Novel convenient 2-step synthesis of pyrido[1,2-a]indoles from pyrylium salts and o-bromoanilines.

A novel convenient 2-step synthesis of substituted pyrido[1,2-a]indoles is developed starting from easily available pyrylium tetrafluoroborates and ortho-bromoanilines. A conversion of the pyrylium tetrafluoroborates to pyridinium ones followed by their palladium catalyzed intramolecular cyclization allows the formation of 24 examples of N-fused heterocycles. A one-pot two-stage cyclization procedure was developed. The utility of the methodology was demonstrated with the synthesis of new pyrido[1,2-a]indoles bearing different alkyl, aryl, chlorine, fluorine and methoxy substituents.

Synthesis of 5-(Aryl)amino-1,2,3-triazole-containing 2,1,3-Benzothiadiazoles via Azide-Nitrile Cycloaddition Followed by Buchwald-Hartwig Reaction.

An efficient access to the novel 5-(aryl)amino-1,2,3-triazole-containing 2,1,3-benzothiadiazole derivatives has been developed. The method is based on 1,3-dipolar azide-nitrile cycloaddition followed by Buchwald-Hartwig cross-coupling to afford the corresponding N-aryl and N,N-diaryl substituted 5-amino-1,2,3-triazolyl 2,1,3-benzothiadiazoles under NHC-Pd catalysis. The one-pot diarylative Pd-catalyzed heterocyclization opens the straightforward route to triazole-linked carbazole-benzothiadiazole D-A systems. The optical and electrochemical properties of the compound obtained were investigated to estimate their potential application as emissive layers in OLED devises. The quantum yield of photoluminescence (PLQY) of the synthesized D-A derivatives depends to a large extent on electron-donating strengths of donor (D) component, reaching in some cases the values closed to 100%. Based on the most photoactive derivative and wide bandgap host material mCP, a light-emitting layer of OLED was made. The device showed a maximum brightness of 8000 cd/m2 at an applied voltage of 18 V. The maximum current efficiency of the device reaches a value of 3.29 cd/A.

Synthesis of ß-iodovinyl sulfones via direct photoinitiated difunctionalization of internal alkynes.

The reaction of direct photoinitiated iodosulfonylation of internal acetylenes with p-tolylsulfonyl iodide and its regioselectivity of the products was studied. Methods for the subsequent functionalization of ß-iodovinylsulfones using cross-coupling reactions to obtain valuable and non-available compounds are proposed.

New Allosteric Modulators of AMPA Receptors: Synthesis and Study of Their Functional Activity by Radioligand-Receptor Binding Analysis.

The synthetic approaches to three new AMPA receptor modulators-derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.13,11]tetradecane-4,8,12-trione-had been developed and all steps of synthesis were optimized. The structures of the compounds contain tricyclic cage and indane fragments necessary for binding with the target receptor. Their physiological activity was studied by radioligand-receptor binding analysis using [3H]PAM-43 as a reference ligand, which is a highly potent positive allosteric modulator of AMPA receptors. The results of radioligand-binding studies indicated the high potency of two synthesized compounds to bind with the same targets as positive allosteric modulator PAM-43 (at least on AMPA receptors). We suggest that the Glu-dependent specific binding site of [3H]PAM-43 or the receptor containing this site may be one of the targets of the new compounds. We also suggest that enhanced radioligand binding may indicate the existence of synergistic effects of compounds 11b and 11c with respect to PAM-43 binding to the targets. At the same time, these compounds may not compete directly with PAM-43 for its specific binding sites but bind to other specific sites of this biotarget, changing its conformation and thereby causing a synergistic effect of cooperative interaction. It can be expected that the newly synthesized compounds will also have pronounced effects on the glutamatergic system of the mammalian brain.

Synthesis, Characterization, and Properties of High-Energy Fillers Derived from Nitroisobutylglycerol.

Herein we report a comprehensive laboratory synthesis of a series of energetic azidonitrate derivatives (ANDP, SMX, AMDNNM, NIBTN, NPN, 2-nitro-1,3-dinitro-oxypropane) starting from the readily available nitroisobutylglycerol. This simple protocol allows obtaining the high-energy additives from the available precursor in yields higher than those reported using safe and simple operations not presented in previous works. A detailed characterization of the physical, chemical, and energetic properties including impact sensitivity and thermal behavior of these species was performed for the systematic evaluation and comparison of the corresponding class of energetic compounds.

