New sulfonamide complexes with essential metal ions [Cu (II), Co (II), Ni (II) and Zn (II)]. Effect of the geometry and the metal ion on DNA binding and nuclease activity. BSA protein interaction.

Mixed divalent Cu, Co, Ni and Zn complexes containing the new sulfonamide ligand N-(2-(pyridin-2-yl)ethyl)quinoline-8-sulfonamide (HQSEP) were prepared and characterized by physico-chemical techniques. The tetracoordinate [Cu(QSEP)X] [X = Br (1), Cl (2)] compounds present a seesaw geometry (τ4 = 0.56 (1) and 0.50 (2)). The Cu(II) in the [Cu(QSEP)(NO3)(MeOH)] (3) complex is five coordinate with a slightly distorted SP geometry (τ = 0.11). The [M(QSEP)(benz)] [M = Cu(II) (4), Ni(II) (5), Co(II) (6) and Zn(II) (7); benz = benzoate] compounds are configurationally isotypic. The coordination geometries of the M(II) ions can be best described as distorted SP (τ = 0.29, 0.15, 0.34 and 0.18 for 4, 5, 6 and 7, respectively). The interaction of the compounds with CT-DNA was studied by different techniques. Notably, these studies indicated that the tetracoordinate complexes (1 and 2) present higher DNA affinity than pentacoordinate compounds (3-7). In line with the Irving-Williams order of stability, 5 presented higher propensity for DNA binding than 6. Interestingly, the cleavage activity of 1-4 in the presence of ascorbate/H2O2 follows the same trend as that found for DNA binding affinity, being the tetracoordinate 1 and 2 more effective as nucleases than the five coordinate 3 and 4. Also, the DNA cleavage reaction mechanism was investigated. DNA cleavage experiments upon irradiation indicated the important role of the aromatic nature of the coligand in the photocleavage activity of 1-4. Finally, the interaction of the compounds with bovine serum albumin (BSA) was studied and the binding constants were calculated.

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines.

Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the potential applications as antitumor compounds. A part of the biological activity of the TSC-CuII complexes rests on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the [Cu(PTSC)(ONO2)]n compound (1) (HPTSC=pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu(PTSC*)(ONO2)}2] derivative (2, HPTSC*=pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with the release of CuI ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with those shown by the free HPTSC and HPTSC* ligands.

Mixed-ligand copper(II)-sulfonamide complexes: effect of the sulfonamide derivative on DNA binding, DNA cleavage, genotoxicity and anticancer activity.

Four ternary complexes, [Cu(L1)2(bipy)] (1) [HL1 = N-(6-chlorobenzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide], [Cu(L2)2(bipy)] (2) [HL2 = N-(benzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide], [Cu(L3)2(bipy)]·1/2H2O (3) [HL3 = N-(5,6-dimethylbenzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide] and [Cu(L4)2(bipy)] (4) [HL4 = N-(5,6-dimethylbenzo[d]thiazol-2-yl)benzenesulfonamide], were prepared and then characterized by X-ray crystallography, spectroscopy and magnetic measurements. Whereas the molecular structure of 1 and 2 consists of a discrete monomeric copper(II) species with a distorted square planar geometry, that of 3 and 4 consists of two independent molecules. In 3, both molecules present a different coordination geometry (distorted square planar and distorted square pyramidal) while in 4 they have an identical coordination environment (distorted square planar). The propensity for binding of 1-4 to calf thymus DNA was studied by thermal denaturation, viscosimetry, and fluorescence measurements. Results indicated that the N-sulfonamide derivative plays an important role in governing the type of interaction with DNA. The ability of the complexes to cleave DNA was studied in vitro with ascorbate activation and was tested by monitoring the expression of the yEGFP gene containing the RAD54 reporter. Moreover, their antiproliferative activity was verified in two cellular models: yeast and human tumor cells in culture. Their DNA cleavage efficiency at the cellular level was found to be: 1 < 3 ~ 4 < 2. The higher propensity of 2 for inflicting DNA damage was related with its higher binding affinity to DNA. The biological studies carried out with human tumor cells, colon adenocarcinoma Caco-2 cells and leukemia Jurkat T lymphocytes confirmed that the compounds produce cell death mainly by apoptosis, the complex 2 being the most effective.

