine rings and a carbonyl oxygen from a pteridine ring. The coordinated-metal environment is a square-based pyramid, with increasing trigonality from Hg(ii) to Zn(ii) complexes. To coordinate the metals, the ligand folds itself, establishing four intramolecular σ-π interactions with the pyrimidine and pyrazine rings. A topological analysis of the electron density using the Quantum Theory of Atoms in Molecules and the complexes stability has been performed.

Structural and theoretical studies on rhodium and iridium complexes with 5-nitrosopyrimidines. Effects on the proteolytic regulatory enzymes of the renin-angiotensin system in human tumoral brain cells.

The reactions of [RhCl(CO)(PPh3)2], [RhCl(CO)2]2 and [IrCl(CO)(PPh3)2] with different 5-nitrosopyrimidines afforded sixteen complexes which have been structurally characterized by elemental analysis, IR and NMR ((1)H and (13)C) spectral methods and luminescence spectroscopy. The crystal and molecular structures of [Rh(III)Cl(VIOH-1)2(PPh3)], [Rh(III)Cl(DVIOH-1)2(PPh3)] and [Rh(II)(DVIOH-1)2(PPh3)2] have been established from single crystal x-ray structure analyses. The three complexes are six-coordinated with both violurato ligands into an equatorial N5,O4-bidentate fashion, but with different mutually arrangements. Theoretical studies were driven on the molecular structure of [Rh(III)Cl(VIOH-1)2(PPh3)] to assess the nature of the metal-ligand interaction as well as the foundations of the cis-trans (3L-2L) isomerism. An assortment of density functional (SOGGA11-X, B1LYP, B3LYP, B3LYP-D3 and wB97XD) has been used, all of them leading to a similar description of the target system. Thus, a topological analysis of the electronic density within AIM scheme and the study of the Mulliken charges yield a metal-ligand link of ionic character. Likewise, it has been proved that the cis-trans isomerism is mainly founded on that metal-ligand interaction with the relativistic effects playing a significant role. Although most of the compounds showed low direct toxicity against the human cell lines NB69 (neuroblastoma) and U373-MG (astroglioma), they differently modify in several ways the renin-angiotensin system (RAS)-regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). Therefore, these complexes could exert antitumor activity against both brain tumor types, acting through the paracrine regulating system mediated by tissue RAS rather than exerting a direct cytotoxic effect on tumor cells.

Silver(I)/6-hydroxyiminolumazine compounds differently modify renin-angiotensin system-regulating aminopeptidases A and N in human neuroblastoma and glioma cells.

We have described that local tissue renin-angiotensin-system (RAS) is involved in tumor growth in a rat model of experimental glioma in vivo, through the modification of their corresponding local proteolytic regulatory enzymes. Thus, we have found a time-dependent significant decrease in aminopeptidase N (APN) and a significant increase in aminopeptidase A (APA) activities concomitantly with tumor growth in tumor tissue whereas no changes were found in circulating aminopeptidase activities; we suggested that angiotensin peptides may play an essential step in both tumor infiltration and associated angiogenesis. Here we analyze in vitro the antiproliferative efficacy, apoptotic properties and effects of three new disilver complexes containing E-6-(hydroxyimino)ethyl-1,3,7-trimethyllumazine (lumazine=pteridine-2,4(1H,3H)-dione) on RAS-regulating APA and APN specific activities in human neuroblastoma and glioma cell lines NB69 and U373-MG. Disilver compounds showed cytotoxicity against both cell lines, although their potency was different for each cell type. Furthermore, NB69 cells need higher concentrations of silver complexes than U373-MG cells to obtain a 50% growth inhibition. All compounds showed apoptotic effects, with U373-MG cells being more susceptible. The three silver complexes tested also show a dose-dependent inhibitory effect on APA activity in NB69 and U373-MG cells, although U373-MG cells are more sensitive. On the contrary, none of them showed effects on APN activity in NB69 neuroblastoma cells whereas the three compounds showed a dose-dependent stimulatory effect on APN activity in U373-MG glioma cells with a similar potency. Disilver complexes show specific antitumor activity against brain tumor cells acting through the paracrine regulating system mediated by local tissue RAS.

Antiproliferative effects of palladium(II) complexes of 5-nitrosopyrimidines and interactions with the proteolytic regulatory enzymes of the renin-angiotensin system in tumoral brain cells.