General Method of Synthesis of 5-(Het)arylamino-1,2,3-triazoles via Buchwald-Hartwig Reaction of 5-Amino- or 5-Halo-1,2,3-triazoles.

An efficient access to the novel 5-(het)arylamino-1,2,3-triazole derivatives has been developed. The method is based on Buchwald-Hartwig cross-coupling reaction of 5-Amino or 5-Halo-1,2,3-triazoles with (het)aryl halides and amines, respectively. As result, it was found that palladium complex [(THP-Dipp)Pd(cinn)Cl] bearing expanded-ring N-heterocyclic carbene ligand is the most active catalyst for the process to afford the target molecules in high yields.

Making endo-cyclizations favorable again: a conceptually new synthetic approach to benzotriazoles via azide group directed lithiation/cyclization of 2-azidoaryl bromides.

Although benzotriazoles are important and ubiquitous, currently there is only one conceptual approach to their synthesis: bridging the two ortho-amino groups with an electrophilic nitrogen atom. Herein, we disclose a new practical alternative - the endo-cyclization of 2-azidoaryl lithiums obtained in situ from 2-azido-aryl bromides. The scope of the reaction is illustrated using twenty-four examples with a variety of alkyl, alkoxy, perfluoroalkyl, and halogen substituents. We found that the directing effect of the azide group allows selective metal-halogen exchange in aryl azides containing several bromine atoms. Furthermore, (2-bromophenyl)diazomethane undergoes similar cyclization to give an indazole. Thus, cyclizations of aryl lithiums containing an ortho-X = Y = Z group emerge as a new general approach for the synthesis of aromatic heterocycles. DFT computations suggested that the observed endo-selectivity applies to the anionic cyclizations of other functionalities that undergo "1,1-additions" (i.e., azides, diazo compounds, and isonitriles). In contrast, cyclizations with the heteroatomic functionalities that follow the "1,2-addition" pattern (cyanates, thiocyanates, isocyanates, isothiocyanates, and nitriles) prefer the exo-cyclization path. Hence, such reactions expand the current understanding of stereoelectronic factors in anionic cyclizations.

Toward reliable characterization of energetic materials: interplay of theory and thermal analysis in the study of the thermal stability of tetranitroacetimidic acid (TNAA).

The thermal stability of energetic materials, being of the utmost importance for safety issues, is often considered in terms of kinetics, e.g., the Arrhenius parameters of the decomposition rate constant. The latter, in turn, are commonly determined using conventional thermoanalytical procedures with the use of simple Kissinger or Ozawa methods for kinetic data processing. However, thermal decomposition of energetic materials typically occurs via numerous exo- and endothermal processes including fast parallel reactions, phase transitions, autocatalysis, etc. This leads to numerous drawbacks of simple approaches. In this paper, we proposed a new methodology for characterization of the thermochemistry and thermal stability of melt-cast energetic materials, which is comprised of a complementary set of experimental and theoretical techniques in conjunction with a suitable kinetic model. With the aid of the proposed methodology, we studied in detail a novel green oxidizer, tetranitroacetimidic acid (TNAA). The experimental mass loss kinetics in the melt was perfectly fitted with a model comprised of zero-order reaction (sublimation or evaporation) and first-order thermal decomposition of TNAA with the effective Arrhenius parameters Ea = 41.0 ± 0.2 kcal mol-1 and log(A/s-1) = 20.2 ± 0.1. We rationalized the experimental findings on the basis of highly accurate CCSD(T)-F12 quantum chemical calculations. Computations predict that thermolysis of TNAA involves an intricate interplay of multiple decomposition channels of the three tautomers, which are equilibrated via either monomolecular reactions or concerted double hydrogen atom transfer in the H-bonded dimers; the calculated Arrhenius parameters of the effective rate constant coincide well with experiment. Most importantly, calculations provide detailed mechanistic evidence missing in the thermoanalytical experiment and explain formation of the experimentally observed primary products N2O and NO2. Along with the kinetics and mechanism of decomposition, the proposed approach yields accurate thermochemistry and phase change data of TNAA.

