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The behavior of the peptide substrates GlyArgArgGly and GlyLysArgGly, which contain arginine or lysine at the Р2 position, in the active site of oligopeptidase В from the gamma-proteobacterium Serratia proteamaculans was studied by molecular dynamics simulations. The nature of the residue at the Р2 position was shown not only to influence the position of this residue and its contacts with the amino-acid environment in the substrate-binding pocket but also to affect the conformational dynamics of the entire peptide. Only the residue at the Р1 position forms persistent contacts with the S1-substrate-binding site of the enzyme, whereas contacts of the residue at the Р2 position may vary depending on its nature. Molecular dynamics simulations are shown to complement and improve the knowledge extracted from X-ray diffraction studies that enable the determination of the three-dimensional structures of molecules in one of numerous alternative conformations.

Pyridoxal-5′-phosphate (PLP)-dependent transaminases are industrially important enzymes catalyzing the stereoselective amination of ketones and keto acids. Transaminases of PLP fold type IV are characterized by (R)- or (S)-stereoselective transfer of amino groups, depending on the substrate profile of the enzyme. PLP fold type IV transaminases include branched-chain amino acid transaminases (BCATs), D-amino acid transaminases and (R)-amine:pyruvate transaminases. Recently, transaminases with a mixed type of activity were identified and characterized. Here, we report biochemical and structural characterization of a transaminase from myxobacterium Haliangium ochraceum (Hoch3033), which is active towards keto analogs of branched-chain amino acids (specific substrates for BCATs) and (R)-(+)-α-methylbenzylamine (specific substrate for (R)-amine:pyruvate transaminases). The enzyme is characterized by an alkaline pH optimum (pH 10.0–10.5) and a tolerance to high salt concentrations (up to 2 M NaCl). The structure of Hoch3033 was determined at 2.35 A resolution. The overall fold of the enzyme was similar to those of known enzymes of PLP fold type IV. The mixed type of activity of Hoch3033 was implemented within the BCAT-like active site. However, in the active site of Hoch3033, we observed substitutions of specificity-determining residues that are important for substrate binding in canonical BCATs. We suggest that these changes result in the loss of activity towards α-ketoglutarate and increase the affinity towards (R)-(+)-α-methylbenzylamine. These results complement our knowledge of the catalytic diversity of transaminases and indicate the need for further research to understand the structural basis of substrate specificity in these enzymes.

The L232H mutant of the enhanced green fluorescent protein (EGFP) was expressed and crystallized. An X-ray diffraction data set was collected from the crystals to 1.53 A resolution. An analysis of the three-dimensional structure revealed a stacking interaction between the amino-acid residues Н78 and Н232, which contributes to the fastening of the C-terminal region of the protein in the vicinity of the chromophore and influences chromophore maturation of hybrid fluorescent proteins produced by fusion of the target proteins with the C-terminus of EGFP. This hypothesis was experimentally confirmed by investigating chromophore maturation of the hybrid proteins fused to the N- and C-termini of EGFP and EGFP-L232H.

Functionally selective ligands stabilize conformations of G protein-coupled receptors (GPCRs) that induce a preference for signaling via a subset of the intracellular pathways activated by the endogenous agonists. The possibility to fine-tune the functional activity of a receptor provides opportunities to develop drugs that selectively signal via pathways associated with a therapeutic effect and avoid those causing side effects. Animal studies have indicated that ligands displaying functional selectivity at the D2 dopamine receptor (D2R) could be safer and more efficacious drugs against neuropsychiatric diseases. In this work, computational design of functionally selective D2R ligands was explored using structure-based virtual screening. Molecular docking of known functionally selective ligands to a D2R homology model indicated that such compounds were anchored by interactions with the orthosteric site and extended into a common secondary pocket. A tailored virtual library with close to 13 000 compounds b...

