Search Results (32)

A series of novel fluorescent donor–acceptor–donor (D-A-D) dyes containing [1,2,5]oxadiazolo[3,4-d]pyridazine and its 1-oxide as electron-withdrawing groups has been synthesized and thoroughly investigated using X-ray diffraction and molecular spectroscopy methods. This study showed that the introduction of N-oxide into the 1,2,5-oxadiazole ring in the acceptor fragment leads to a significant decrease in the luminescence intensity and quantum yield of the dyes. A comprehensive comparison of the photophysical properties of the obtained compounds containing the 1,2,5-oxadiazole ring with the previously studied [1,2,5]thia- and 1,2,5-selenadiazolo[3,4-d]pyridazine analogs showed that the oxygen substitution in the acceptor fragment shifts the phosphorescence maximum from the NIR region of 980–1100 nm to the red region of 690–770 nm. In contrast, for oxygen- and sulfur-containing dyes, purely red fluorescence with a maximum in the spectral range of 620–900 nm is observed. The crystal structures of furoxan-containing 3d·½CHCl₃ and furazan-containing 4d exhibit a non-planar [1,2,5]oxadiazolo[3,4-d]pyridazine fragment. We have found that short non-covalent interactions of the furoxan system with a lattice chloroform molecule in 3d lead to luminescence quenching. Meanwhile, in the 4d dye, the intermolecular π-π interactions of pyridazine nitrogen atoms with the N-carbazolyl group of the adjacent molecule should facilitate intermolecular charge transfer (ICT) emission. Thus, the luminescence maxima for these dyes can be tuned across a broad range of 700–1100 nm by varying the number of chalcogen atoms, highlighting the potential for tailoring optical properties in optoelectronic applications. Full article

In this study, twenty-four new furoxan and seco-coumarin hybrids were synthesized, and their antiproliferative activities against four breast cancer cells (MCF-7/ADR, MCF-7, MDA-MB-231, and MDA-MB-468) were evaluated. Among them, compound 9e exhibited significant toxicity against MCF-7/ADR cells compared to MCF-7 cells, with a 1401-fold increase, indicating its high collateral sensitivity. Meanwhile, 9e exhibited relatively lower toxicity to normal cell lines and improved solubility compared to the previous active compound, 4A93, which features a coumarin integrity core. Preliminary pharmacological studies revealed that 9e might be a potential P-glycoprotein substrate, which enters the lysosomes of MCF-7/ADR to release effective concentrations of nitric oxide, producing reactive oxygen species and inducing apoptosis. Moreover, laser confocal microscopy and Western Blot experiments showed that 9e could induce autophagy in MCF-7/ADR cells. Additionally, the anti-tumor activity of compound 9e could be inhibited by the ferroptosis inhibitor Fer-1. These results suggest that the remarkable antiproliferative potency of these hybrids in MCF-7/ADR may be related to multiple anticancer mechanisms. As a novel nitric oxide donor, compound 9e was used to explore the potential development of an anti-tumor candidate with special pharmacological mechanisms to overcome multidrug resistance in breast cancer. Full article

Background: Nitric oxide (NO) has been linked to the pathogenesis of asbestos-related pleural diseases, including an extremely aggressive cancer called malignant pleural mesothelioma (MPM). Given that MPM cells are characterized by a higher expression of NO synthases and elevated NO production relative to normal cells, the use of NO-donor compounds could potentially saturate the cancerous cells with NO, triggering their death. Methods: We developed a novel class of NO prodrugs by merging two NO-releasing components, 1,2,5-oxadiazole 2-oxides (furoxans) and 1,2,4-oxadiazoles, and studied their NO-releasing characteristics in a time-dependent manner using the Griess assay. The cytotoxicity against two human MPM cell lines and non-cancerous lung fibroblasts was evaluated using a colorimetric MTT assay. Results: All compounds exhibited excellent NO-donating properties, surpassing the capacity of two reference NO donor compounds, 3-carbamoyl-4-(hydroxymethyl)furoxan (CAS-1609) and 4-ethoxy-3-phenylsulphonylfuroxan (CHF-2363), by at least 1.5–3 times. All oxadiazole hybrids demonstrated high cytotoxicity against MPM cell lines in a low micromolar range, comparable or higher than the cytotoxicity of the standard-of-care drug cisplatin. Conclusions: Notably, the novel compounds displayed a markedly greater selectivity towards cancerous cells than cisplatin when compared with non-cancerous lung fibroblasts, aligning with the intended design. Full article

The synthesis and characterization of low-melting-point insensitive energetic materials are crucial due to their increasing applications in melt–cast explosives. In this work, a furazan-derived energetic compound, 3,4-bis[3(2-azidoethoxy)furazan-4-yl]furoxan (DAeTF), exhibiting insensitive and high-energy characteristics, is rationally designed and synthesized. The structure of DAeTF is characterized by nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, elemental analysis, mass spectrometry, and single-crystal X-ray diffraction. The thermal properties of DAeTF are investigated using differential scanning calorimetry, in situ FTIR spectroscopy and thermogravimetric-differential scanning calorimetry–Fourier transform infrared–mass spectrometry and thermal decomposition mechanism was elucidated in combination with bond energy calculations. The detonation performance of DAeTF is predicted by the EXPLO5 program. The results indicate that DAeTF has thermal stability (T_d = 251.7 °C), high energy level (D = 7270 m/s) and significant insensitivity (IS = 60 J). Additionally, its relatively low melting point (T_m = 60.5 °C) facilitates processing and loading. These characteristics indicate that DAeTF is a promising candidate as an insensitive melt–cast explosive in future applications. Full article

