tellurium and diphenylditelluride

Tellurium is a rare element that has been regarded as a toxic, nonessential element, and its biological role is not clearly established. In addition, the biological effects of elemental tellurium and some of its organic and inorganic derivatives have been studied, leading to a set of interesting and promising applications. Diphenyl ditelluride (DPDT), an organic tellurium derivate, showed antioxidant, antigenotoxic, antimutagenic, and anticancer properties. The antioxidant and prooxidant properties of DPDT are complex and depend on experimental conditions, which may explain the contradictory reports of these properties. In addition, DPDT may exert its effects through different pathways, including distinct ones to those responsible for chemotherapy resistance phenotypes: transcription factors, membrane receptors, adhesion, structural molecules, cell cycle regulatory components, and apoptosis pathways. This review aims to present recent advances in our understanding of the biological effects, therapeutic potential, and safety of DPDT treatment. Moreover, original results demonstrating the cytotoxic effects of DPDT in different mammalian cell lines and systems biology analysis are included, and emerging approaches for possible future applications are inferred.

Topics: Antioxidants; Benzene Derivatives; Humans; Organometallic Compounds; Oxidation-Reduction; Tellurium

Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution.

Topics: Animals; Benzene Derivatives; Cattle; Cell Line; Cell Survival; Cells, Cultured; Endothelial Cells; Epithelial Cells; Fibroblasts; Humans; LLC-PK1 Cells; Models, Chemical; Molecular Structure; Myocytes, Smooth Muscle; Organometallic Compounds; Organoselenium Compounds; Swine; Tellurium

The interest in diphenyl ditelluride (Ph₂Te₂) is related to its strict analogy to diphenyl diselenide (Ph₂Se₂), whose capacity to reduce organic peroxides is largely exploited in catalysis and green chemistry. Since the latter is also a promising candidate as an antioxidant drug and mimic of the ubiquitous enzyme glutathione peroxidase (GPx), the use of organotellurides in medicinal chemistry is gaining importance, despite the fact that tellurium has no recognized biological role and its toxicity must be cautiously pondered. Both Ph₂Se₂ and Ph₂Te₂ exhibit significant conformational freedom due to the softness of the inter-chalcogen and carbon⁻chalcogen bonds, preventing the existence of a unique structure in solution. Therefore, the accurate calculation of the NMR chemical shifts of these flexible molecules is not trivial. In this study, a detailed structural analysis of Ph₂Te₂ is carried out using a computational approach combining classical molecular dynamics and relativistic density functional theory methods. The goal is to establish how structural changes affect the electronic structure of diphenyl ditelluride, particularly the

Topics: Benzene Derivatives; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Dynamics Simulation; Organometallic Compounds; Organoselenium Compounds; Quantum Theory; Structure-Activity Relationship; Tellurium; Thermodynamics

Diphenyl ditelluride (DPDT) and tellurium tetrachloride (TeCl(4)) were evaluated for toxicity in transformed (HT-29, Caco-2) and non-transformed colon cells (CCD-18Co). Significant decreases in viability were observed with DPDT exposure in HT-29 (62.5-1000 μM), Caco-2 (31.25-1000 μM) and CCD-18Co cells (500-1000 μM) and with TeCl(4) in HT-29 (31.25-1000 μM), Caco-2 (31.25-1000 μM) and CCD-18Co cells (500-1000 μM). Light microscopy confirmed viability analysis. Significant increases in caspase 3/7 and 9 activity were observed with DPDT in HT-29 (500-1000 μM) and CCD-18Co cells (1000 μM) indicating apoptosis. No significant increases in caspases were seen with TeCl(4) indicating necrosis. Apoptosis or necrosis was confirmed with fluorescent staining (FITC-Annexin, Hoechst 33342 and Ethidium Homodimer). Significant decreases in GSH/GSSG ratio were observed with DPDT in HT-29 (62.5-1000 μM), and CCD-18Co cells (1000 μM) and with TeCl(4) in HT-29 (62.5-1000 μM) and CCD-18Co cells (250-1000 μM). We concluded that cells treated with DPDT resulted in apoptosis and TeCl(4) treatment in necrosis. GSH/GSSG ratio shifts indicate oxidative mechanisms are involved.

Topics: Benzene Derivatives; Caco-2 Cells; Caspases; Cell Transformation, Neoplastic; Hazardous Substances; HT29 Cells; Humans; Organometallic Compounds; Tellurium