A combination of the common quantum mechanics based transition state theory and exhaustive conformational search for the modeling of difficult reactions with hundreds of competing transition states is proposed. This approach is applied to study all transition state conformations of a reaction occurring in the catechol O -methyltransferase (COMT) active site in the absence of a major part of the enzyme, and the results are compared to the recent QM/MM modeling of this reaction within the enzyme. The main points of the method are (i) constraining of forming bonds upon conformer generation and (ii) preliminary constrained optimizations of located conformations to minima using a quantum mechanical method. Importantly, this methodology is applicable to the quantum mechanical part in QM/MM calculations and can reduce demand for large sampling in difficult cases.

A t(9;22) chromosomal translocation which forms the chimeric tyrosine kinase breakpoint cluster region (BCR)‑Abelson murine leukemia viral oncogene homolog 1 (ABL) is a key mechanism underlying the pathogenesis of chronic myelogenous leukemia (CML). Pharmacological inhibition of BCR‑ABL with imatinib (Gleevec) has been reported as an effective targeted therapy; however, mutations (including the kinase domain of ABL) suppress the efficacy of inhibitors. PF‑114, a derivative of the third generation BCR‑ABL inhibitor ponatinib, demonstrated a high inhibitory activity against wild-type and mutant BCR‑ABL forms, such as the clinically important T315I. Furthermore, PF‑114 exhibited preferential kinase selectivity, safety, notable pharmacokinetic properties and therapeutic efficacy in a murine model. Investigation into the mechanisms of CML cell death revealed an exceptional potency of PF‑114 (at low nanomolar concentrations) for the CML‑derived K562 cell line, whereas leukemia cell lines that lack the chimeric tyrosine kinase were markedly more refractory. The molecular ordering of events mechanistically associated with K562 cell death included the dephosphorylation of CrkL adaptor protein followed by inhibition of ERK1/2 and Akt, G1 arrest, a decrease of phosphorylated Bcl‑2‑associated death promoter, Bcl‑2‑like protein 11, BH3 interacting‑domain death agonist, Bcl‑extra large and Bcl‑2 family apoptosis regulator, and reduced mitochondrial transmembrane potential. Increased Annexin V reactivity, activation of caspases and poly(ADP‑ribose)polymerase cleavage were proposed to lead to internucleosomal DNA fragmentation. Thus, PF‑114 may be a potent inducer of apoptosis in CML cells. Nevertheless, activation of STAT3 phosphorylation in response to PF‑114 may permit cell rescue; thus, a combination of BCR‑ABL and STAT3 inhibitors should be considered for improved therapeutic outcome. Collectively, the targeted killing of BCR‑ABL‑positive cells, along with other beneficial properties, such as in vivo characteristics, suggests PF‑114 as a potential candidate for analysis in clinical trials with CML patients.

Investigation of charge delocalization (redistribution) in a SpnF-catalyzed reaction that proceeds through overlapping Diels–Alder and bis-pericyclic mechanisms has shown that it is better represented as a nonpolar cycloaddition rather than a cationic rearrangement.

Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or nonmutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the 'gatekeeper' mutation T315I. However, a broad spectrum of kinase inhibition increases the off-target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of (i) targeting T315I and other resistance mutations in BCR/ABL; (ii) achieving a high selectivity to improve safety; and (iii) overcoming nonmutational resistance in Ph+ leukemias. PF-114 inhibited BCR/ABL and clinically important mutants including T315I at nanomolar concentrations. It suppressed primary Ph+ acute lymphatic leukemia-derived long-term cultures that either displayed nonmutational resistance or harbor the T315I. In BCR/ABL- or BCR/ABL-T315I-driven murine leukemia as well as in xenograft models of primary Ph+ leukemia harboring the T315I, PF-114 significantly prolonged survival to a similar extent as ponatinib. Our work supports clinical evaluation of PF-114 for the treatment of resistant Ph+ leukemia.

