Diphenyl Diselenide Through Reduction of Inflammation, Oxidative Injury and Caspase-3 Activation Abates Doxorubicin-Induced Neurotoxicity in Rats.

Neurotoxicity associated with chemotherapy is a debilitating side effect of cancer management in humans which reportedly involves inflammatory and oxidative stress responses. Diphenyl diselenide (DPDS) is an organoselenium compound which exhibits its anti-tumoral, anti-oxidant, anti-inflammatory and anti-mutagenic effects. Nevertheless, its possible effect on chemotherapy-induced neurotoxicity is not known. Using rat model, we probed the behavioral and biochemical effects accompanying administration of antineoplastic agent doxorubicin (7.5 mg/kg) and DPDS (5 and 10 mg/kg). Anxiogenic-like behavior, motor and locomotor insufficiencies associated with doxorubicin were considerably abated by both DPDS doses with concomitant enhancement in exploratory behavior as demonstrated by reduced heat maps intensity and enhanced track plot densities. Moreover, with exception of cerebral glutathione (GSH) level, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, biochemical data demonstrated reversal of doxorubicin-mediated decline in cerebral and cerebellar antioxidant status indices and the increase in acetylcholinesterase (AChE) activity by both doses of DPDS. Also, cerebellar and cerebral lipid peroxidation, hydrogen peroxide as well as reactive oxygen and nitrogen species levels were considerably diminished in rats administered doxorubicin and DPDS. In addition, DPDS administration abated myeloperoxidase activity, tumour necrosis factor alpha and nitric oxide levels along with caspase-3 activity in doxorubicin-administered rats. Chemoprotection of doxorubicin-associated neurotoxicity by DPDS was further validated by histomorphometry and histochemical staining. Taken together, DPDS through offsetting of oxido-inflammatory stress and caspase-3 activation elicited neuroprotection in doxorubicin-treated rats.

Biological Evaluation of Isosteric Applicability of 1,3-Substituted Cuneanes as m-Substituted Benzenes Enabled by Selective Isomerization of 1,4-Substituted Cubanes.

We herein evaluate a biological applicability of 1,3-substituted cuneanes as an isostere of m-substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3-substituted cuneanes by selective isomerization of 1,4-substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m-substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry.

Indene, indane and naphthalene in a mixture with BTEX affect aerobic compound biodegradation kinetics and indigenous microbial community development.

BTEX (benzene, toluene, ethylbenzene, xylene) are common pollutants often found in former gasworks sites together with some other contaminants like indene, indane and naphthalene (Ie, Ia, N). This study aimed to evaluate the inhibitory or stimulative substrate interactions between BTEX, and Ie, Ia, N during aerobic biodegradation. For this, batch bottles, containing originally anaerobic subsurface sediments, groundwater and indigenous microorganisms from a contaminated former gasworks site, were spiked with various substrate combinations (BTEX, BTEXIe, BTEXIa, BTEXN, BTEXIeIa, BTEXIeN, BTEXIaN, BTEXIeIaN). Subsequently concentrations were monitored over time. For the BTEXIeIaN mixture, initial concentrations were between 1 and 5 mg L-1, and all compounds were completely degraded by the microbial consortia within 39 days of incubation. The experimental data were fitted to a first order kinetic degradation model for interpretation of inhibition/stimulation between the compounds. Results showed that indene, indane, and naphthalene inhibited the degradation of benzene, toluene, ethylbenzene, o-xylene, with benzene being the most affected. M/p-xylene is the only compound whose biodegradation is stimulated by the presence of indene and indane (individually or mixed) but inhibited by the presence of naphthalene. 16S rRNA amplicon sequencing revealed differentiation in the microbial communities within the batches with different substrate mixtures, especially within the two microbial groups Micrococcaceae and Commamonaceae. Indene had more effect on the BTEX microbial community than indane or naphthalene and the presence of indene increased the relative abundance of Micrococcaceae family. In conclusion, co-presence of various pollutants leads to differentiation in degradation processes as well as in microbial community development. This sheds some light on the underlying reasons for that organic compounds present in mixtures in the subsurface of former gasworks sites are either recalcitrant or subjective towards biodegradation, and this understanding helps to further improve the bioremediation of such sites.

Reactions of 1,2-Azaborinine, a BN-Benzyne, with Organic π Systems.