Seventeen new palladium(II) complexes of general formulaes PdCl2L, PdCl(LH-1)(solvent) and PdCl2(PPh3)2L containing pyrimidine ligands derived from 6-amino-5-nitrosouracil and violuric acid have been prepared and characterized by elemental analysis, IR and NMR ((1)H and (13)C) methods and, two of them, PdCl(DANUH-1)(CH3CN)]·½H2O and [PdCl(2MeOANUH-1)(CH3CN)] by X-ray single-crystal diffraction (DANU: 6-amino-1,3-dimethyl-5-nitrosouracil; 2MeOANU: 6-amino-2-methoxy-5-nitroso-3H-pyrimidin-4-one). The coordination environment around palladium is nearly square planar in the two compounds with different supramolecular arrangements. Crystallographic and spectral data are consistent with a bidentate coordination mode through N5 and O4 atoms when the ligands act in neutral form and N5 and N6 atoms in the monodeprotonated ones. The cytotoxicity of the complexes against human neuroblastoma (NB69) and human glioma (U373-MG) cell lines has been tested showing a considerable antiproliferative activity. Also, the study of the effects of palladium(II) complexes on the renin-angiotensin system (RAS) regulating proteolytic regulatory enzymes aminopeptidase A (APA), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP) shows a strong dependence on the compound tested and the tumoral cell type, also affecting different catalytic routes; the compounds affect in a different way the activities of enzymes of the RAS system, changing their functional roles as initiators of cell proliferation in tumors as autocrine/paracrine mediators.

A potential antitumor agent, (6-amino-1-methyl-5-nitrosouracilato-N3)-triphenylphosphine-gold(I): structural studies and in vivo biological effects against experimental glioma.

The synthesis and molecular and supramolecular structures of the compound (6-amino-1-methyl-5-nitrosouracilato-N3)-triphenylphosphine-gold(I) with interesting abilities to inhibit tumor growth in an animal model of experimental glioma are reported. Thus, its antitumor properties, effects on both enzyme and non-enzyme antioxidant defense systems and the response of several biochemical biomarkers have been analyzed. After seven days of treatment, the gold compound decreased the tumor growth to ca. one-tenth and reduced oxidative stress biomarkers (thiobarbituric acid-reactive substances (TBARS) and protein oxidation levels) compared to animals treated with the vehicle. Also, gold compound maintained non-enzyme antioxidant defense systems as in non-tumor animals and increased enzyme antioxidant defenses, such as superoxide dismutase and glutathione peroxidase activities, and decreased catalase activity. Analysis of serum levels of electrolytes, nitrogenous compounds, glucose, lipids, total protein, albumin, transaminases and alkaline phosphatase indicated that gold compound treatment showed few adverse effects, while effectively inhibiting tumor growth through mechanisms that involved endogenous antioxidant defenses.

Heteropolyhedral silver compounds containing the polydentate ligand N,N,O-E-[6-(hydroxyimino)ethyl]-1,3,7-trimethyllumazine. Preparation, spectral and XRD structural study and AIM calculations.

The oxime derived from 6-acetyl-1,3,7-trimethyllumazine (1) ((E-6-(hydroxyimino)ethyl)-1,3,7-trimethylpteridine-2,4(1H,3H)-dione, DLMAceMox) has been prepared and its molecular and crystal structure determined from spectral and XRD data. The oxime ligand was reacted with silver nitrate, perchlorate, thiocyanate, trifluoromethylsulfonate and tetrafluoroborate to give complexes with formulas [Ag(2)(DLMAceMox)(2)(NO(3))(2)](n) (2), [Ag(2)(DLMAceMox)(2)(ClO(4))(2)](n) (3), [Ag(2)(DLMAceMox)(2)(SCN)(2)] (4), [Ag(2)(DLMAceMox)(2)(CF(3)SO(3))(2)(CH(3)CH(2)OH)]·CH(3)CH(2)OH (5) and [Ag(DLMAceMox)(2)]BF(4) (6). Single-crystal XRD studies show that the asymmetrical residual unit of complexes 2, 3 and 5 contains two quite different but connected silver centers (Ag1-Ag2, 2.9-3.2 Å). In addition to this, the Ag1 ion displays coordination with the N5 and O4 atoms from both lumazine moieties and a ligand (nitrato, perchlorato or ethanol) bridging to another disilver unit. The Ag2 ion is coordinated to the N61 oxime nitrogens, a monodentate and a (O,O)-bridging nitrato/perchlorato or two monodentate O-trifluoromethylsulfonato anions. The coordination polyhedra can be best described as a strongly distorted octahedron (around Ag1) and a square-based pyramid (around Ag2). The Ag-N and Ag-O bond lengths range between 2.22-2.41 and 2.40-2.67 Å, respectively. Although the structure of 4 cannot be resolved by XRD, it is likely to be similar to those described for 2, 3 and 5, containing Ag-Ag units with S-thiocyanato terminal ligands. Finally, the structure of the tetrafluoroborate compound 6 is mononuclear with a strongly distorted tetrahedral AgN(4) core (Ag-N, 2.27-2.43 Å). Always, the different Ag-N distances found clearly point to the more basic character of the oxime N61 nitrogen atom when compared with the pyrazine N5 one. A topological analysis of the electron density within the framework provided by the quantum theory of atoms in molecules (QTAIM) using DFT(M06L) levels of theory has been performed. Every Ag-Ag and Ag-ligand interaction has been characterized in terms of Laplacian of the electron density, [nabla](2)ρ(r), and the total energy density, H(r).