A new method involving laccase-mediator system has been developed for environmentally friendly synthesis of polyaniline/multi-walled carbon nanotubes (PANI/MWCNT) composite. Fungal laccase, potassium octocyanomolibdate (4 + ) and atmospheric oxygen served as catalyst, redox-mediator and terminal oxidant, respectively. The structure, morphology and electrical conductivity of composites with different PANI content were investigated. The energy storage of enzymatically obtained composite consists of an electrical double layer capacitance as well as pseudocapacitance of conducting polymer. The obtained PANI/MWCNT composite with PANI content ca . 49 wt.% had high specific capacitance and cycle stability during doping/dedoping. The specific capacitance of this composite measured by cyclic voltammetry technique with potential scan rate of 5 mV/s was ca . 440 F/g. The specific capacitance of the composite decreased by less than 7% of its maximum value after 1000 scan cycles between -0.1 and 0.7 V. Supercapacitor (SC) shell was made from flexible adhesive tape (regular Scotch tape) and current collector was formed after its separation from the surface of graphite foil. The ethanol dispersion of PANI/MWCNT composite was deposited on the current collector surface. The gel polymer electrolyte (polyvinyl alcohol in 1 M phosphoric acid) was employed as both electrolyte medium and separator. The energy and power densities under an operating window of 0.7 V were ca . 7.03 Wh/kg and 5.2 kW/kg, respectively.

Theoretical predictions suggested that particulates (large clusters and droplets) in pulsed-laser ablation deposition (PLD) move towards the surface normal and constitute a small fraction of the total plume mass. Contrary to expectations, here we report that, independently of the laser beam direction, large clusters are ejected towards the laser direction of incidence, which generally differs from the surface normal. Moreover, fragments and droplets constitute the major fraction of the ablated mass. Cross-sectional SEM investigations performed on the Si targets show that the direction of growth of the columns follows the laser beam direction. These observations have been explained by the change of the microscopic ablation mechanism from monomer evaporation at low local laser fluences to phase explosion at higher local fluences.

Six novel potential PARP1 inhibitors were identified by means of substructure search and molecular docking into PAPR1 active site; one compound (STK970217) potentiated the cytotoxicity of doxorubicin in hepatocellular carcinoma HepG2 cells being non-cytotoxic as a single agent, while three other identified compounds inhibited the growth of HepG2 cells both individually and in combination with doxorubicin.

Electromechanical coupling via membrane depolarization-mediated activation of voltage-dependent Ca2+ channels (VDCC) is an important mechanism in regulating pulmonary vascular tone, while mouse is an animal model often used to study pathogenic mechanisms of pulmonary vascular disease. The function of VDCC in mouse pulmonary artery (PA) smooth muscle cells (PASMC), however, has not been characterized, and their functional role in reactive oxygen species (ROS)-mediated regulation of vascular function remains unclear. In this study, we characterized the electrophysiological and pharmacological properties of VDCC in PASMC and the divergent effects of ROS produced by xanthine oxidase (XO) and hypoxanthine (HX) on VDCC in PA and mesenteric artery (MA). Our data show that removal of extracellular Ca2+ or application of nifedipine, a dihydropyridine VDCC blocker, both significantly inhibited 80 mM K+-mediated PA contraction. In freshly dissociated PASMC, the maximum inward Ca2+ currents were −2.6 ± 0.2 pA/pF at +10 mV (with a holding potential of −70 mV). Window currents were between −40 and +10 mV with a peak at −15.4 mV. Nifedipine inhibited currents with an IC50 of 0.023 μM, and 1 μM Bay K8644, a dihydropyridine VDCC agonist, increased the inward currents by 61%. XO/HX attenuated 60 mM K+-mediated increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) due to Ca2+ influx through VDCC in PASMC. Exposure to XO/HX caused relaxation in PA preconstricted by 80 mM K+ but not in aorta and MA. In contrast, H2O2 inhibited high K+-mediated increase in [Ca2+]cyt and caused relaxation in both PA and MA. Indeed, RT-PCR and Western blot analysis revealed significantly lower expression of CaV1.3 in MA compared with PA. Thus our study characterized the properties of VDCC and demonstrates that ROS differentially regulate vascular contraction by regulating VDCC in PA and systemic arteries.

