Isolation of a Moderately Stable but Sensitive Zwitterionic Diazonium Tetrazolyl-1,2,3-triazolate.

An unexpected formation of a diazonium compound was observed by nitration of an amino substituted triazolyl tetrazole with mixed acid. The crystal structure determination revealed a zwitterionic diazonium tetrazolyl-1,2,3-triazolate, whose constitution was supported by NMR and vibrational spectroscopic analysis. The thermal stability and sensitivity toward impact and friction were determined. In contrast, diazotriazoles are rather unstable and are mainly handled in solution and/or low temperatures, which is not the case for this diazonium tetrazolyl-1,2,3-triazolate, being stable at ambient temperature.

Combining the Advantages of Tetrazoles and 1,2,3-Triazoles: 4,5-Bis(tetrazol-5-yl)-1,2,3-triazole, 4,5-Bis(1-hydroxytetrazol-5-yl)-1,2,3-triazole, and their Energetic Derivatives.

In the development of new energetic materials, the main challenge is the combination of high energy content with chemical and mechanical stability, two properties that are often contradictory. In this study, the syntheses and comprehensive characterizations of 4,5-bis(tetrazole-5-yl)-1,2,3-triazole and the novel 4,5-bis(1-hydroxytetrazole-5-yl)-1,2,3-triazole, as well as their energetic properties, are presented, combining the advantages of the more energetic tetrazole and the more stable 1,2,3-triazole rings. Nitrogen-rich salts of both compounds were synthesized to investigate their detonation performances and combustion behavior calculated by computer codes for potential application in erosion-reduced gun propellant mixtures due to their high nitrogen content. The structures of several of the compounds were studied by single-crystal X-ray diffraction and, especially in the case of 4,5-bis(tetrazol-5-yl)-1,2,3-triazole, revealed the site of deprotonation.

Energetic derivatives of 5-(5-amino-2H-1,2,3-triazol-4-yl)-1H-tetrazole.

This study presents the preparation of the novel nitrogen-rich compound 5-(5-amino-2H-1,2,3-triazol-4-yl)-1H-tetrazole (5) from commercially available chemicals in a five step synthesis. The more energetic derivatives with azido (6) and nitro (7) groups, as well as a diazene bridge (8) were also successfully prepared. The energetic compounds were comprehensively characterized by various means, including vibrational (IR, Raman) and multinuclear ((1)H, (13)C, (14)N, (15)N) NMR spectroscopy, mass spectrometry and differential thermal analysis. The sensitivities towards important outer stimuli (impact, friction, electrostatic discharge) were determined according to BAM standards. The enthalpies of formation were calculated on the CBS-4M level of theory, revealing highly endothermic values, and were utilized to calculate the detonation parameters using EPXLO5 (6.02).

Investigations of the Vicarious C-Aminations of 5,7-Dinitrobenzotriazole and 4,6-Dinitrobenzotriazol-3-ium-1-oxide and Their Energetic Properties.

This combined experimental and theoretical study details the vicarious nucleophilic substitution by amination of 5,7-dinitrobenzotriazol (1) and 4,6-dinitrobenzotriazole-3-ium-1-oxide (4) with trimethylhydrazinium iodide to afford the new corresponding one- and two-time aminated compounds and investigations of its mechanism by EPR spectroscopy. The preferred position for the first amination is computed by spin density population and verified by X-ray crystallography. The zwitterionic structure of 4 is investigated in solution by (1) H NMR spectroscopy and in solid state by X-ray diffraction. Furthermore, the crystal structure of 1 is presented. The energetic behavior of the aminated products as well as the starting materials 1 and 4 was investigated, regarding sensitivities and performance.

Gold(I) carbene complexes causing thioredoxin 1 and thioredoxin 2 oxidation as potential anticancer agents.

Gold(I) complexes with 1,3-substituted imidazole-2-ylidene and benzimidazole-2-ylidene ligands of the type NHC-Au-L (NHC = N-heterocyclic carbene L = Cl or 2-mercapto-pyrimidine) have been synthesized and structurally characterized. The compounds were evaluated for their antiproliferative properties in human ovarian cancer cells sensitive and resistant to cisplatin (A2780S/R), as well in the nontumorigenic human embryonic kidney cell line (HEK-293T), showing in some cases important cytotoxic effects. Some of the complexes were comparatively tested as thioredoxin reductase (TrxR) and glutathione reductase (GR) inhibitors, directly against the purified proteins or in cell extracts. The compounds showed potent and selective TrxR inhibition properties in particular in cancer cell lines. Remarkably, the most effective TrxR inhibitors induced extensive oxidation of thioredoxins (Trxs), which was more relevant in the cancerous cells than in HEK-293T cells. Additional biochemical assays on glutathione systems and reactive oxygen species formation evidenced important differences with respect to the classical cytotoxic Au(I)-phosphine compound auranofin.

Brain derived neurotrophic factor inhibits apoptosis in enteric glia during gut inflammation.