Tellurium tetrachloride (TeCl(4)) and diphenyl ditelluride (DPDT) cytotoxicity, was investigated in rat astrocytes. Concentrations of 0.24-250μM (24h) were tested for viability using MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) and trypan blue exclusion. MTT showed significant decreases at all concentrations tested for both compounds. Significant decreases in viability were seen in 1.95-250μM of DPDT and 0.97-250μM of TeCl(4) with trypan blue exclusion. The LC(50) for both compounds was 62.5μM. Light and scanning microscopy confirm toxicity observed at higher concentrations. Thiobarbituric acid reactive substances (TBARs) assay, TUNEL, cytochrome c and caspase release were carried out. No significant increase in TBARS with either agent was observed (15.625-62.5μM). TUNEL and cytochrome c assays demonstrated apoptosis in TeCl(4) treated cells (31.25-125μM). Non-apoptotic cells were observed in DPDT treated cells. Studies of caspase 3/7 and caspase 9 indicated increased activity in TeCl(4) but not in DPDT treated cells. Optical Emission Spectroscopy of DPDT and TeCl(4) treated cells demonstrated significant accumulation of elemental tellurium in all treatment groups (31.25-125μM). We conclude that DPDT and TeCl(4) are cytotoxic to astrocytes. TeCl(4) treated cells die via the intrinsic apoptotic pathway. Accumulation of tellurium occurs with both compounds, but results in different mechanisms of cell death.

Topics: Animals; Astrocytes; Benzene Derivatives; Caspases; Cell Survival; Cytochromes c; Formazans; Hippocampus; Microscopy, Electron, Scanning; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Tellurium; Tetrazolium Salts; Thiobarbituric Acid Reactive Substances

The relationship of acidosis and lipid peroxidation in liver homogenate was studied and the effect of pH on the antioxidant potential of diphenyl ditelluride is reported. Low pH increased the rate of lipid peroxidation both in the absence and presence of Fe (II), while diphenyl ditelluride (DPDT) inhibited the rate of lipid peroxidation in a concentration-dependent manner at all studied pH values. However, the change in pH did not alter the antioxidant activity of the compound. This study shows acidosis catalyzed oxidative stress in liver homogenate and the antioxidant potential of diphenyl ditelluride.

Topics: Acidosis; Animals; Antioxidants; Benzene Derivatives; Free Radical Scavengers; Hydrogen-Ion Concentration; Kinetics; Lipid Peroxidation; Liver; Male; Microsomes, Liver; Organometallic Compounds; Oxidative Stress; Rats; Rats, Wistar; Sulfhydryl Compounds; Tellurium

It is well established that diphenyl ditelluride, (PhTe)(2), is a potent teratogen in rats, however, little is known about its effects on embryo/fetal development in mice. The present study was undertaken to investigate whether any differences exist on embryo/fetal development of mice exposed to (PhTe)(2) during distinctive periods of gestation compared to rats. Dams were treated subcutaneously (s.c.) with 0.12 or 60.0 mg/kg (PhTe)(2) on gestational day (GD) 4, 8 or 14. Cesarean section was performed on GD18 and external and skeletal alterations were examined. The lower dose did not affect any parameter evaluated in mouse fetuses. The maternal body weight for 60 mg/kg (PhTe)(2) groups, at all periods studied, was not affected. Maternal liver and spleen weights were increased at GD8. At GD14, maternal relative weight of kidney was also increased. A significant reduction in the number of implantation sites at GD4 was found. At GD4 and GD14, there was a reduction in the fetal weight and biometry. A few signs of reduced ossification in sternebrae and limbs were observed at GD14 in (PhTe)(2) group. In conclusion, (PhTe)(2) was not toxic to dams and affected some fetal endpoints only at the dose about 500-fold higher than the dose that was teratogenic in rats, suggesting a different developmental toxicity induced by (PhTe)(2) among species. Thus, the mice were less susceptible to toxic effects induced by (PhTe)(2) than were rats.

Topics: Animals; Benzene Derivatives; Bone and Bones; Dose-Response Relationship, Drug; Embryo Implantation; Embryonic Development; Female; Fetal Development; Fetal Weight; Injections, Subcutaneous; Liver; Maternal Exposure; Mice; Organ Size; Organometallic Compounds; Osteogenesis; Pregnancy; Species Specificity; Spleen; Tellurium; Teratogens; Time Factors

In this study, we evaluated the effects of three simple organochalcogenides (diphenyl diselenide, diphenyl ditelluride and diphenyl telluride) and ebselen on the glutamate-driven 45Ca2+ influx into chick embryonic retinal cells, as well as their effects on the excitotoxic injury in retina cells. None of the compounds tested interfered with basal 45Ca2+ uptake. Diphenyl diselenide and diphenyl ditelluride had no effects on glutamate-driven 45Ca2+ influx. Diphenyl telluride (100-400 microM) decreased and ebselen (100-400 microM) completely blocked the glutamate-driven 45Ca2+ influx (P < 0.01) into chick retinal explants. The assessment of neural injury was made spectrophotometrically by quantification of cellularly reduced MTT (3(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) 24 h after the beginning of glutamate exposure (8 h). Ebselen had no effects on retinal MTT reduction when co-incubated with glutamate for 8 h. However, when ebselen (100 and 400 microM) was co-incubated for 8 h with glutamate and remained in the incubation media until MTT evaluation (24 h after the beginning of incubation), it protected retinal cells against the decrease in MTT reduction induced by glutamate. These data indicate that besides its capacity of interacting with Ca2+ channels, other mechanisms are involved in the neuroprotection afforded by ebselen in this work, possibly its antioxidant properties.