XRD and DFT-modelized structures of a pteridine-2,4(1H,3H)-dithione/N,N'-dimethylformamide H-bonded cluster (2:2). MO study of the coordination ability.

The title compound, C(6)H(4)N(4)S(2)·C(3)H(7)NO, crystallizes in the monoclinic space group C 2/c with a = 26.673(5), b = 5.397(1), c = 16.522(3) Å, ß = 95.49(3)°, Z = 8, R = 0.0461 for 1891 reflections with I > 2σ(I) and 174 parameters (4 restraints). Single pteridine-2,4(1 H,3 H)-dithione and dimethylformamide molecules are packed via N-H···O and N-H···N hydrogen bonds into centrosymmetric clusters containing two molecules of each class; these are roughly planar and placed into two different sets of planes -both containing the [-1,0,2] direction- mutually angled by 77.8°. Despite the distance between two neighbor planes in each set is ca. 3.4 Å, the analysis of π,π-stacking interactions shows too large slippage distance between aromatic rings from contiguous planes. Additional σ-π interactions between S2, S4 and O1S atoms and pyrazine or pyrimidine rings from adjacent molecules are present. The structure for the cluster [DTLM-DMF](2) has been simulated by using the density functionals B1B95 (6-31 G(d) and 6-31+G(d) basis sets) and M06-2X (6-31 G(d) basis set). As a result, the M06-2X/6-31 G(d) approach provides the best agreement with the experimental XRD data. For a better evaluation of the intermolecular interactions, the superposition of two dimeric adducts [DTLM-DMF](2) has been modelized. The binding capability of DTLM ligand was simulated on systems containing two metal-binding modes to palladium (N5-S4 and N1-S2) with different chelate size. The analysis of the frontier orbitals points out that the link with the metallic centers will take place through the sulfur atoms.

(6-Acetyl-1,3,7-trimethyl-lumazine-κO,N,O)bis-(triphenyl-phosphine-κP)copper(I) hexa-fluorido-phosphate.

The title compound, [Cu(C(11)H(12)N(4)O(3))(C(18)H(15)P)(2)]PF(6), is the third example reported in the literature of a five-coordinated Cu(I)P(2)NO(2) system. The metal is coordinated to both PPh(3) mol-ecules through the P atoms and to the pyrazine ring of the lumazine mol-ecule through an N atom in a trigonal-planar arrangement; two additional coordinated O atoms, at Cu-O distances longer than 2.46 Å, complete the coordination. The coordination environment can be described as an inter-mediate square-pyramidal/trigonal-bipyramidal (SP/TBP) polyhedron.

1,3,7-Trimethyl-2,4-dioxo-1,2,3,4-tetra-hydro-pteridine-6-carboxylic acid hemihydrate.