3,4-bis(3-nitrofurazan-4-yl) furoxan (DNTF) is an explosive with excellent performance, and the use of DNTF as a high-energy component is of great significance for improving the comprehensive performance of weapons. To explore the effect of DNTF on low-melting-point molten carrier explosives, the compatibility between DNTF and other low-melting-point explosives was analyzed by differential scanning calorimetry, and mechanical sensitivity was tested. The compatibility and cohesive energy density between DNTF and other low-melting-point explosives were calculated by Materials Studio. The results showed that DNTF has good compatibility with most low-melting-point explosives, and the peak temperature change of the mixed system formed by melt-casting is not obvious. Among them, DNTF has the best compatibility with MTNP, TNT, and DNAN; moderate compatibility with DFTNAN and DNP; and the worst compatibility with DNMT. The sensitivity test results indicate that the combination of DNTF and TNT has the most significant reduction in mechanical sensitivity. DFTNAN and MTNP have better stability than DNTF and can generate strong interaction forces with DNTF. Other low-melting-point explosives mixed with DNTF have lower intermolecular forces than DNTF. The DNTF/MTNP system requires the most energy to phase change when heated compared to other mixed systems and is the least sensitive to heat. The DNTF/DNMT system has the lowest cohesive energy density and is the most sensitive to heat. Full article

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C–H functionalization (R–CH₃ to R–CH₂OC(O)R’) and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization. Full article

A facile and efficient method for the regioselective [3 + 2] cycloaddition of 4-azidofuroxans to 1-dimethylamino-2-nitroethylene under p-TSA catalysis affording (4-nitro-1,2,3-triazolyl)furoxans was developed. This transformation is believed to proceed via eliminative azide–olefin cycloaddition resulting in its complete regioselectivity. The developed protocol has a broad substrate scope and enables a straightforward assembly of the 4-nitro-1,2,3-triazole motif. Moreover, synthesized (4-nitro-1,2,3-triazolyl)furoxans were found to be capable of NO release in a broad range of concentrations, thus providing a novel platform for future drug design and related biomedical applications of heterocyclic NO donors. Full article

In response to the problem of the high friction sensitivity of 3,4-bis(3-nitrofurazan-4-yl) furoxan (DNTF) in solid propellants, the inherent component of solid propellants, nitrocellulose (NC), was used to coat DNTF explosives via the water suspension method. The coated samples were characterized by scanning electron microscopy (SEM) and friction sensitivity tests at a fixed 66° swing angle, and molecular dynamics calculations were performed to study the friction sensitivity and desensitization mechanism of NC-based DNTF coatings. The results show that NC, when used as a coating layer, can form a white gel on the surface of DNTF crystals, which can effectively reduce the friction sensitivity of DNTF. The coating effect becomes more obvious as the NC content increases. When the NC content is 5%, the friction sensitivity decreases by 72%, and a prediction formula for the exponential decay of DNTF friction sensitivity is obtained. MD calculation data show that NC can weaken the stiffness, enhance the elastic-plastic properties, increase the ductility and toughness of DNTF materials, and effectively improve the mechanical properties of DNTF. By combining experiments and simulation calculations, while considering the compatibility of new components and changes in propellant energy and other unpredictable new issues, NC can be referred to as a better coating layer for DNTF, as it has a certain feasibility for improving the friction sensitivity of DNTF. Full article

Physiologically, smooth muscle cells (SMC) and nitric oxide (NO) produced by endothelial cells strictly cooperate to maintain vasal homeostasis. In atherosclerosis, where this equilibrium is altered, molecules providing exogenous NO and able to inhibit SMC proliferation may represent valuable antiatherosclerotic agents. Searching for dual antiproliferative and NO-donor molecules, we found that furoxans significantly decreased SMC proliferation in vitro, albeit with different potencies. We therefore assessed whether this property is dependent on their thiol-induced ring opening. Indeed, while furazans (analogues unable to release NO) are not effective, furoxans’ inhibitory potency parallels with the electron-attractor capacity of the group in 3 of the ring, making this effect tunable. To demonstrate whether their specific block on G1-S phase could be NO-dependent, we supplemented SMCs with furoxans and inhibitors of GMP- and/or of the polyamine pathway, which regulate NO-induced SMC proliferation, but they failed in preventing the antiproliferative effect. To find the real mechanism of this property, our proteomics studies revealed that eleven cellular proteins (with SUMO1 being central) and networks involved in cell homeostasis/proliferation are modulated by furoxans, probably by interaction with adducts generated after degradation. Altogether, thanks to their dual effect and pharmacological flexibility, furoxans may be evaluated in the future as antiatherosclerotic molecules. Full article