DNA binding, nuclease activity, DNA photocleavage and cytotoxic properties of Cu(II) complexes of N-substituted sulfonamides.

Ternary copper(II) complexes [Cu(NST)2(phen)] (1) and [Cu(NST)2(NH3)2]·H2O (2) [HNST=N-(4,5-dimethylthiazol-2-yl)naphthalene-1-sulfonamide] were prepared and characterized by physico-chemical techniques. Both 1 and 2 were structurally characterized by X-ray crystallography. The crystal structures show the presence of a distorted square planar CuN4 geometry in which the deprotonated sulfonamide, acting as monodentate ligand, binds to the metal ion through the thiazole N atom. Both complexes present intermolecular π-π stacking interactions between phenanthroline rings (compound 1) and between naphthalene rings (compound 2). The interaction of the complexes with CT DNA was studied by means of thermal denaturation, viscosity measurements and fluorescence spectroscopy. The complexes display good binding propensity to the calf thymus DNA giving the order: 1>2. Complex 1, which has a higher capability for binding to DNA, showed better nuclease activity than 2 in the presence of ascorbate/H2O2. Both the kinetics and the mechanism of the DNA cleavage reaction were investigated. Furthermore, complex 1 showed efficient photo-induced DNA cleavage activity on irradiation with UV light in the absence of any external reagent. The UV light induced DNA cleavage follows a photo-redox pathway with generation of hydroxyl radicals as reactive species. In addition, the cytotoxic properties of both complexes (1 and 2) were evaluated in human cancer cells (HeLa, Caco-2 and MDA-468). The low IC50 values, in particular those against Caco-2, have indicated that the compounds can be considered as promising chemotherapeutic agents.

Biological assays and noncovalent interactions of pyridine-2-carbaldehyde thiosemicarbazonecopper(II) drugs with [poly(dA-dT)](2), [poly(dG-dC)] (2), and calf thymus DNA.

The interaction of the Cu(II) drugs CuL(NO(3)) and CuL'(NO(3)) (HL is pyridine-2-carbaldehyde thiosemicarbazone and HL' is pyridine-2-carbaldehyde 4N-methylthiosemicarbazone, in water named [CuL](+) and [CuL'](+)) with [poly(dA-dT)](2), [poly(dG-dC)](2), and calf thymus (CT) DNA has been probed in aqueous solution at pH 6.0, I = 0.1 M, and T = 25 degrees C by absorbance, fluorescence, circular dichroism, and viscosity measurements. The results reveal that these drugs act as groove binders with [poly(dA-dT)](2), with a site size n = 6-7, whereas they act as external binders with [poly(dG-dC)](2) and/or CT-DNA, thus establishing overall electrostatic interaction with n = 1. The binding constants with [CuL'](+) were slightly larger than with [CuL](+). The title compounds display some cleavage activity in the presence of thiols, bringing about the rupture of the DNA strands by the reactive oxygen species formed by reoxidation of Cu(I) to Cu(II); this feature was not observed in the absence of thiols. Mutagenic assays performed both in the presence and in the absence of S9 mix, probed by the Ames test on TA 98, TA 100, and TA 102, were negative. Weak genotoxic activity was detected for [CuL](+) and [CuL'](+), with a significative dose-response effect for [CuL'](+), which was shown to be more cytotoxic in the Ames test and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assays. Methylation of the terminal NH(2) group enhances the antiproliferative activity of the pyridine-2-carbaldehyde thiosemicarbazones.

In vivo and in vitro anti-leishmanial activities of 4-nitro-N-pyrimidin- and N-pyrazin-2-ylbenzenesulfonamides, and N2-(4-nitrophenyl)-N1-propylglycinamide.