In the title compound, C(10)H(10)N(4)O(4)·0.5H(2)O, the two rings of the pteridine system are nearly coplanar [dihedral angle = 4.25 (9)°]. The atoms of the carboxyl group are also coplanar with the pteridine unit [r.m.s. deviation from the mean plane of the pteridine skeleton = 0.092 (2) Å]. In the crystal, the presence of the water molecule of crystallization (O atom site symmetry 2) leads to a hydrogen-bonding pattern different from the one shown by many carboxylic acid compounds (dimers formed through O-H⋯O hydrogen bonds between neighbouring carboxyl groups): in the present structure, the water mol-ecule, which lies on a binary axis, acts as a bridge between two mol-ecules, forming a hydrogen-bonded dimer. In addition to the hydrogen bonds, there are π-π ring stacking inter-actions involving the pyrimidine and pyrazine rings [centroid-centroid distance = 3.689 (1)Å], and two different pyrazine rings [centroid-centroid distance = 3.470 (1)Å]. Finally, there is a C-O⋯π contact involving a carboxyl-ate C-O and the pyrimidine ring with a short O⋯Cg distance of 2.738 (2) Å.

New 2,6-bis-[uracil-imino] ethylpyridine complexes containing the CdN(6) core: Synthesis, crystal structures, luminescent properties and antiproliferative activity against C6 glioma cells.

Three new Cd(II) complexes with the Schiff base ligand derived from the condensation 1+2 of 2,6-diacetylpyridine and 5,6-diamino-1,3-dimethyluracil have been "in template" synthesized. The molecular structures of complexes were determined by single-crystal X-ray diffraction. The metal center shows a very distorted mer-bis-tridentate CdN(6) octahedral geometry as consequence of the reduced bite angles of the ligand and the existence of long-distanced interactions with donor atoms in the neighbourhood. The luminescent properties of complexes in CH(3)CN solution were investigated showing the emission energies depend on the uracil part of the ligand. The evaluation of their biological properties against C6 glioma cell line indicates that cadmium(II) complexes could be an interesting tools to treat drug-resistant brain tumors.

Chloro-fac-tricarbonylrhenium(I) complexes of asymmetric azines derived from 6-acetyl-1,3,7-trimethylpteridine-2,4(1H,3H)-dione with hydrazine and aromatic aldehydes: preparation, structural characterization and biological activity against several human tumor cell lines.

A number of new asymmetric azines derived from hydrazine and 6-acetyl-1,3,7-trimethyllumazine (lumazine=pteridine-2,4(1H,3H)-dione) and its derivatives with several aromatic aldehydes have been prepared and characterized by usual procedures (XRD, IR, (1)H and (13)C NMR). These were reacted with [ReCl(CO)(5)] to give the corresponding mononuclear chloro-fac-tricarbonylrhenium(I) [ReCl(CO)(3)L] compounds. The complexes were characterized by elemental analysis, thermogravimetry (TG) and differential scanning calorimetry (DSC), IR, (1)H and (13)C NMR. Furthermore, single-crystal X-ray diffraction studies have also allowed to report two different coordination modes of the ligands, which are strongly influenced by the basicity of the heteroatoms on the aromatic aldehyde; thus, the hydrazones derived from hydrazine and hydroxyaldehydes are linked to Re(I) through N5 atom from the pyrazine ring and the N61 one from the hydrazino group, whereas with the ligand derived from pyridin-2-carbaldehyde, the N62 atom of the hydrazino group and the N1 from the pyridine moiety are preferred ligand-to-metal binding sites. The study of the effects of the compounds on the growth of four human tumor cell lines (neuroblastoma NB69, glioma U373, and breast cancer MCF-7 and EVSA-T) suggests a modulator behaviour, according to the concentration, of cell growth due to their estrogen-like characteristics.

A new five-coordinated CuIP2NO2 system: XRD structure of 6-acetyl-1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione and its Cu(I) (N5,O61,O4)-tridentate complex with triphenylphosphine. An AIM study of the nature of metal-ligand bonds.