Ortho-benzyne and 1,2-azaborinine are related by the formal exchange of the CC triple bond by the isoelectronic BN unit. The (2 + 2) and (2 + 4) cycloaddition reactions of 1,2-azaborinine with the different organic π systems (ethene, ethyne, 1,3-butadiene, 1,3-cyclopentadiene, furan, benzene) were examined computationally using density functional, second-order perturbation, and coupled-cluster methods. All reactions of 1,2-azaborinine with the studied substrates are highly exothermic and involve the formation of Lewis acid-base complexes of 1,2-azaborinine and respective π systems. The interaction between the π bond of the substrates and the empty p orbital of the boron atom in these complexes is remarkably strong, resulting in two-step mechanisms for the (2 + 2) and (2 + 4) cycloaddition reactions. Cycloaddition reactions have lower barriers than CH insertion reactions, and (2 + 4) reactions are favored over (2 + 2) cycloadditions.

Performance and Mechanism of Chlorine Dioxide on BTEX Removal in Liquid and Indoor Air.

With the development of the chemical industry, benzene, toluene, ethylbenzene, and xylene (BTEX) have gradually become the major indoor air pollutants. Various gas treatment techniques are widely used to prevent the physical and mental health hazards of BTEX in semi-enclosed spaces. Chlorine dioxide (ClO2) is an alternative to chlorine as a secondary disinfectant with a strong oxidation ability, a wide range of action, and no carcinogenic effects. In addition, ClO2 has a unique permeability which allows it to eliminate volatile contaminants from the source. However, little attention has been paid to the removal of BTEX by ClO2, due to the difficulty of removing BTEX in semi-enclosed areas and the lack of testing methods for the reaction intermediates. Therefore, this study explored the performance of ClO2 advanced oxidation technology on both liquid and gaseous benzene, toluene, o-xylene, and m-xylene. The results showed that ClO2 was efficient in the removal of BTEX. The byproducts were detected by gas chromatography-mass spectrometry (GC-MS) and the reaction mechanism was speculated using the ab initio molecular orbital calculations method. The results demonstrated that ClO2 could remove the BTEX from the water and the air without causing secondary pollution.

Direct Arylation of Silicon Nanocrystals with Hexadehydro-Diels-Alder-Derived Benzynes.

Colloidal silicon nanocrystals (SiNCs) have garnered significant interest in optoelectronics and biomedical applications. Direct arylation provides pathways to enhance the solution processability of particles and manipulate the photophysical and electronic properties of SiNCs. Unfortunately, existing methods employed to prepare aryl-functionalized SiNCs are based on organometallic coupling or transition-metal-catalyzed strategies, which require metal-based reagents for preactivation or the precursors and complicated post-treatment processes for product purification. Herein, we demonstrate a metal-free method that directly functionalizes SiNCs with aryl-based ligands. We design a series of benzyne derivatives formed from the thermal cyclization of predesigned alkynes, allowing efficient arylation on hydride-terminated silicon surfaces under mild conditions. These aryl-functionalized SiNCs exhibit strong blue emissions with nanosecond-scaled decay, suggesting the formation of a new radiative recombination channel on SiNC surfaces.

Development of reliable quantitative structure-toxicity relationship models for toxicity prediction of benzene derivatives using semiempirical descriptors.

The Health and environmental hazards of benzene and nitrobenzene (NB) derivatives have remained a topic of interest of researchers. In silico methods for prediction of toxicity of chemicals have proved their worth in accurate forecast of environmental as well as health toxicity and are strongly recommended by regulatory authorities. Two quantitative structure-toxicity relationship (QSTR) models explaining Scenedesmus obliquus toxicity trends among 39 benzene derivatives and Tetrahymena pyriformis toxicity of 103 NB and 392 benzene derivatives are developed using semiempirical quantum chemical parameters. The best constructed QSTR models have good fitting ability (R2 = 0.8053, 0.7591, and 0.8283) and robustness (Q2LOO = 0.7507, 0.7227, and 0.8194; Q2LMO = 0.7338, 0.7153, and 0.8172). The external predictivity of all the models are quite good (R2EXT = 0.8256, 0.9349, and 0.8698). Electronegativity, Cosmo volume, total energy, and molecular weight are responsible for the increase and decrease of toxicity of benzene derivatives against S. obliquus while electronegativity, electrophilicity index, the heat of formation, total energy, hydrophobicity, and cosmo volume are responsible for modulation of toxicity of NB and benzene derivatives toward T. pyriformis. These models fulfill the requirements of all the five OECD principles.

Benzenesulfonamides Incorporating Hydantoin Moieties Effectively Inhibit Eukaryoticand Human Carbonic Anhydrases.

A series of novel 1-(4-benzenesulfonamide)-3-alkyl/benzyl-hydantoin derivatives were synthesized and evaluated for the inhibition of eukaryotic and human carbonic anhydrases (CAs, EC 4.2.1.1). The prepared compounds were screened for their hCA inhibitory activities against three cytosolic isoforms as well as two ß-CAs from fungal pathogens. The best inhibition was observed against hCA II and VII as well as Candida glabrata enzyme CgNce103. hCA I and Malassezia globosa MgCA enzymes were, on the other hand, less effectively inhibited by these compounds. The inhibitory potency of these compounds against CAs was found to be dependent on the electronic and steric effects of substituent groups on the N3-position of the hydantoin ring, which included alkyl, alkenyl and substituted benzyl moieties. The interesting results against CgNce103 make the compounds of interest for investigations in vivo as potential antifungals.