A series of compounds containing the nitrobenzene and sulfonamido moieties were synthesized and their leishmanicidal effect was assessed in vitro against Leishmaniainfantum promastigotes. Among the compounds evaluated, the p-nitrobenzenesulfonamides 4Aa and 4Ba, and the p-nitroaniline 5 showed significant activity with a good selectivity index. In a Balb/c mice model of L. Infantum, administration of compounds 4Aa, 4Ba or 5 (5mg/kg/day for 10 days, injected ip route) led to a clear-cut parasite burden reduction (ca. 99%). In an attempt to elucidate their mechanism of action, the DNA interaction of 4Aa and 5 was investigated by means of viscosity studies, thermal denaturation and nuclease activity assay. Both compounds showed nuclease activity in the presence of copper salt. The results suggest that compounds 4Aa, 4Ba and 5 represent possible candidates for drug development in the therapeutic control of leishmaniasis.

Synthesis and copper-mediated nuclease activity of a tetracationic tris(2,2'-bipyridine) ligand.

We report herein the synthesis of a novel tetracationic tris(2,2'-bipyridine) ligand 4. We show that this ligand metalated with copper(II), and in the presence of ascorbate as a reducing agent, strongly damages pUC18 plasmid DNA. Copper complex formation was demonstrated by ESI-MS (electrospray ionization-mass spectrum) at a 1:3 ligand to metal ratio. Binding of both 4 and its copper(II) complex to CT-DNA (calf thymus DNA) was characterized by viscosimetry, thermal denaturation and fluorescence-based competition assays. The viscosimetric data indicated that 4 and its copper(II) complex bind DNA through partial intercalation and thermal denaturation studies revealed a significant increase of duplex DNA stability in the presence of these species (DeltaT(m)=16.4 and 18.3 degrees C, respectively). Moreover, 4 and its copper(II) complex were found to effectively compete with ethidium bromide for the intercalative binding sites of DNA. Overall, the copper(II)-4 complex constitutes a very efficient DNA cleaving agent in the presence of ascorbate. Experiments with scavengers further suggest that the generation of Cu(I), hydrogen peroxide, superoxide, hydroxyl radical and singlet oxygen-like species contributes to the DNA breakage induced by the Cu(II) complex of 4.

Toward the development of metal-based synthetic nucleases: DNA binding and oxidative DNA cleavage of a mixed copper(II) complex with N-(9H-purin-6-yl)benzenesulfonamide and 1,10-phenantroline. Antitumor activity in human Caco-2 cells and Jurkat T lymphocytes. Evaluation of p53 and Bcl-2 proteins in the apoptotic mechanism.

The complex [Cu(N9-ABS)(phen)2].3.6H2O, H2N9-ABS = N-(9H-purin-6-yl)benzenesulfonamide and phen = 1,10-phenanthroline, has been synthesized and then characterized with the aid of X-ray diffraction, analytical, and spectroscopic techniques. The geometry of Cu(II) is distorted square pyramidal with the equatorial positions occupied by three N atoms from two phenantroline molecules and one N atom from the adenine ring of the sulfonamide ligand. The interaction of the complex with DNA was studied by means of viscosity measurements and fluorescence spectroscopy. The results pointed to a classic intercalation of the complex between the DNA base pairs. The complex was found to be a very efficient agent of plasmid DNA cleavage in the presence of ascorbate. Both the kinetics and the mechanism of the cleavage reaction were studied. In addition, the cytotoxic properties of the complex were evaluated in human Jurkat T and Caco-2 cell lines. The cytotoxicity of the compound was higher than that of the reference ([Cu(phen)2]2+). The mechanism and type of cell death induced by the compound was determined by flow cytometry and Hoechst dye staining. The compound demonstrated a significant ability to induce cell death by apoptosis. The apoptosis induced by [Cu(N9-ABS)(phen)2].3.6H2O was associated with an increase in p53 protein levels while those of Bcl-2 were reduced.