14 Single- and multi-walled carbon nanotubes from different sources were characterized in detail, and the characteristics obtained were carefully analyzed. The carbon material with the highest capacitance, and also other superior properties (“Taunit-M” from “NanoTechCenter”, Russia), was chosen for further modification and fabrication of buckypaper based electrodes. These electrodes were biomodified with plant and fungal laccases, as well as fungal bilirubin oxidase. The designed biocathodes were investigated in simple buffers and also in a complex physiological fluid (human serum). Biocathodes based on immobilized fungal laccase were bioelectrocatalytically inactive in chloride containing media at neutral pH. In spite of the quite high current densities realized using biodevices based on plant laccase and fungal bilirubin oxidase, the limited thermal stability of the enzymes renders the biocathodes inadequate for practical applications in implanted situations.

Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of "focusing" on one specific conformational state that binds to a protein. The calculated conformer focusing term made a considerable difference of 5-10 kJ/mol in computed relative binding free energies of studied Syk inhibitors and significantly improved the resulting accuracy of predictions.

Electroconductive interpolymer polyaniline complexes are synthesized on the DNA matrix, using the method of oxidative polymerization of aniline with two different biocatalyzers: horseradish root peroxidase and micropiroxidase-11 biomimetic. The spectral characteristics and morphology of the acquired biocomposites have been studied. The stereospecificity of the acquired samples of interpolymer complexes is shown, depending on the biocatalyzers used. The results acquired indicate the important role of a biocatalyzer in the formation of the twist direction of an electroconductive polymer spiral on the DNA matrix; i.e., the optical activity of the polymer samples acquired is apparently associated with the biocatalyzer properties.

This paper presents the amperometric biosensor that determines choline and cholinesterase activity using a screen printed graphite electrode. In order to detect H 2 O 2 we have blanket modified the electrode material with manganese dioxide nanoparticles layer. Using layer-by-layer technique on the developed hydrogen peroxide sensitive electrode surface choline oxidase was incorporated into the interpolyelectrolyte nanofilm. Its ability to serve as a detector of choline in bulk analysis and cholinesterase assay was investigated. We examined the interferences from red-ox species and heavy metals in the blood and in the environmental sample matrixes. The sensor exhibited a linear increase of the amperometric signal at the concentration of choline ranging from 1.3 × 10 −7 to 1.0 × 10 −4 M, with a detection limit (evaluated as 3 σ ) of 130 nM and a sensitivity of 103 mA M −1 cm −2 under optimized potential applied (480 mV vs. Ag/AgCl). The biosensor retained its activity for more than 10 consecutive measurements and kept 75% of initial activity for three weeks of storage at 4 °C. The R.S.D. was determined as 1.9% for a choline concentration of 10 −4 M ( n = 10) with a typical response time of about 10 s. The developed choline biosensor was applied for butyrylcholinesterase assay showing a detection limit of 5 pM (3 σ ). We used the biosensor to develop the cholinesterase inhibitor assay. Detection limit for chlorpyrifos was estimated as 50 pM.

A new graph-theoretical approach called thermodynamic sampling of amino acid residues (TSAR) has been elaborated to explicitly account for the protein side chain flexibility in modeling conformation-dependent protein properties. In TSAR, a protein is viewed as a graph whose nodes correspond to structurally independent groups and whose edges connect the interacting groups. Each node has its set of states describing conformation and ionization of the group, and each edge is assigned an array of pairwise interaction potentials between the adjacent groups. By treating the obtained graph as a belief-network-a well-established mathematical abstraction-the partition function of each node is found. In the current work we used TSAR to calculate partition functions of the ionized forms of protein residues. A simplified version of a semi-empirical molecular mechanical scoring function, borrowed from our Lead Finder docking software, was used for energy calculations. The accuracy of the resulting model was validated on a set of 486 experimentally determined pK(a) values of protein residues. The average correlation coefficient (R) between calculated and experimental pK(a) values was 0.80, ranging from 0.95 (for Tyr) to 0.61 (for Lys). It appeared that the hydrogen bond interactions and the exhaustiveness of side chain sampling made the most significant contribution to the accuracy of pK(a) calculations.