Simple and rapid electrochemical monitoring for depolymerization of polyamic acid.

Excellent thermal and mechanical properties of aromatic polyimides (PIs) make them attractive materials in various fields. PIs is performed using polyamic acid (PAA) precursors due to their limited solubility. However, PAAs can be easily depolymerized by moisture and heat, which can degrade the properties of PIs. Therefore, quality control of PAAs is an important task in researches and industrial applications. Here, we propose a simple, rapid, and novel method to observe the depolymerization of PAAs. The method is based on the principle that, as the molecular weight of the polymer decreases, the solution viscosity decreases, and the viscosity of the solution can be easily and rapidly measured using electrochemistry. We accelerated depolymerization by applying heat to a PAA solution and measured the change in viscosity of the solution through cyclic voltammetry. The proposed method, which also makes it possible to determine the dynamic viscosity of a polymer solution, is presented as a model system to observe state changes in various polymers.

Synthesis and Luminescent Properties of s-Tetrazine Derivatives Conjugated with the 4H-1,2,4-Triazole Ring.

New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined.

Empirical Guidelines for the Development of Remote Directing Templates through Quantitative and Experimental Analyses.

The ability to differentiate and selectively activate remote C-H bonds represents a perennial challenge in the field of C-H activation. Since its first report in 2012, a now-established "directing template" (DT) approach remains demonstrably effective for the functionalization of remote C-H bonds. As selectivity is hypothesized to be principally determined by the optimal positioning of the reactive catalyst to a target C-H bond, a DT's spatial factors are particularly important toward achieving high selectivity, though a systematic study on its requisite factors remain unelucidated. Through an in-depth analysis of 119 structurally unique published remote DTs, this report summarizes the key factors that are central toward achieving high selectivity at defined aryl positions, which are experimentally corroborated through the development of new aliphatic meta and para-selective DTs for electronically unbiased arenes. These empirical rules, which summarize key distance and geometric factors, are expected to be useful tools for the future development of site-selective arene C-H activation as well as other reactions that rely on covalent/noncovalent DT-mediated remote regioselection.

Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Modification of the benzenoid part.

Bacterial resistance to currently used antibiotics demands the development of novel antibacterial agents with good safety margins and sufficient efficacy against multi-drug resistant isolates. We have previously described the synthesis of N-butyl-2-(butylthio)quinazolin-4-amine (I) as an optimized hit with broad-spectrum antibacterial activity and low cytotoxicity. In addition, we have identified a potential growing vector for this series of compounds. Herein, we describe further hit optimization which includes systematic diversifications of both the benzenoid part and the substituents at position 6 and 7 of compound I. Growing of the molecule beside the core modifications yielded several compounds with remarkable anti(myco)bacterial activity against a panel of pathogenic bacteria, including drug-resistant strains. Compound 12 showed a 2-4 fold improvement in activity than I against S. aureus Newman, S. pneumoniae DSM-20566 and E. faecalis DSM-20478. The compounds also showed a good safety profile towards human HepG2 cells.

Isonitrile induced bioorthogonal activation of fluorophores and mutually orthogonal cleavage in live cells.

Fluorophores with different emission wavelengths were efficiently quenched by a tert-butyl terminated tetrazylmethyl group and activated by an isonitrile-tetrazine click-to-release reaction. Nucleic acid templated chemistry significantly accelerated this bioorthogonal cleavage. Moreover, two mutually orthogonal fluorogenic cleavage reactions were simultaneously conducted in live cells for the first time.

Construction and activity evaluation of novel benzodioxane derivatives as dual-target antifungal inhibitors.

Ergosterol exert the important function in maintaining the fluidity and osmotic pressure of fungal cells, and its key biosynthesis enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) displayed the obvious synergistic effects. Therefore, we expected to discover the novel antifungal compounds with dual-target (SE/CYP51) inhibitory activity. In the progress, we screened the different kinds of potent fragments based on the dual-target (CYP51, SE) features, and the method of fragment-based drug discovery (FBDD) was used to guide the construction of three different series of benzodioxane compounds. Subsequently, their chemical structures were synthesized and evaluated. These compounds displayed the obvious biological activity against the pathogenic fungal strains. Notably, target compounds 10a-2 and 22a-2 possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125-2.0 µg/mL) and the activity against drug-resistant strains (MIC50, 0.5-2.0 µg/mL). Preliminary mechanism studies have confirmed that these compounds effectively inhibited the dual-target (SE/CYP51) activity, they could cause fungal rupture and death by blocking the bio-synthetic pathway of ergosterol. Further experiments discovered that compounds 10a-2 and 22a-2 also maintained a certain of anti-fungal effect in vivo. In summary, this study not only provided the new dual-target drug design strategy and method, but also discover the potential antifungal compounds.