The second example of a five-coordinated CuIP2NO2 system, [Cu(DLMAceM)(PPh3)2]ClO4 (DLMAceM=6-acetyl-1,3,7-trimethyl-pteridine-2,4(1H,3H)-dione), is reported. The structural characterization of both the DLMAceM ligand and the Cu(I) compound has been achieved by IR, 13C and 1H NMR and XRD methods. The metal is coordinated to the PPh3 molecules (Cu-P 2.224(2) and 2.258(2) A) and the pyrazine N(5) atom (Cu-N(5) 2.058(6) A) in a trigonal planar arrangement; two additional semi-coordinated atoms (Cu...O(4) 2.479(5) and Cu...O(61) 2.559(5) A) can be observed, forming an intermediate SP/TBP polyhedron. To define the nature of the metal-ligand bonds for the Cu(I) compound, especially in regards to the semi-coordinated oxygen atoms, a topological analysis of the electron density rhob within the framework provided by the quantum theory of atoms in a molecule (QTAIM) using Hartree-Fock and DFT(B3LYP) levels of theory has been performed. Five bond critical points (BCP) have been found, whose associated bond paths connect the Cu metal with the atoms P(1), P(2), O(4) O(61) and N(5). The type of interaction between the Cu and ligand binding sites has been characterized in terms of the Laplacian of the electron density, nabla2rhob, the total energy density, Hb, and the delocalization index, deltaAB.

Metal complexes with the ligand derived from 6-acetyl-1,3,7-trimethyllumazine and benzohydrazide. Molecular structures of two new Co(II) and Rh(III) complexes and analysis of in vitro antitumor activity.

The structures and spectroscopic properties of new Mn(II), Co(II), Cd(II), Hg(II), Ag(I), Rh(III), and Ir(I) complexes with the ligand BZLMH derived from 6-acetyl-1,3,7-trimethyllumazine (lumazine=pteridine-2,4(1H,3H)-dione) and benzohydrazide are reported. Complexes have been characterized by elemental analyses, spectroscopic studies (IR, UV-vis, (1)H, (13)C and (15)N NMR) and magnetic measurements. In all the complexes, the lumazine-derived ligand appears to be coordinated in either tridentate (N5, N61 and O63) or tetradentate forms (O4, N5, N61 and O63). The molecular structures of the [Co(BZLMH)(H(2)O)(CH(3)CN)(2)](ClO(4))(2) x CH(3)CN and [RhCl(2)(BZLM)(CH(3)CN)] x CH(3)CN complexes, determined by single crystal X-ray diffraction, have allowed to corroborate both coordination behaviours. The cytotoxic activity of the free ligand and complexes against human neuroblastoma NB69 cell line is also described. The differential analysis of the initial cytotoxic screening data has shown good activity only for the [RhCl(2)(BZLM)(CH(3)CN)] x CH(3)CN compound at concentrations at around 2 microM; for the other complexes, a modulation of the cell growth was not found upon complexation, this non-specific effect strongly suggesting an apoptotic behaviour.

Versatile coordinative abilities of a new hybrid pteridine-thiosemicarbazone ligand: crystal structure, spectroscopic characterization, and luminescent properties.

The synthesis and characterization of the first thiosemicarbazone-lumazine (TSCLMH=the thiosemicarbazone of 6-acetyl-1,3,7-trimethyllumazine) hybrid ligand is reported. The influence of the conformation of this compound on its energy and the atomic contribution to the molecular orbitals have been theoretically investigated. Ni(II), Cu(I), Zn(II), and Cd(II) complexes of this ligand have been synthesized and characterized by elemental analysis, thermogravimetric studies, IR, 1H, 13C, and 15N NMR, and UV-vis-NIR spectroscopy, magnetic measurements, and X-ray crystallography. Four types of coordination modes for the ligand may be predicted: (a) double bidentate; (b) tetradentate; (c) tridentate; (d) bidentate. Structures of representative complexes of types a, b, and d have been determined by X-ray crystallography. In the [Cu(TSCLMH)]2(ClO4)2 complex, TSCLMH acts as a doubly bidentate bridging ligand forming a dimer with a Cu...Cu distance of 2.876 A. The geometry around the metal ion is trigonally distorted tetrahedral with a relatively long (four-atom) bridge between the metal centers instead of the shorter, mainly single atom, bridges present in other thiosemicarbazone derivatives complexes. In the [Cd(NO3)2(TSCLMH)(EtOH)] complex, the metal ion displays eight-coordinated geometry with the TSCLMH ligand acting in a tetradentate planar fashion and two nitrate anions, one monodentate and the other bidentate. The coordination polyhedron in [Cd(TSCLM)2(H2O)].MeOH.2H2O is a square pyramid with two monoanionic ligands acting as bidentate NS donors and a water molecule completing the coordination sphere. Fluorescence spectroscopic properties of TSCLMH have been studied as well as the changes in position and intensity of fluorescence bands caused by the complexation with different metal ions (Ni2+, Cu+, Zn2+, Cd2+).

