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.

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.

Accessing diverse bicyclic peptide conformations using 1,2,3-TBMB as a linker.

Bicyclic peptides are a powerful modality for engaging challenging drug targets such as protein-protein interactions. Here, we use 1,2,3-tris(bromomethyl)benzene (1,2,3-TBMB) to access bicyclic peptides with diverse conformations that differ from conventional bicyclisation products formed with 1,3,5-TBMB. Bicyclisation at cysteine residues under aqueous buffer conditions proceeds efficiently, with broad substrate scope, compatibility with high-throughput screening, and clean conversion (>90%) for 96 of the 115 peptides tested. We envisage that the 1,2,3-TBMB linker will be applicable to a variety of peptide screening techniques in drug discovery.

High-performance activation of ozone by sonocavitation for BTEX degradation in water.

This work presents a novel advanced oxidation process (AOP) for degradation of emerging organic pollutants - benzene, toluene, ethylbenzene and xylenes (BTEXs) in water. A comparative study was performed for sonocavitation assisted ozonation under 40-120 kHz and 80-200 kHz dual frequency ultrasounds (DFUS). Based on the obtained results, the combination of 40-120 kHz i.e., low-frequency US (LFDUS) with O3 exhibited excellent oxidation capacity degrading 99.37-99.69% of BTEXs in 40 min, while 86.09-91.76% of BTEX degradation was achieved after 60 min in 80-200 kHz i.e., high-frequency US (HFDUS) combined with O3. The synergistic indexes determined using degradation rate constants were found as 7.86 and 2.9 for LFDUS/O3 and HFDUS/O3 processes, respectively. The higher extend of BTEX degradation in both processes was observed at pH 6.5 and 10. Among the reactive oxygen species (ROSs), hydroxyl radicals (HO•) were found predominant according to scavenging tests, singlet oxygen also importantly contributed in degradation, while O2•- radicals had a minor contribution. Sulfate (SO42-) ions demonstrated higher inhibitory effect compared to chloride (Cl-) and carbonate (CO32-) ions in both processes. Degradation pathways of BTEX was proposed based on the intermediates identified using GC-MS technique.

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.

Hexadehydro-Diels-Alder Reaction: Benzyne Generation via Cycloisomerization of Tethered Triynes.

The hexadehydro-Diels-Alder (HDDA) reaction is the thermal cyclization of an alkyne and a 1,3-diyne to generate a benzyne intermediate. This is then rapidly trapped, in situ, by a variety of species to yield highly functionalized benzenoid products. In contrast to nearly all other methods of aryne generation, no other reagents are required to produce an HDDA benzyne. The versatile and customizable nature of the process has attracted much attention due not only to its synthetic potential but also because of the fundamental mechanistic insights the studies often afford. The authors have attempted to provide here a comprehensive compilation of publications appearing by mid-2020 that describe experimental results of HDDA reactions.

Bioorthogonal Reactions of Triarylphosphines and Related Analogues.

Bioorthogonal phosphines were introduced in the context of the Staudinger ligation over 20 years ago. Since that time, phosphine probes have been used in myriad applications to tag azide-functionalized biomolecules. The Staudinger ligation also paved the way for the development of other phosphorus-based chemistries, many of which are widely employed in biological experiments. Several reviews have highlighted early achievements in the design and application of bioorthogonal phosphines. This review summarizes more recent advances in the field. We discuss innovations in classic Staudinger-like transformations that have enabled new biological pursuits. We also highlight relative newcomers to the bioorthogonal stage, including the cyclopropenone-phosphine ligation and the phospha-Michael reaction. The review concludes with chemoselective reactions involving phosphite and phosphonite ligations. For each transformation, we describe the overall mechanism and scope. We also showcase efforts to fine-tune the reagents for specific functions. We further describe recent applications of the chemistries in biological settings. Collectively, these examples underscore the versatility and breadth of bioorthogonal phosphine reagents.

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.

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.

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.

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.

A peroxisomal ß-oxidative pathway contributes to the formation of C6-C1 aromatic volatiles in poplar.