Fluorinated Unsymmetrical N,N'-Diaryl Imidazolium Salts-New Functionalized NHC-Ligand Precursors.

An efficient and scaled-up synthesis of the imidazol-2-ylidene-based unsymmetrical NHC precursors bearing the sterically demanding hexafluoroisopropylalkoxy group [(CF3 )2 (OR)C-] at the ortho position of the N-aryl substituent was developed. The key step of the method involved the transformation of a Mes-substituted oxazolinium tetrafluoroborate salt through the reaction with the corresponding binucleophilic fluoroalkyl-substituted aniline. The subsequent post-modification of the resulting hydroxyl-containing salt through a simple one-step O-alkylation protocol provided access to a new family of unsymmetrical fluorinated NHC precursors. These compounds were successfully utilized for the preparation of several novel metal complexes. The molecular structures of some NHC precursors and their metal complexes have been unambiguously characterized by single-crystal X-ray diffraction analysis. A preliminary evaluation of the catalytic activity of the palladium complexes was performed on a Buchwald-Hartwig amination reaction. As a result, two PEPPSI-type (PEPPSI=pyridine-enhanced pre-catalyst preparation stabilization and initiation) Pd complexes have demonstrated promising activity in alkane solvents.

A general method of Suzuki-Miyaura cross-coupling of 4- and 5-halo-1,2,3-triazoles in water.

A general method of the synthesis of 1,4,5-trisubstituted-1,2,3-triazoles by Suzuki-Miyaura cross-coupling from 4- and 5-halo-1,2,3-triazoles is reported. The reaction is mediated by an expanded-ring N-heterocyclic carbene palladium complex in water. The developed reaction protocol meets the requirements of "green chemistry". Cross-coupling of 4- and 5-chlorotriazoles is reported for the first time.

Pursuing reliable thermal analysis techniques for energetic materials: decomposition kinetics and thermal stability of dihydroxylammonium 5,5'-bistetrazole-1,1'-diolate (TKX-50).

Thermal decomposition of a novel promising high-performance explosive dihydroxylammonium 5,5'-bistetrazole-1,1'-diolate (TKX-50) was studied using a number of thermal analysis techniques (thermogravimetry, differential scanning calorimetry, and accelerating rate calorimetry, ARC). To obtain more comprehensive insight into the kinetics and mechanism of TKX-50 decomposition, a variety of complementary thermoanalytical experiments were performed under various conditions. Non-isothermal and isothermal kinetics were obtained at both atmospheric and low (up to 0.3 Torr) pressures. The gas products of thermolysis were detected in situ using IR spectroscopy, and the structure of solid-state decomposition products was determined by X-ray diffraction and scanning electron microscopy. Diammonium 5,5'-bistetrazole-1,1'-diolate (ABTOX) was directly identified to be the most important intermediate of the decomposition process. The important role of bistetrazole diol (BTO) in the mechanism of TKX-50 decomposition was also rationalized by thermolysis experiments with mixtures of TKX-50 and BTO. Several widely used thermoanalytical data processing techniques (Kissinger, isoconversional, formal kinetic approaches, etc.) were independently benchmarked against the ARC data, which are more germane to the real storage and application conditions of energetic materials. Our study revealed that none of the Arrhenius parameters reported before can properly describe the complex two-stage decomposition process of TKX-50. In contrast, we showed the superior performance of the isoconversional methods combined with isothermal measurements, which yielded the most reliable kinetic parameters of TKX-50 thermolysis. In contrast with the existing reports, the thermal stability of TKX-50 was determined in the ARC experiments to be lower than that of hexogen, but close to that of hexanitrohexaazaisowurtzitane (CL-20).

Expanded-ring N-heterocyclic carbenes efficiently stabilize gold(I) cations, leading to high activity in π-acid-catalyzed cyclizations.