Optimization of asymmetric reduction conditions of 1-(benzo [d] [1,3] dioxol-5-yl) ethanone by Lactobacillus fermentum P1 using D-optimal experimental design-based model.

The biocatalytic asymmetric reduction of prochiral ketones is a significant transformation in organic chemistry as chiral carbinols are biologically active molecules and may be used as precursors of many drugs. In this study, the bioreduction of 1-(benzo [d] [1,3] dioxol-5-yl) ethanone for the production of enantiomerically pure (S)-1-(1,3-benzodioxal-5-yl) ethanol was investigated using freeze-dried whole-cell of Lactobacillus fermentum P1 and the reduction conditions was optimized with a D-optimal experimental design-based optimization methodology. This is the first study using this optimization methodology in a biocatalytic asymmetric reduction. Using D-optimal experimental design-based optimization, optimum reaction conditions were predicted as pH 6.20, temperature 30 °C, incubation time 30 h, and agitation speed 193 rpm. For these operating conditions, it was estimated that the product could be obtained with 94% enantiomeric excess (ee) and 95% conversion rate (cr). Besides, the actual ee and cr were found to be 99% tested under optimized reaction conditions. These findings demonstrated that L. fermentum P1 as an effective biocatalyst to obtain (S)-1-(1,3-benzodioxal-5-yl) ethanol and with the D-optimal experimental design-based optimization, this product could be obtained with the 99% ee and 99% cr. Finally, the proposed mathematical optimization technique showed the applicability of the obtained results for asymmetric reduction reactions.

Red-emitting fluorogenic BODIPY-tetrazine probes for biological imaging.

A series of new BODIPY-tetrazine derivatives have been developed with a twist intramolecular charge transfer (TICT) state in polar solvents, which is an electron transfer process that occurs upon photoexcitation in a molecule that usually consists of an electron donor and acceptor linked by a single bond. Among them, the BODIPY-tetrazine derivative 6i was stable towards long-term storage and red-emitting with excellent performance, and was further used to image trans-cyclooctene-labeled lipids in mammalian cells and cyclopropene-labeled sugars in cancer cells under no-wash conditions.

Organocatalytic synthesis of (Het)biaryl scaffolds via photoinduced intra/intermolecular C(sp2)-H arylation by 2-pyridone derivatives.

A unique N,O-bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp2)-H (intra/intermolecular) arylation of unactivated arenes has been developed to expedite access to (Het)biaryl scaffolds under UV-irradiation at room temperature. The protocol tolerated diverse functional groups and substitution patterns, affording the target products in moderate to excellent yields. Mechanistic investigations were also carried out to better understand the reaction pathway. Furthermore, the synthetic applicability of this unified approach has been showcased via the construction of biologically relevant 4-quinolone, tricyclic lactam and sultam derivatives.

Effects of Substitution on Cytotoxicity of Diphenyl Ditelluride in Cultured Vascular Endothelial Cells.

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. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.

Mitochondrial Membrane Disrupting Molecules for Selective Killing of Senescent Cells.

Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammonium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.

Dihydroisocoumarins and Dihydroisoflavones from the Rhizomes of Dioscorea collettii with Cytotoxic Activity and Structural Revision of 2,2'-Oxybis(1,4-di-tert-butylbenzene).

The investigation of the constituents of the rhizomes of Dioscorea collettii afforded one new dihydroisocoumarin, named (-)-montroumarin (1a), along with five known compounds-montroumarin (1b), 1,1'-oxybis(2,4-di-tert-butylbenzene) (2), (3R)-3'-O-methylviolanone (3a), (3S)-3'-O-methylviolanone (3b), and (RS)-sativanone (4). Their structures were elucidated using extensive spectroscopic methods. To the best of our knowledge, compound 1a is a new enantiomer of compound 1b. The NMR data of compound 2 had been reported but its structure was erroneous. The structure of compound 2 was revised on the basis of a reinterpretation of its NMR data (1D and 2D) and the assignment of the 1H and 13C NMR data was given rightly for the first time. Compounds 3a-4, three dihydroisoflavones, were reported from the Dioscoreaceae family for the first time. The cytotoxic activities of all the compounds were tested against the NCI-H460 cell line. Two dihydroisocoumarins, compounds 1a and 1b, displayed moderate cytotoxic activities, while the other compounds showed no cytotoxicity.