Benzenoids (C6-C1 aromatic compounds) play important roles in plant defense and are often produced upon herbivory. Black cottonwood (Populus trichocarpa) produces a variety of volatile and nonvolatile benzenoids involved in various defense responses. However, their biosynthesis in poplar is mainly unresolved. We showed feeding of the poplar leaf beetle (Chrysomela populi) on P. trichocarpa leaves led to increased emission of the benzenoid volatiles benzaldehyde, benzylalcohol, and benzyl benzoate. The accumulation of salicinoids, a group of nonvolatile phenolic defense glycosides composed in part of benzenoid units, was hardly affected by beetle herbivory. In planta labeling experiments revealed that volatile and nonvolatile poplar benzenoids are produced from cinnamic acid (C6-C3). The biosynthesis of C6-C1 aromatic compounds from cinnamic acid has been described in petunia (Petunia hybrida) flowers where the pathway includes a peroxisomal-localized chain shortening sequence, involving cinnamate-CoA ligase (CNL), cinnamoyl-CoA hydratase/dehydrogenase (CHD), and 3-ketoacyl-CoA thiolase (KAT). Sequence and phylogenetic analysis enabled the identification of small CNL, CHD, and KAT gene families in P. trichocarpa. Heterologous expression of the candidate genes in Escherichia coli and characterization of purified proteins in vitro revealed enzymatic activities similar to those described in petunia flowers. RNA interference-mediated knockdown of the CNL subfamily in gray poplar (Populus x canescens) resulted in decreased emission of C6-C1 aromatic volatiles upon herbivory, while constitutively accumulating salicinoids were not affected. This indicates the peroxisomal ß-oxidative pathway participates in the formation of volatile benzenoids. The chain shortening steps for salicinoids, however, likely employ an alternative pathway.

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.

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.

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.

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.

Reperfusion mediates heme impairment with increased protein cysteine sulfonation of mitochondrial complex III in the post-ischemic heart.

A serious consequence of myocardial ischemia-reperfusion injury (I/R) is oxidative damage, which causes mitochondrial dysfunction. The cascading ROS can propagate and potentially induce heme bleaching and protein cysteine sulfonation (PrSO3H) of the mitochondrial electron transport chain. Herein we studied the mechanism of I/R-mediated irreversible oxidative injury of complex III in mitochondria from rat hearts subjected to 30-min of ischemia and 24-h of reperfusion in vivo. In the I/R region, the catalytic activity of complex III was significantly impaired. Spectroscopic analysis indicated that I/R mediated the destruction of hemes b and c + c1 in the mitochondria, supporting I/R-mediated complex III impairment. However, no significant impairment of complex III activity and heme damage were observed in mitochondria from the risk region of rat hearts subjected only to 30-min ischemia, despite a decreased state 3 respiration. In the I/R mitochondria, carbamidomethylated C122/C125 of cytochrome c1 via alkylating complex III with a down regulation of HCCS was exclusively detected, supporting I/R-mediated thioether defect of heme c1. LC-MS/MS analysis showed that I/R mitochondria had intensely increased complex III PrSO3H levels at the C236 ligand of the [2Fe2S] cluster of the Rieske iron­sulfur protein (uqcrfs1), thus impairing the electron transport activity. MS analysis also indicated increased PrSO3H of the hinge protein at C65 and of cytochrome c1 at C140 and C220, which are confined in the intermembrane space. MS analysis also showed that I/R extensively enhanced the PrSO3H of the core 1 (uqcrc1) and core 2 (uqcrc2) subunits in the matrix compartment, thus supporting the conclusion that complex III releases ROS to both sides of the inner membrane during reperfusion. Analysis of ischemic mitochondria indicated a modest reduction from the basal level of complex III PrSO3H detected in the mitochondria of sham control hearts, suggesting that the physiologic hyperoxygenation and ROS overproduction during reperfusion mediated the enhancement of complex III PrSO3H. In conclusion, reperfusion-mediated heme damage with increased PrSO3H controls oxidative injury to complex III and aggravates mitochondrial dysfunction in the post-ischemic heart.

Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor.

G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the Gi/o-coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.

Sulfurane [S(IV)]-Mediated Fusion of Benzynes Leads to Helical Dibenzofurans.

Here we disclose a sulfurane-mediated method for the formation of dimeric dibenzofuran helicenes via the reaction between diaryl sulfoxides and hexadehydro-Diels-Alder (HDDA) derived benzynes. A variety of S-shaped and U-shaped helicenes were formed under thermal conditions. Both experimental and DFT studies support a sulfur(IV)-based coupling (aka ligand coupling) mechanism involving tetracarbo-ligated S(IV) intermediates undergoing reductive elimination to afford the helicene products. This process involves the de novo generation of five new rings in a single operation and constitutes a new method for the construction of topologically interesting, polycyclic aromatic compounds.

Packing Biomolecules into Sierpinski Triangles with Global Organizational Chirality.

Fractals are found in nature and play important roles in biological functions. However, it is challenging to controllably prepare biomolecule fractals. In this study, a series of Sierpinski triangles with global organizational chirality is successfully constructed by the coassembly of l-tryptophan and 1,3-bi(4-pyridyl)benzene molecules on Ag(111). The chirality is switched when replacing l-tryptophan by d-tryptophan. The fractal structures are characterized by low-temperature scanning tunneling microscopy at the single-molecule level. Density functional theory calculations reveal that intermolecular hydrogen bonds stabilize the Sierpinski triangles.