A series of six- and seven-membered expanded-ring N-heterocyclic carbene (er-NHC) gold(I) complexes has been synthesized using different synthetic approaches. Complexes with weakly coordinating anions [(er-NHC)AuX] (X(-) = BF4(-), NTf2(-), OTf(-)) were generated in solution. According to their (13)C NMR spectra, the ionic character of the complexes increases in the order X(-) = Cl(-) < NTf2(-) < OTf(-) < BF4(-). Additional factors for stabilization of the cationic complexes are expansion of the NHC ring and the attachment of bulky substituents at the nitrogen atoms. These er-NHCs are bulkier ligands and stronger electron donors than conventional NHCs as well as phosphines and sulfides and provide more stabilization of [(L)Au(+)] cations. A comparative study has been carried out of the catalytic activities of five-, six-, and seven-membered carbene complexes [(NHC)AuX], [(Ph3 P)AuX], [(Me2S)AuX], and inorganic compounds of gold in model reactions of indole and benzofuran synthesis. It was found that increased ionic character of the complexes was correlated with increased catalytic activity in the cyclization reactions. As a result, we developed an unprecedentedly active monoligand cationic [(THD-Dipp)Au]BF4 (1,3-bis(2,6-diisopropylphenyl)-3,4,5,6-tetrahydrodiazepin-2-ylidene gold(I) tetrafluoroborate) catalyst bearing seven-membered-ring carbene and bulky Dipp substituents. Quantitative yields of cyclized products were attained in several minutes at room temperature at 1 mol % catalyst loadings. The experimental observations were rationalized and fully supported by DFT calculations.

Highly efficient synthesis of 3,4-diarylbutadiene sulfones using Heck-Matsuda reaction.

For the first time we describe a general method for the synthesis of previously not synthesized unsymmetrical 3,4-diarylbutadiene sulfones which can be stable convenient precursors for 2,3-diaryl-1,3-butadienes. Our method for arylation of butadiene sulfones via Heck-Matsuda reaction allows to obtain unsymmetrical 3,4-diarylbutadiene sulfones with a variety of alkyl, alkoxy, nitro, ethoxycarbonyl, perfluoroalkyl and halogen substituents (30 examples) in very good yields using readily available reagents and catalysts.

One-Pot Modified Madelung Synthesis of 3-Tosyl- and 3-Cyano-1,2-disubstituted Indoles.

A One-pot, two-step procedure for the synthesis of 1,2-disubstituted-3-tosyl and 1,2-disubstituted-3-cyanoindoles from the corresponding N-(o-tolyl)benzamides is reported. The developed procedure is operationally simple, does not utilize any transition metals, and provides variably substituted indoles in good yields from readily available starting materials.

The Physicochemical Characterization of New "Green" Epoxy-Resin Hardener Made from PET Waste.

"Green" thermally stable hardener was synthesized from a PET waste. The rigid molecular linear structure of the new hardener suggests that it will provide the polymer matrix with the necessary physical and mechanical characteristics. It also allows the expectation that cured matrix based on this hardener can provide increased toughness. New hardener was used as a curing agent for three epoxy resins-tetraglycidyl methylenedianiline (TGDMA, 111-117 EEW), diglycidylether of bisphenol A (DGEBA, 170-192 EEW) and solid epoxy resin (SER)-with a medium molecular weight (860-930 EEW) based on DGEBA. The mixtures were found to have the highest Tg for the DGEBA resin, and high of that for TGDMA and SER. According to the DMA analysis for two cured matrices, the hardener proved to be no worse than the standard ones, and made it possible to obtain cured matrices with excellent mechanical properties, which allows us to hope for further application of new hardener cured epoxy matrices in appropriate composite materials at high temperatures.

Structure-Activity Relationships and Transcriptomic Analysis of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors.

To evaluate the differences in action of commercially available 2-oxoglutarate mimetics and "branched-tail" oxyquinoline inhibitors of hypoxia-inducible factor prolyl hydroxylase (HIF PHD), the inhibitors' IC50 values in the activation of HIF1 ODD-luciferase reporter were selected for comparative transcriptomics. Structure-activity relationship and computer modeling for the oxyquinoline series of inhibitors led to the identification of novel inhibitors, which were an order of magnitude more active in the reporter assay than roxadustat and vadadustat. Unexpectedly, 2-methyl-substitution in the oxyquinoline core of the best HIF PHD inhibitor was found to be active in the reporter assay and almost equally effective in the pretreatment paradigm of the oxygen-glucose deprivation in vitro model. Comparative transcriptomic analysis of the signaling pathways induced by HIF PHD inhibitors showed high potency of the two novel oxyquinoline inhibitors (#4896-3249 and #5704-0720) at 2 µM concentrations matching the effect of 30 µM roxadustat and 500 µM dimethyl oxalyl glycine in inducing HIF1 and HIF2-linked pathways. The two oxyquinoline inhibitors exerted the same activation of HIF-triggered glycolytic pathways but opposite effects on signaling pathways linked to alternative substrates of HIF PHD 1 and 3, such as p53, NF-κB, and ATF4. This finding can be interpreted as the specificity of the 2-methyl-substitute variant for HIF PHD2.