Oxidative nuclease activity of ferromagnetically coupled mu-hydroxo-mu-propionato copper(II) complexes [Cu3(L)2(mu-OH)2(mu-propionato)2] (L=N-(pyrid-2-ylmethyl)R-sulfonamidato, R=benzene, toluene, naphthalene).

Three doubly-bridged, trinuclear copper(II) compounds with hydroxo and carboxylato bridges, (infinity)(1)[Cu(3)(L1)(2)(mu-OH)(2)(mu-propionato)(2)](1), [Cu(3)(L2)(2)(mu-OH)(2)(mu-propionato)(2)(DMF)(2)] (2) and (infinity)(1){[Cu(3)(L3)(2)(mu-OH)(2)(mu-propionato)(2)]} [Cu(3)(L3)(2)(mu-OH)(2)(mu-propionato)(2)(DMF)(2)]} (3) [HL1=N-(pyrid-2-ylmethyl)benzenesulfonylamide, HL2=N-(pyrid-2-ylmethyl)toluenesulfonylamide, HL3=N-(pyrid-2-ylmethyl)naphthalenesulfonylamide], have been synthesized and characterized. 1 is built from [Cu(3)(L1)(2)(mu-OH)(2)(mu-propionato)(2)] clusters. Each unit contains three copper(II) with two different coordination environments: the terminal centers are square-base pyramidal whereas the central copper is square planar. 2 presents a similar square-base pyramidal geometry in the terminal centers, but the central copper is six-coordinate. 3 shows an unusual 1D coordination polymer comprised of two distinct building blocks: one similar to that found in 1 and the other similar to that found in 2. The magnetic susceptibility measurements (2-300K) reveal a ferromagnetic interaction between the Cu(II) ions with J values of 76.0, 55.0, and 48.0cm(-1) for 1, 2, and 3, respectively. Emission spectroscopy, thermal denaturation, viscosimetry and cyclic voltammetry show an interaction of the complexes with DNA through the sugar-phosphate backbone. All three Cu(II) complexes were found to be very efficient agents of plasmid DNA cleavage in the presence of ascorbato or mercaptopropionic acid. Both the kinetics and the mechanism of the cleavage reaction have also been examined.

Structure, magnetic properties and nuclease activity of pyridine-2-carbaldehyde thiosemicarbazonecopper(II) complexes.

New complexes of formulae [Cu(HL(2))(H(2)O)(NO(3))](NO(3)) (1), [{Cu(L(1))(tfa)}(2)] (2), [{Cu(L(1))}(2)(pz)](ClO(4))(2) (3) and {[{Cu(L(1))}(2)(dca)](ClO(4))}(n) (4), where HL(1)=pyridine-2-carbaldehyde thiosemicarbazone, HL(2)=pyridine-2-carbaldehyde 4N-methylthiosemicarbazone, Htfa=trifluoroacetic acid (CF(3)COOH), pz=pyrazine (C(4)H(4)N(2)) and dca=dicyanamide [N(CN)(2)](-), have been synthesized and characterized. The crystal structures of these compounds are built up of monomers (1), dinuclear entities with the metal centers bridged through the non-thiosemicarbazone coligand (2 and 3) and 1D chains of dimers (4). In all the cases, square-pyramidal copper(II) ions are present, except for the square-planar ones in 3. Magnetic measurements show antiferromagnetic couplings in 2, 3 and 4. The susceptibility data were fitted by the Bleaney-Bowers' equation for copper(II) dimers derived from H=-2JS(1)S(2) being the obtained J/k values -4.8, -4.3 and -5.1K for compounds 2-4, respectively. The magnetic susceptibility of the already known [{Cu(HL(1))(tfa)}(2)](tfa)(2) compound has been also measured for the first time. The J/k value is -0.3K, lower than that in 2. The nuclease activity of 3 and 4 has been analyzed.