Synthesis, characterization and antiproliferative activity of metal complexes with the Schiff base derived from the condensation 1:2 of 2,6-diformyl-4-methylphenol and 5,6-diamino-1,3-dimethyluracil.

A series of mononuclear complexes with Co(II), Ni(II), Cu(II), Zn(II), Hg(II), Mo(VI) and Pd(II) containing the ligand derived from the 1:2 condensation of 2,6-diformyl-4-methylphenol and 5,6-diamino-1,3-dimethyluracil (hereafter denoted as BDFDAAU) were synthesized. The complexes were characterized by elemental analysis, thermogravimetry (TG) and differential scanning calorimetry (DSC), IR, (1)H, (13)C and (15)N NMR, UV-visible-near IR (UV-VIS-NIR), EPR and magnetic measurements. The deprotonated ligand in the phenolic oxygen shows a symmetric tridentate coordination mode through the two azomethine nitrogen atoms and the phenolic oxygen atom whereas the coordination of the neutral ligand takes place through the phenolic oxygen atom and one azomethine nitrogen atom. In the Mo(VI) complex, the ligand is bideprotonated in the phenolic oxygen and an amino group from one uracil unit; so, the coordination mode changes again into an asymmetric way: phenolic oxygen atom, one azomethine nitrogen atom and the nitrogen atom from the deprotonated amino group. The antiproliferative behaviour against the five human tumor cell lines (human neuroblastoma NB69, human breast cancer MCF-7 and EVSA-T, human glioma H4 and human bladder carcinoma cell line ECV) suggested a modulator behaviour, according to the concentration, of cell growth due to their estrogen-like characteristics.

Synthesis, structure and biological activity of a new and efficient Cd(II)-uracil derivative complex system for cleavage of DNA.

The new complex formed by Cd(II) and the 1:2 Schiff-base-type ligand 2,6-bis[1-(4-amino-1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxopyrimidin-5-yl)imino]ethylpyridine (DAPDAAU) has been chemically and structurally characterized by X-ray diffraction: the ion Cd(II) is surrounded by six nitrogen atoms from two DAPDAAU ligands which coordinates each one in a tridentate fashion through the pyridine ring (N1) and both azomethine nitrogen atoms (N5). The interaction of the Cd(II) complex (compound I) with calf-thymus DNA as observed by circular dichroism spectroscopy suggests the initial unwinding of the DNA double helix strongly depends on increasing incubation times and metal-to-nucleic acid molar ratios. Electrophoretic experiments indicate that the cadmium complex induces cleavage of the plasmid pBR322 DNA to give ulterior nicking and shortening of this molecule, as a result of the complex binding to DNA, resulting in the conclusion that compound I behaves as a chemical nuclease. Cytotoxic activity of the Cd(II) complex against selected different human cancer cell lines is specific and increases with increasing concentration of the metal compound; this fact indicates the potential antitumor character of the complex. When the culture medium is supplemented with compound I, a remarkable inhibition of the growing cell is observed, important cell degeneration appears before 48 h and abundant precipitates are formed that correspond to cell residues and denatured proteins.

Synthesis, characterization and antiproliferative behavior of tricarbonyl complexes of rhenium(I) with some 6-amino-5-nitrosouracil derivatives: crystal structure of fac-[ReCl(CO)3(DANU-N5,O4)] (DANU=6-amino-1,3-dimethyl-5-nitrosouracil).

New complexes of rhenium(I) with some 5-nitrosopyrimidines with general formula [ReCl(CO)3L] have been prepared and characterized by elemental analysis, conductivity measurements, IR and 1H, 13C and 15N NMR spectroscopic methods. The complexes appear to be monomeric and the pyrimidine ligands act in a neutral form. The structure of [ReCl(CO)3(DANU)].CH3CN has been solved by X-ray diffraction. The coordination environment around the Re(I) may be described as a distorted octahedron in which the ligand behaves in a bidentate fashion through N5 and O4 atoms, making a five-membered chelate ring. The coordination sphere is completed with three carbonyl groups in fac-arrangement and one chlorine atom. The evaluation of the antiproliferative behavior against five human tumor cell lines (human breast cancer MCF-7 and EVSA-T, human neuroblastoma NB69, human glioma H4 and human bladder carcinoma cell line ECV) suggested a modulator behavior of cell growth at low concentrations due to their estrogenic-like characteristics.