A Set of Active Promoters with Different Activity Profiles for Superexpressing Rhodococcus Strain.

Rhodococcus bacteria are a promising platform for biodegradation, biocatalysis, and biosynthesis, but the use of rhodococci is hampered by the insufficient number of both platform strains for expression and promoters that are functional and thoroughly studied in these strains. To expand the list of such strains and promoters, we studied the expression capability of the Rhodococcus rhodochrous M33 strain, and the functioning of a set of recombinant promoters in it. We showed that the strain supports superexpression of the target enzyme (nitrile hydratase) using alternative inexpensive feedings-acetate and urea-without growth factor supplementation, thus being a suitable expression platform. The promoter set included Ptuf (elongation factor Tu) and Psod (superoxide dismutase) from Corynebacterium glutamicum ATCC13032, Pcpi (isocitrate lyase) from Rhodococcus erythropolis PR4, and Pnh (nitrile hydratase) from R. rhodochrous M8. Activity levels, regulation possibilities, and growth-phase-dependent activity profiles of these promoters were studied in derivatives of the M33 strain. The activities of the promoters were significantly different (Pcpi < Psod ≪ Ptuf < Pnh), covering 103-fold range, and the most active Pnh and Ptuf produced up to a 30-50% portion of target protein in soluble intracellular proteins. On the basis of the mRNA quantification and amount of target protein, the production level of Pnh was positioned close to the theoretical upper limit of expression in a bacterial cell. A selection method for the laboratory evolution of such active promoters directly in Rhodococcus was also proposed. Concerning regulation, Ptuf could not be regulated (2-fold change), while others were tunable (6-fold for Psod, 79-fold for Pnh, and 44-fold for Pcpi). The promoters possessed four different activity profiles, including three with peak of activity at different growth phases and one with constant activity throughout the growth phases. Ptuf and Pcpi did not change their activity profile under different growth conditions, whereas the Psod and Pnh profiles changed depending on the growth media. The results allow flexible construction of Rhodococcus strains using the studied promoters, and demonstrate a valuable approach for complex characterization of promoters intended for biotechnological strain construction.

Ring size and nothing else matters: unusual regioselectivity of alkyne hydration by NHC gold(I) complexes.

We have investigated the role of ring sizes and substituents in NHC ligands in some (NHC)Au(i) complexes in the hydration of internal alkynes. Despite the fact that using (NHC)Au(i) complexes in the hydration of diarylacetylenes leads to Markovnikov-type products, the precise tuning of ligands allows changing the regioselectivity in arylalkylacetylene hydration to the anti-Markovnikov-type.

Ln(II) amido complexes coordinated by ring-expanded N-heterocyclic carbenes - promising catalysts for olefin hydrophosphination.

First Ln(ii) ring-expanded NHC complexes (er-NHC)Ln[N(SiMe3)2]2 (Ln = Sm, Yb) are synthesized and proved to be highly efficient pre-catalysts for the intermolecular hydrophosphination of such indolent substrates as 1-alkenes, cyclohexene and norbornene.

Breast cancer organoid model allowed to reveal potentially beneficial combinations of 3,3'-diindolylmethane and chemotherapy drugs.

Epigenetic alterations represent promising therapeutic targets in cancer treatment. Recently it was revealed that small molecules have the potential to act as microRNA silencers. Capacity to bind the discrete stem-looped structure of pre-miR-21 and prevent its maturation opens opportunities to utilize such compounds for the prevention of initiation, progression, and chemoresistance of cancer. Molecular simulations performed earlier identified 3,3'-diindolylmethane (DIM) as a potent microRNA-21 antagonist. However, data on DIM and microRNA-21 interplay is controversial, which may be caused by the limitations of the cell lines.