Topics: Animals; Azoles; Benzene Derivatives; Calcium; Calcium Channels; Chalcogens; Chick Embryo; Dose-Response Relationship, Drug; Glutamic Acid; Isoindoles; Nerve Degeneration; Neurons; Neuroprotective Agents; Neurotoxins; Organometallic Compounds; Organoselenium Compounds; Retina; Tellurium; Tetrazolium Salts; Thiazoles

Despite the growing use of organotellurium compounds in the chemical and biomedical fields, there has been no great concern about their toxicity until now. To test the possibility that diphenyl ditelluride (DPDT) and tellurium chloride (TeCl2), organic and inorganic tellurium compounds, may exert adverse action on mammals, their effects on rat thymocytes were examined under in vitro conditions using a flow cytometer with fluorescent probes. Incubation of thymocytes with DPDT at 300 nM or more for 24 h significantly increased the populations of shrunken cells and of cells with hypodiploidal DNA. Z-VAD-FMK, a paninhibitor of caspases, greatly suppressed the DPDT-induced increase in the hypodiploidal cell population, suggesting the involvement of caspase activation in DPDT toxicity. Hence, it is possible that DPDT would increase the population of thymocytes undergoing apoptosis if the blood concentration in mammals reached at least 300 nM or more. TeCl2 was much less potent than DPDT in increasing the population of hypodiploidal cells.

Topics: Animals; Apoptosis; Benzene Derivatives; Cell Culture Techniques; Cell Size; Dose-Response Relationship, Drug; Flow Cytometry; Male; Organometallic Compounds; Rats; Rats, Wistar; Tellurium; Thymus Gland

The increasing use of tellurium compounds in organic synthesis, industrial applications, and as a possible component in pesticides means that its introduction into the environment will increase in the future. Therefore, knowledge of the relative toxicity and mode of toxic action of tellurium-containing compounds is important. The studies detailed here used three model compounds: diphenyl ditelluride, 3,3'-diaminodiphenyl ditelluride, and 4,4'-diisopropyldiphenyl ditelluride. Experiments with human promyelocytic (line HL-60) cells indicate that all of the organotellurium compounds induce an apoptotic form of cell death. The induction of apoptosis occurs in a time- and dose-dependent manner as assayed by three different analytical methods: fluorescence microscopy, gel electrophoresis, and flow cytometry. Apoptotic cells were evident as early as 2 h following treatment with 1x10(-6) M concentrations of the compounds. Based on these results, future care should be afforded these compounds in laboratory as well as industrial settings.

Topics: Apoptosis; Benzene Derivatives; DNA; DNA Fragmentation; Dose-Response Relationship, Drug; Electrophoresis, Agar Gel; Flow Cytometry; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Organometallic Compounds; Tellurium

The aim of this study was to investigate the possible involvement of the glutamatergic system in the toxicity of organochalcogens, since this is an important neurotransmitter system for signal transduction and neural function. The results indicated that 100 microM diphenyl diselenide (PhSe)(2) and diphenyl ditelluride (PhTe)(2) inhibit by 50 and 70% (P<0.05), respectively, [(3)H]glutamate binding in vitro. Acute administration of 25 micromol/kg (PhSe)(2) or 3 micromol/kg (PhTe)(2) caused a significant reduction in [(3)H]glutamate (30%, P<0.05) or [(3)H]MK-801 binding (30%, P<0.05) to rat synaptic membranes. These results suggest that (PhSe)(2) and (PhTe)(2) affect, in a rather complex way, the glutamatergic system after acute in vivo exposure in rats. In vitro, total [(3)H]GMP-PNP binding was inhibited about 40% at 100 microM (PhSe)(2) and (PhTe)(2). Acute exposure in vivo to (PhSe)(2) decreased the stable [(3)H]GMP-PNP binding to 25% and (PhTe)(2) to 68% of the control value (P<0.05, for both compounds). Simultaneously, the unstable binding of [(3)H]GMP-PNP was decreased about 30 and 50% (P<0.05, for both compounds) after exposure to (PhSe)(2) and (PhTe)(2), respectively. GMP-PNP stimulated adenylate cyclase (AC) activity significantly in control animals. (PhSe)(2)- and (PhTe)(2)-treated animals increased the basal activity of this enzyme, but GMP-PNP stimulation was totally abolished. These results suggest that the toxic effects of organochalcogens could result from action at different levels of neural signal transduction pathways, possibly involving other neurotransmitters besides the glutamatergic system.

Topics: Animals; Benzene Derivatives; Binding, Competitive; Brain; Dithiothreitol; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanylyl Imidodiphosphate; Male; Neurotoxins; Organometallic Compounds; Organoselenium Compounds; Presynaptic Terminals; Rats; Rats, Wistar; Subcellular Fractions; Synaptic Membranes; Synaptic Transmission; Tellurium; Tritium