Three new compounds based on the combination of furoxan (1,2,5-oxadiazole N-oxide) and oxa-[5,5]bicyclic ring were synthesized. Among them, the nitro compound showed satisfactory detonation properties (Dv, 8565 m s⁻¹; P, 31.9 GPa), which is comparable to the performance of RDX (a classic high-energy secondary explosive). Additionally, the introduction of the N-oxide moiety and oxidation of the amino group more effectively improved the oxygen balance and density (d, 1.81 g cm⁻³; OB%, +2.8%) of the compounds compared to furazan analogues. Combined with good density and oxygen balance as well as moderate sensitivity, this type of furoxan and oxa-[5,5]bicyclic structure will open up a platform for the synthesis and design of new high-energy materials. Full article

A new series of nitric oxide-releasing estra-1,3,5,16-tetraene analogs (NO-∆-16-CIEAs) was designed and synthesized as dual inhibitors for EGFR and MRP2 based on our previous findings on estra-1,3,5-triene analog NO-CIEA 17 against both HepG2 and HepG2-R cell lines. Among the target compounds, 14a (R-isomer) and 14b (S-isomer) displayed potent anti-proliferative activity against both HepG2 and HepG2-R cell lines in comparison to the reference drug erlotinib. Remarkably, compound 14a resulted in a prominent reduction in EGFR phosphorylation at a concentration of 1.20 µM with slight activity on the phosphorylation of MEK1/2 and ERK1/2. It also inhibits MRP2 expression in a dose-dependent manner with 24% inhibition and arrested the cells in the S phase of the cell cycle. Interestingly, compound 14a (estratetraene core) exhibited a twofold increase in anti-proliferative activity against both HepG2 and HepG2-R in comparison with the lead estratriene analog, demonstrating the significance of the designed ∆-16 unsaturation. The results shed a light on compound 14a and support further investigations to combat multidrug resistance in chemotherapy of hepatocellular carcinoma patients. Full article

1,2,5-Oxadiazole oxides (furoxans) are well known nitric oxide donors; among them, 4-fluorofuroxans have recently been found to be important photoinduced nitric oxide donors. In this research, it was shown that the reaction of 4,4′-dinitro-[3,3′-bi(1,2,5-oxadiazole)] 2,2′-dioxide with fluoro-containing reagents (tetrabutylammonium fluoride or cesium fluoride) selectively gave the bis-substitution product 4,4′-difluoro-[3,3′-bi(1,2,5-oxadiazole)] 2,2′-dioxide. The structure of the synthesized compound was established by elemental analysis, ¹³C, ¹⁹F-NMR and IR spectroscopy, and mass-spectrometry. Full article

The external electric field (E-field), which is an important stimulus, can change the decomposition mechanism and sensitivity of energetic materials. As a result, understanding the response of energetic materials to external E-fields is critical for their safe use. Motivated by recent experiments and theories, the two-dimensional infrared (2D IR) spectra of 3,4-bis (3-nitrofurazan-4-yl) furoxan (DNTF), which has a high energy, a low melting point, and comprehensive properties, were theoretically investigated. Cross-peaks were observed in 2D IR spectra under different E-fields, which demonstrated an intermolecular vibration energy transfer; the furazan ring vibration was found to play an important role in the analysis of vibration energy distribution and was extended over several DNTF molecules. Measurements of the non-covalent interactions, with the support of the 2D IR spectra, indicated that there were obvious non-covalent interactions among different DNTF molecules, which resulted from the conjugation of the furoxan ring and the furazan ring; the direction of the E-field also had a significant influence on the strength of the weak interactions. Furthermore, the calculation of the Laplacian bond order, which characterized the C-NO₂ bonds as trigger bonds, predicted that the E-fields could change the thermal decomposition process of DNTF while the positive E-field facilitates the breakdown of the C-NO₂ in DNTFⅣ molecules. Our work provides new insights into the relationship between the E-field and the intermolecular vibration energy transfer and decomposition mechanism of the DNTF system. Full article

To investigate the crystallization of DNTF in modified double-base propellants, glycidyl azide polymer (GAP) was used as the coating material for the in situ coating of DNTF, and the performance of the coating was investigated to inhibit the crystallization. The results show that GAP can form a white gel on the surface of DNTF crystals and has a good coating effect which can significantly reduce the impact sensitivity and friction sensitivity of DNTF. Molecular dynamics was used to construct a bilayer interface model of GAP and DNTF with different growth crystal surfaces, and Molecular dynamics calculations of the binding energy and mechanical properties of the composite system were carried out. The results showed that GAP could effectively improve the mechanical properties of DNTF. The values of K/G, γ and ν are higher than those of DNTF crystals, and the values of C₁₂-C₄₄ are positive, indicating that GAP can improve DNTF ductility while also improving toughness. Combining the experimental results with the simulation calculations, energetic binder GAP can be referred to as a better cladding layer for DNTF, which is feasible for inhibiting the DNTF crystallization problem in propellants. Full article

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01–1.0 μg/mL. The free drug fraction (f_u) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (C_max) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development. Full article