The dG prediction accuracy by the Lead Finder docking software on the CSAR test set was characterized by R(2)=0.62 and rmsd=1.93 kcal/mol, and the method of preparation of the full-atom structures of the test set did not significantly affect the resulting accuracy of predictions. The primary factors determining the correlation between the predicted and experimental values were the van der Waals interactions and solvation effects. Those two factors alone accounted for R(2)=0.50. The other factors that affected the accuracy of predictions, listed in the order of decreasing importance, were the change of ligand's internal energy upon binding with protein, the electrostatic interactions, and the hydrogen bonds. It appears that those latter factors contributed to the independence of the prediction results from the method of full-atom structure preparation. Then, we turned our attention to the other factors that could potentially improve the scoring function in order to raise the accuracy of the dG prediction. It turned out that the ligand-centric factors, including Mw, cLogP, PSA, etc. or protein-centric factors, such as the functional class of protein, did not improve the prediction accuracy. Following that, we explored if the weak molecular interactions such as X-H...Ar, X-H...Hal, CO...Hal, C-H...X, stacking and π-cationic interactions (where X is N or O), that are generally of interest to the medicinal chemists despite their lack of proper molecular mechanical parametrization, could improve dG prediction. Our analysis revealed that out of these new interactions only CO...Hal is statistically significant for dG predictions using Lead FInder scoring function. Accounting for the CO...Hal interaction resulted in the reduction of the rmsd from 2.19 to 0.69 kcal/mol for the corresponding structures. The other weak interaction factors were not statistically significant and therefore irrelevant to the accuracy of dG prediction. On the basis of our findings from our participation in the CSAR scoring challenge we conclude that a significant increase of accuracy predictions necessitates breakthrough scoring approaches. We anticipate that the explicit accounting for water molecules, protein flexibility, and a more thermodynamically accurate method of dG calculation rather than single point energy calculation may lead to such breakthroughs.

We compared explicit and implicit solvation approaches in modeling the free energy profile of the final step of Suzuki-Miyaura coupling. Both approaches produced similar ΔG(≠) in all the studied solvents (benzene, toluene, DMF, ethanol, and water). Solvation free energies of individual reaction components reasonably correlated for explicit and implicit models in aprotic solvents (RMSE = 30-50 kJ mol(-1), R(2)0.71). However for ethanol and water the correlation was poor. We attributed this difference to the formation of the PdH-O hydrogen bond with Pd(PPh3)2 which was surprisingly observed in explicit modeling. Further QM calculations of the Pd(PPh3)2-H2O system confirmed the direction (PdH) and stability of this bonding. Therefore we stress the need for considering explicit solvation for modeling Pd-catalyzed reactions in protic solvents.

Novel rationally-designed Syk-kinase inhibitor MT-SYK-03 demonstrated equal potency with R406 (active metabolite of Fostamatinib, a phase III clinical trial candidate) in cellular models of autoimmunity and cancer with EC50 values in sub-micromolar range, while MT-SYK-322 was less active.

A preliminary simulation of bioactive compounds followed by their synthesis have been carried out: a set of new fragment PARP1 inhibitors – 3,5,6,7-tetrahydro-4 H -cyclopenta[4,5]thieno[2,3- d ]pyrimidin-4-one derivatives – have been obtained. Molecular simulation has shown that binding is characterized by correlated hydrogen bonds with PARP1 and displacement of the highly-conservative water molecule by a polar group.