BACKGROUND: Enteric glia cells (EGCs) are essential for the integrity of the bowel. A loss of EGCs leads to a severe inflammation of the intestines. As a diminished EGC network is postulated in Crohn's disease (CD), we aimed to investigate if EGCs could be a target of apoptosis during inflammation in CD, which can be influenced by Brain derived neurotrophic factor (BDNF). MATERIAL/METHODS: GFAP, BDNF and cCaspase-3 were detected in the gut of patients with CD. Primary EGC cultures were established and cultivated. Tyrosine receptor kinase (TrkB) receptors on these cells were investigated by western blot and immunofluorescence. Rate of apoptosis was induced by tumor necrosis factor (TNF-alpha) and interferon (IFN-gamma). Apoptosis was determined by a fluorometric caspase 3/7 activation assay after preincubation of these cells with BDNF or neutralizing anti-BDNF antibodies. RESULTS: Mucosal GFAP-positive EGCs undergo apoptosis revealed by cCaspase-3 in the gut of patients with CD expressing BDNF highly. The combination of TNF-alpha and IFN-gamma was able to induce apoptosis in primary EGCs, whereas these factors alone did not. Brain derived neurotrophic factor (BDNF) attenuate glia cell apoptosis to a small extent, but neutralizing antibodies against BDNF dramatically increased apoptosis. CONCLUSIONS: Mucosal EGC apoptosis is an important finding in the gut of patients with CD. Proinflammatory cytokines, which are highly increased in CD, induce EGC apoptosis, whereas the neurotrophin BDNF might be protective for EGC. Since EGCs are implicated in the maintenance of the enteric mucosal integrity, EGC apoptosis may contribute to the pathophysiological changes in CD.

NOD2 polymorphism predicts response to treatment in Crohn's disease--first steps to a personalized therapy.

BACKGROUND AND AIMS: Great efforts have been made to predict disease behavior over time and the response to treatment in Crohn's disease (CD). Such understanding could personalize therapy. Early introduction of more aggressive therapies to patients at high risk and no introduction of predictable refractory treatments could become possible. We hence tested the influence of the NOD2 carrier status on treatment response. PATIENTS AND METHODS: In 185 CD patients (age 45 ± 9.8 years, female n = 108, minimum disease duration 10 years), the three most common polymorphisms (p.Arg702Trp, p.Gly908Arg, p.Leu1007fsX1008) of NOD2 were tested by polymerase chain reaction and sequencing. Detailed clinical and medical history were obtained with a standardized questionnaire and by reviewing the medical charts. Treatments introduced were chosen by physicians blinded to genotype data. RESULTS: The frequency of the NOD2 variant allele was about one-third (67, 30.2%) of CD patients. NOD2 carriers were more often treated with systemic and locally active steroids and with an immunosuppressant (Azathioprine/6-MP). NOD2 mutation carrier status was more often associated with systemic steroid [8.9% vs. wild-type (WT) 1.2%, P = 0.0086] and local-steroid refractory (14.9% vs. WT 3.5%; P = 0.001). The WT patients were significantly higher refractory to immunosuppressant (12.8% vs. NOD2 carriers, 0.5%, P = 0.03). Most WT patients were treated with TNF-α antagonists and remission rates were significantly higher in this group after 1 year of treatment (84% vs. NOD2 carriers, 33%, P = 0.07). CONCLUSIONS: The study presents first hints for the NOD2 carrier status to be predictive for response to therapy. A higher percentage of CD patients with NOD2 mutation carrier status was steroid refractory but could be treated well with immunosuppressants. The WT status showed a higher response to steroids and remission rates within 1 year of anti-TNF-α therapy. On the way to personalized medicine, this approach should be further investigated in larger studies.

Distribution of enteric glia and GDNF during gut inflammation.

BACKGROUND: The enteric glia network may be involved in the pathogenesis of inflammatory bowel disease (IBD). Enteric glia cells (EGCs) are the major source of glial-derived neurotrophic factor (GDNF), which regulates apoptosis of enterocytes. The aim of the study was to determine the distribution of EGCs and GDNF during gut inflammation and to elucidate a possible diminished enteric glia network in IBD. METHODS: The expression of glial fibrillary acidic protein (GFAP) in colonic biopsies of patients with IBD, controls and patients with infectious colitis was detected by immunohistochemistry and Western blot. Tissue GDNF levels were measured by ELISA. RESULTS: The expression of GFAP and GDNF in the mucosal plexus is highly increased in the inflamed colon of patients with ulcerative colitis (UC) and infectious colitis. Although the GDNF and GFAP content are increased in Crohn's disease (CD), it is significantly less. Additionally the non-inflamed colon of CD patients showed a reduced GFAP and no GDNF expression compared to controls and the non-inflamed colon of UC patients. CONCLUSIONS: GFAP and GDNF as signs of activated EGCs are increased in the inflamed mucosa of patients with UC and infectious colitis, which underline an unspecific role of EGC in the regulation of intestinal inflammation. The reduced GFAP and GDNF content in the colon of CD patients suggest a diminished EGC network in this disease. This might be a part of the pathophysiological puzzle of CD.