Evaluation of antiproliferative activities and apoptosis induction caused by copper(II)-benzothiazolesulfonamide complexes in Jurkat T lymphocytes and Caco-2 cells.

Two copper(II) complexes with a benzothiazolesulfonamide ligand, [Cu(L)2(py)2] (1) and [Cu(en)2(L)2] (2) [HL is N-2-(4-methylbenzothiazole)toluenesulfonamide, py is pyridine, en is ethylenediamine], were prepared and then characterized with the aid of X-ray crystallography and spectroscopy. Whereas the copper(II) ion in 1 presents a square-planar geometry, in 2 it has a distorted octahedral environment. In addition, although the ligand is monodentate in both complexes, it exhibits different coordination behavior in each, interacting through the benzothiazole nitrogen atom in 1 and through the sulfonamide nitrogen atom in 2. The propensity for binding of 1 and 2 to calf thymus DNA was studied by thermal denaturation, viscosimetry, and cyclic voltammetry. The ability of the complexes to cleave DNA was studied in vitro through ascorbate activation and was tested by monitoring the expression of the yEGFP gene containing the RAD54 reporter. Moreover, their antiproliferative activity was verified in two cellular models: yeast and human tumor cells in culture. While 1 was found to be the more active cleaving agent in vitro, 2 showed a higher propensity for inflicting DNA damage at the cellular level. The biological studies carried out with human tumor cells, namely, colon adenocarcinoma Caco-2 cells (HTB-37) and leukemia Jurkat T lymphocytes (TIB-152), confirmed that both compounds inhibit the growth of these cell lines, although 2 is more effective. This difference is associated with the latter compound's greater ability to induce cell death by apoptosis.

Copper-mediated DNA photocleavage by a tetrapyridoacridine (tpac) ligand.

We have focused our interest on the tetrapyridoacridine ligand tetrapyrido[3,2-a:2',3'-c:3'',2''-h: 2''',3'''-j]acridine (tpac), as a model system for the preparation of novel copper-based artificial nucleases. The complex of copper(II)-tpac cleaves supercoiled pUC18 plasmid DNA in an oxidative manner by photoactivation with visible light, exhibiting maximum cleaving efficiency at 1:2 metal-ligand stoichiometric ratio. We propose an interaction of the copper-tpac complex with DNA through both major and minor grooves and a photocleavage mechanism via the formation of hydroxyl radicals and singlet oxygen or singlet oxygen-like species.

A dinuclear copper(II) complex with adeninate bridge ligands and prominent DNA cleavage activity. Structural and spectroscopic characterization and magnetic properties.

A new dinuclear copper(II) complex has been synthesized and structurally characterized: [Cu(mu-ade)(tolSO3)(phen)]2.2H2O (Hade = adenine, tolSO3- = toluenesulfonate anion). Its magnetic properties and electronic paramagnetic resonance (EPR) spectra have been studied in detail. The compound has two metal centers bridged by two adeninate NCN groups. The coordination geometry of the copper(II) ions in the dinuclear entity is distorted square pyramidal, with the four equatorial positions occupied by two phenanthroline N atoms and two N atoms from different adenine molecules. The axial position is occupied by one sulfonate O atom. Magnetic susceptibility data show antiferromagnetic behavior with an estimated exchange constant of -2J = 65 cm-1. The EPR spectrum has been obtained at both X- and Q-band frequencies; a study at different temperatures has been carried out at the latter. Above 20 K, the Q-band spectra are characteristic of S = 1 species with a small zero-field splitting parameter (D = 0.0970 cm-1). A detailed study of the DNA-complex interaction has been performed. The title complex efficiently cleaves the pUC18 plasmid in the presence of reducing agents. Both the kinetics and the mechanism of the cleavage reaction are examined and described herein.

One-dimensional metal-organic framework with unprecedented heptanuclear copper units.