A computational approach that combines the molecular dynamics (MD) breathing sphere model for simulation of the initial stage of laser ablation and the direct simulation Monte Carlo (DSMC) method for simulation of the multi-component ablation plume development on the time- and length-scales of real experimental configurations is presented. The combined multiscale model addresses different processes involved in the laser ablation phenomenon with appropriate resolutions and, at the same time, accounts for the interrelations among the processes. Preliminary results demonstrate the capabilities of the model and provide new insights into complex processes occurring during the ablation plume expansion. The spatial distribution of monomers in the plume is found to be strongly affected by the presence of large clusters. Interaction between the clusters and monomers can result in splitting of the monomer distribution into faster and slower components. The overall spatial mass distribution is found to have little relation with the monomer distribution.

A two-stage computational model of evolution of a plume generated by laser ablation of an organic solid is proposed and developed. The first stage of the laser ablation, which involves laser coupling to the target and ejection of molecules and clusters, is described by the molecular dynamics (MD) method. The second stage of a long-term expansion of the ejected plume is modeled by the direct simulation Monte Carlo (DSMC) method. The presence of clusters, which comprise a major part of the overall plume at laser fluences above the ablation threshold, presents the main computational challenge in the development of the combined model. An extremely low proportion of large-sized clusters hinders both the statistical estimation of their characteristics from the results of the MD model and the following representation of each cluster size as a separate species, as required in the conventional DSMC. A number of analytical models are proposed and verified for the statistical distributions of translational and inter...

Diastereoselective synthesis of 4-amino-7-hydroxyheptanoic acids 1 , new GABA analogues, was performed involving reduction of C-3 functionalized 5,6-dihydro-4 H -1,2-oxazines available from nitroethane. Molecular docking studies showed that amino acids of type 1 may bind to GABA transaminase, however, no inhibition was observed in the experiments with the enzyme.

The formation of a columnar structure, different expansion directions of the luminous (monomers) and obscure (droplets) plume species, and gradual deflection of the luminous plume are found to be interrelated in special experiments on pulsed laser deposition of Si. The obscure species always expands in the direction of incidence, which leads to a characteristic skewed angular distribution of the deposition rate. These observations are explained by the change of the microscopic mechanism of laser ablation from monomer evaporation at low local fluences to phase explosion at higher local fluences.

The enantioselectivity of the Diels–Alder reaction between (E)-3-(4-nitrophenyl)-1-(pyridin-3-yl)prop-2-en-1-one and cyclopenta-1,3-diene in the chiral ionic liquids 3-butyl-1-methylimidazolium (S)-camphorsulfonate and (S)-1-methyl-3-(pyrrolidin-2-ylmethyl)- imidazolium tosylate or upon chiral promotion with chiral oxazaborolidine was modeled by molecular and quantum mechanics and then experimentally studied; computations were in good agreement with the experimental data, resulting in no stereoselectivity with a chiral ionic liquid used as a co-solvent and prominent stereoselectivity upon chiral promotion.

4-Fluoro-6-pentafluoroethyl-5-trifluoromethylpyrimidines have been synthesized by the reaction of perfluoro-2-methylpent-2-ene with aceto- and trifluoroacetoamidines. The high activity of the fluorine atom at position 4 of these compounds in reactions with nucleophilic reagents was found.

Rationale: An increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] cyt ) in pulmonary arterial smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation and pulmonary vascular remodeling. The dihydropyridine Ca 2+ channel blockers, such as nifedipine, have been used for treatment of idiopathic pulmonary arterial hypertension (IPAH). Objective: Our previous study demonstrated that the Ca 2+ -sensing receptor (CaSR) was upregulated and the extracellular Ca 2+ -induced increase in [Ca 2+ ] cyt was enhanced in PASMC from patients with IPAH and animals with experimental pulmonary hypertension. Here, we report that the dihydropyridines (eg, nifedipine) increase [Ca 2+ ] cyt by activating CaSR in PASMC from IPAH patients (in which CaSR is upregulated), but not in normal PASMC. Methods and Results: The nifedipine-mediated increase in [Ca 2+ ] cyt in IPAH-PASMC was concentration dependent with a half maximal effective concentration of 0.20 µmol/L. Knockdown of CaSR with siRNA in IPAH-PASMC significantly inhibited the nifedipine-induced increase in [Ca 2+ ] cyt , whereas overexpression of CaSR in normal PASMC conferred the nifedipine-induced rise in [Ca 2+ ] cyt . Other dihydropyridines, nicardipine and Bay K8644, had similar augmenting effects on the CaSR-mediated increase in [Ca 2+ ] cyt in IPAH-PASMC; however, the nondihydropyridine blockers, such as diltiazem and verapamil, had no effect on the CaSR-mediated rise in [Ca 2+ ] cyt . Conclusions: The dihydropyridine derivatives increase [Ca 2+ ] cyt by potentiating the activity of CaSR in PASMC independently of their blocking (or activating) effect on Ca 2+ channels; therefore, it is possible that the use of dihydropyridine Ca 2+ channel blockers (eg, nifedipine) to treat IPAH patients with upregulated CaSR in PASMC may exacerbate pulmonary hypertension.

Diastereoselective synthesis of 4-amino-7-hydroxyheptanoic acids 1 , new GABA analogues, was performed involving reduction of C-3 functionalized 5,6-dihydro-4 H -1,2-oxazines available from nitroethane. Molecular docking studies showed that amino acids of type 1 may bind to GABA transaminase, however, no inhibition was observed in the experiments with the enzyme.

Molecular mechanisms of acute lung injury (ALI) are poorly defined. Our previous study demonstrated that recombinant angiopoietin-1 (Ang1) can protect against oleic acid (OA) induced ALI at an early stage. The purpose of this study was to elucidate whether vascular endothelial growth factor (VEGF), Bcl-2, and Bad, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) play any role in the protective mechanism of recombinant Ang1 in OA-induced ALI. All BALB/C mice were administered a single dose of OA to induce lung injury. Lungs, bronchoalveolar lavage fluid (BALF), and serum were harvested at certain time points. The expression of VEGF, Bcl-2, Bad, PI3K/Akt, and the histological changes in the lung, and the levels of VEGF, IL-6, and IL-10 in serum and BALF were examined. A second cohort of mice was followed for survival for 7 days. We observed increased expression of VEGF in BALF and serum and reduced expression of VEGF in lung tissue. Recombinant Ang1 treatment, however, up-regulated VEGF expression and p-Akt/Akt in lung tissue but down-regulated VEGF expression in BALF and serum. OA led to a decrease of anti-apoptotic marker Bcl-2 and a marked increase of pro-apoptotic marker Bad. Compared with the ALI group, in the recombinant Ang1 treated group, Bcl-2 expression was restored, and Bad expression was clearly attenuated. In addition, recombinant Ang1 attenuated the lung pathological changes and improved the survival of mice. These findings suggest that recombinant Ang1 may be a promising potential treatment for ALI. It seems that VEGF is mediated by PI3K/Akt pathway which is required for Ang1-mediated protection of lung injury. Activation of Akt stimulates expression of Bcl-2 and inhibits the expression of Bad, thus inhibiting the execution of apoptosis.

The reaction of fluoro-olefins ( I ) with hexafluoroacetone cyanohydrin ( II ) catalyzed by Et 3 N gives fluorinated 3-iminotetrahydrofurans ( III ), whose structures have been confirmed by spectral methods and various chemical transformations. A mechanism for the formation of products III is suggested including nucleophilic addition of an O-anion to a CC bond followed by intramolecular cyclization in the intermediate C-anion with participation of the CN group.

Perfluoro-2-methyl-2-pentene and perfluoro-1-methylcyclopentene react with ammonia or aniline under controlled conditions to give monoamination products.

Dichlorofuoromethyl- and 1,1-dichloro-2,2,2-trifluoroethyl-containing alcohols were synthesized by the reductive addition of CCI3F or CCI3CF3 to fluorocarbonyl compounds under the action of amalgamated aluminum.