The reaction of copper(II) sulfate, copper(II) chloride, 3,5-diacetylamino-1,2,4-triazole, and 3-acetylamino-5-amino-1,2,4-triazole in water yields green, plate-shaped crystals of [[{Cu3(mu3-OH(1/2))L(H2O)2Cl}2{mu-Cu(H2O)2Cl2}].12H2O]n (1), where L is a new triazole-derived macrocyclic ligand. The structure of 1 consists of heptanuclear (H)OCuII(3)-CuII-CuII(3)O(H) entities linked in pairs through symmetric mu3-O...H...O-mu3 hydrogen bonds to form a double-stranded one-dimensional network. A significant overall antiferromagnetic behavior has been observed for 1.

DNA interaction of new copper(II) complexes with sulfonamides as ligands.

New copper(II) complexes with sulfonamide ligands have been prepared and characterized. Sulfonamide ligands were prepared through a reaction between 8-aminoquinoline and either 2-mesitylene (Hqmesa), 4-tert-butylbenzene (Hqtbsa), or alpha-toluene (Halphaqtsa) sulfonyl chlorides. The structural analysis carried out for complex [Cu(alphaqtsa)(2)] indicated that the local environment of the Cu(II) cation is between a square planar and a tetrahedral geometry, with stacking of the benzene rings of the sulfonyl ligands between neighbor molecules. Powder EPR spectra at room temperature gave rhombic spectra for the [Cu(alphaqtsa)(2)] and [Cu(qmesa)(2)] complexes and an axial spectrum for the [Cu(qtbsa)(2)] complex, probably due to the steric hindrance of the methyl groups. Complexes [Cu(alphaqtsa)(2)] and [Cu(qmesa)(2)] are artificial chemical nucleases that degrade DNA in the presence of sodium ascorbate. A study of the radical scavengers revealed that the ROS (reactive oxygen species) involved in the DNA damage were hydroxyl, singlet oxygen-like species, and superoxide anion.

Oxidative DNA cleavage induced by an iron(III) flavonoid complex: synthesis, crystal structure and characterization of chlorobis(flavonolato)(methanol) iron(III) complex.

A flavonol iron(III) complex, [Fe(flavonolato)(2)Cl(MeOH)], has been prepared. The compound has been characterized by X-ray crystallography, spectroscopy, magnetism and electronic paramagnetic resonance (EPR) at X- and Q-band. The geometrical environment around the metal is best described as rhombic distorted octahedral. This distortion has also been inferred from the magnetic measurements and from the EPR spectra at different temperatures, E/D(rhombicity parameter) approximately 0.06. The DNA cleavage activity of the iron(III) complex with and without ascorbate/hydrogen peroxide is reported. Mechanisms of the oxidative cleavage have been proposed when DNA strand scission is performed both with and without ascorbate/hydrogen peroxide activation.

Comparison of protective effects against reactive oxygen species of mononuclear and dinuclear Cu(II) complexes with N-substituted benzothiazolesulfonamides.

Copper(II) complexes of N-benzothiazolesulfonamides (HL1=N-2-(4-methylphenylsulfamoyl)-6-nitro-benzothiazole, HL2=N-2-(phenylsulfamoyl)-6-chloro-benzothiazole, and HL3=N-2-(4-methylphenylsulfamoyl)-6-chloro-benzothiazole) with ammonia have been synthesized and characterized. The crystal structures of the [Cu(L1)2(NH3)2].2MeOH, [Cu(L2)2(NH3)2], and [Cu(L3)2(NH3)2] compounds have been determined. Compounds and present a distorted square planar geometry. In both compounds the metal ion is coordinated by two benzothiazole N atoms from two sulfonamidate anions and two NH3 molecules. Complex is distorted square-pyramidal. The Cu(II) ion is linked to the benzothiazole N and sulfonamidate O atoms of one of the ligands, the benzothiazole N of another sulfonamidate anion, and two ammonia N atoms. We have tested the superoxide dismutase (SOD)-like activity of the compounds and compared it with that of two dinuclear compounds [Cu2(L4)2(OCH3)2(NH3)2] and [Cu2(L4)2(OCH3)2(dmso)2] (HL4=N-2-(phenylsulfamoyl)-4-methyl-benzothiazole). In vitro indirect assays show that the dimeric complexes are better SOD mimics than the monomeric ones. We have also assayed the protective action provided by the compounds against reactive oxygen species over Deltasod1 mutant of Saccharomyces cerevisiae. In contrast to the in vitro results, the mononuclear compounds were more protective to SOD-deficient S. cerevisiae strains than the dinuclear complexes.

Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring.

BACKGROUND: Data on long-term central nervous system (CNS) toxicity associated with efavirenz therapy are scarce, and risk factors remain largely unknown. We aimed to determine whether monitoring the plasma concentration of efavirenz could predict neuropsychiatric adverse events associated with long-term therapy with efavirenz. METHODS: We performed a longitudinal study involving 17 consecutive human immunodeficiency virus (HIV)-infected subjects with virological suppression after at least 6 months of antiretroviral therapy with an efavirenz-containing regimen. Efavirenz plasma concentrations were measured at study entry and at different time points through an 18-month study period. RESULTS: Median duration of efavirenz therapy before study entry was 18 months (range, 6-27 months). Ten (58.8%) of the patients experienced CNS-related adverse effects, ranging from insomnia and abnormal dreams to depression with suicidal ideation. In 4 (23.5%) of the cases, CNS toxicity led to efavirenz discontinuation. Mean (+/- standard deviation) plasma levels were higher for patients experiencing neuropsychiatric symptoms (5.10 +/- 2.15 microg/mL vs. 2.79 +/- 1.31 microg/mL; P = .024). A plasma level of 2.74 microg/mL had a sensitivity of 90.9% and specificity of 72% to predict CNS toxicity (area under the curve, 0.839; 95% confidence interval, 0.73-0.95; P < .0001). Patients having efavirenz plasma concentrations > 2.74 microg/mL at any time point of the study were 5.68 times more likely to experiencing CNS toxicity than were other patients (95% confidence interval, 1.97-16.37). CONCLUSIONS: In patients with HIV infection receiving long-term therapy with efavirenz-containing antiretroviral regimens, CNS toxicity is related to efavirenz plasma levels. Patients achieving higher plasma levels are at increased risk of experiencing neuropsychiatric adverse events.

Syntheses, crystal structures, and oxidative DNA cleavage of some Cu(II) complexes of 5-amino-3-pyridin-2-yl-1,2,4-triazole.

Three new monomeric Cu(II) complexes of 5-amino-3-pyridin-2-yl-1,2,4-triazole (Hapt), [Cu(Hapt)(H(2)O)(2)(SO(4))] (1), [Cu(Hapt)(2)(H(2)O)(NO(3))](NO(3)) (2), and [Cu(Hapt)(2)(NCS-N)](NCS).H(2)O (3), have been prepared and characterized by single crystal X-ray diffraction. One distorted [CuN(2)O(2)+O(')] square-pyramidal (1), one distorted [CuN(3)O+N(')+O(')] octahedral (2), and one distorted [CuN(4)+N(')] intermediate between square-pyramidal and trigonal-bipyramidal (3) coordination configuration were found and are suggested to be due to the chelating nature of the ligand, which interacts with Cu(II) through the N4(triazole) and N(pyridine) atoms. Spectral properties of these chelates are in accordance with the X-ray structural data. With ascorbate and H(2)O(2) activation, compound 2 exhibits higher nuclease activity than compound 1. The influence on the DNA cleavage process of different scavengers of reactive oxygen species: dimethyl sulfoxide (DMSO), tert-butyl alcohol, sodium azide, 2,2,6,6-tetramethyl-4-piperidone and superoxide dismutase enzyme (SOD), and of the minor groove binder distamycin, is also studied.