Fluoro- or chlorobenzenes undergo the Friedel-Crafts acylation with perfluoroacyl chlorides ( I ) without complications to give p -halophenylketones ( II ); however, the reaction of I with bromobenzene gives phenylketones ( IV ) and dibromobenzene in addition to p -bromophenylketones ( III ). An intermediate p -bromobenzyl cation ( V ) is assumed to be responsible for the formation of the abnormal products IV and dibromobenzene. Condensation of hexafluoroacetone with bromobenzene in anhydrous HF also affords the products of disproportionation probably via an intermediate benzyl cation ( IX ).

A model of homogeneous nucleation based on first principles of the kinetic theory of gases, and developed for the direct simulation Monte Carlo method, is presented. Key parameters of the model, such as the binding energy and the heat capacity as functions of cluster size, are given for water and argon. For water, two datasets are used, one based on quantum calculations of heat capacity and binding energy available in the literature, and the other based on the present molecular dynamics computations. The model is analyzed using the thermal bath relaxation problem, and applied to compute the water dimer terminal mole fractions in circular orifice expansion.

First-principles kinetic theory is used in this work to analyze non-equilibrium homogeneous condensation of argon and water. The present model uses a recombination-reaction energy-dependent mechanism of the DSMC method for the dimer formation, and RRK model for the evaporation. Three-step validation of the model is conducted, (i) comparison of clusterization rates in an equilibrium heat bath with theoretical predictions, (ii) comparison of the argon dimer fractions in an orifice expansion with semi-analytical correlations, and (iii) comparison of water cluster size distributions with experimental measurements. Reasonable agreement was observed for all three parts of the validation.

Fluoro- or chlorobenzenes undergo the Friedel-Crafts acylation with perfluoroacyl chlorides ( I ) without complications to give p -halophenylketones ( II ); however, the reaction of I with bromobenzene gives phenylketones ( IV ) and dibromobenzene in addition to p -bromophenylketones ( III ). An intermediate p -bromobenzyl cation ( V ) is assumed to be responsible for the formation of the abnormal products IV and dibromobenzene. Condensation of hexafluoroacetone with bromobenzene in anhydrous HF also affords the products of disproportionation probably via an intermediate benzyl cation ( IX ).

Barbier-type reductive alkylation of perfluorocarboxylic acid esters ( I ) with CFCl 3 and activated Al was successfully performed to give α,α-dichloroperfluoroketones ( II ). A similar reaction of CF 3 COOEt with CCl 4 and Al provided a convenient synthesis of CF 3 COCCl 3 . Ketones ( II ) were fluorinated further with SbF 5 to form higher linear perfluoroketones ( IX ). An alternative approach to the synthesis of ketones ( IX ) was proposed by reductive perfluoroalkylation of esters ( I ) under the action of R F I and Al.

The traditional application of the classical homogeneous nucleation theory (CNT) to the condensation in rapidly expanding flows involves the use of the steady‐state nucleation rate. Since this rate is derived under the assumption of both steady‐state and isobaric/isothermal conditions, the applicability of CNT to highly nonequilibrium environments may be questionable. In addition, the usual strategy of CNT — gas dynamics coupling violates the original nucleation theory even in the isothermal/isobaric environment. In this study, we consider condensation in jets freely expanding into a vacuum. Using the isentropic solution, we approximate the time‐dependent pressure and temperature in a given small volume of a gas that is moving along the jet axis with the flow velocity. Several possible strategies of CNT implementation are considered within this volume. It is shown that the terminal cluster distributions are strongly affected by the steady‐state assumption and that the original CNT rate equations should be integrated into a computational scheme to model the coupled condensation flow.

Dichlorofuoromethyl- and 1,1-dichloro-2,2,2-trifluoroethyl-containing alcohols were synthesized by the reductive addition of CCI3F or CCI3CF3 to fluorocarbonyl compounds under the action of amalgamated aluminum.