Hydroxyderivatives of levoglucosenone in reactions of enantioselective reduction of 1,3-diphenylpropan-1-one

The enantioselective reduction of prochiral ketones is an important method for the preparation of enanti-enriched secondary alcohols, which can serve as starting materials for optically active compounds. Chiral metal hydride reagents, such as lithium aluminum hydride (LiAlH4) and sodium borohydride (NaBH4), modified with chiral ligands, have been developed to effect enantioselective reduction. However, in most cases, derivatives are used to obtain chiral hydride reagents, which are rare and hardly available. Therefore, the search for more accessible and effective derivatives suitable for the modification of hydride reagents is an urgent task. Levoglucosenone is an optically pure enone of carbohydrate nature, readily available by pyrolysis of any cellulose-containing materials. Levoglucosenone is considered a promising bioplatform for both laboratory synthesis and industrial use. The prospect of the development of chemistry of levoglucosenone and its derivatives in industry makes it possible to pay attention to these compounds from the point of view of studying their possibilities as chiral inducers or auxiliaries. In this work, we studied the possibilities of chiral induction in the reduction reactions of 1,3-diphenylpropan-1-one with hydride reagents obtained by replacing hydrogens in LiAlH4 and NaBH4 with hydroxy derivatives of levoglucosenone. The reduction of 1,3-diphenylpropan-1-one with chiral aluminum hydride reagents proceeded with low enantioselectivity, mainly with a predominance of (S)-1,3-diphenylpropan-1-ol. It was found that the enantiomeric purity of the S-stereomer decreases with an increase in the substitution of hydrogen atoms in LiAlH4 by hydroxy derivatives of levoglucosenone. Reduction of 1,3-diphenylpropan-1-one with reagents obtained by partial neutralization of NaBH4 with hydroxy derivatives of levoglucosenone, on the contrary, predominantly leads to the formation of (R)-1,3-diphenylpropan-1-ol. The addition of AcOH and Bu4NCl to NaBH4 has a positive effect on the optical frequency of the R-alcohol. At the same time, enantioselectivity in the reactions was almost absent upon reduction of 1,3-diphenylpropan-1-one with reagents obtained by partial neutralization of BH3. The best results of enantioselective reduction were shown by unsaturated alcohols: (1S,4S,5R) -6,8-dioxabicyclo[3.2.1]oct-2-en-4-ol and (1S,4S,5R)-4-methyl-6,8-dioxabicyclo[3.2.1]oct-2-en-4-ol, of which (1S,4S,5R)-6,8-dioxabicyclo[3.2.1]oct-2-en-4-ol was the most effective. It is likely that an increase in the enantioselectivity of reactions carried out in the presence of hydroxy derivatives of levoglucosenone is possible by obtaining more bulky chiral ligands, provided that the double bond is retained.

Assay-Based Differentiation in the Neutralization Profile of Unfractionated Heparin, Enoxaparin, and Fondaparinux by Andexanet Alfa

Andexanet alfa is a recombinant factor Xa decoy protein, designed to reverse bleeding associated with oral anti-Xa agents. Andexanet alfa is also reported to neutralize the effects of heparin-related drugs. This study focused on the neutralization profiles of unfractionated heparin (UFH), enoxaparin, and, a chemically synthetic pentasaccharide, fondaparinux by andexanet alfa. Whole blood clotting studies were carried out using thromboelastography (TEG) and activated clotting time (ACT). The anticoagulant profile of UFH, enoxaparin, and fondaparinux was studied using the activated partial thromboplastin time (aPTT), thrombin time (TT), and amidolytic anti-Xa, and anti-IIa methods. Thrombin generation inhibition was studied using the calibrated automated thrombogram system. Reversal of each of these agents was studied by supplementing andexanet alfa at 100 µg/mL. In the TEG, andexanet alfa produced almost a complete reversal of the anticoagulant effects of UFH and enoxaparin; however, it augmented the effects of fondaparinux. In the ACT, aPTT, and TT, UFH produced strong anticoagulant effects that were almost completely neutralized by andexanet alfa. Enoxaparin produced milder anticoagulant responses that were partially neutralized, whereas fondaparinux did not produce any sizeable effects. In the anti-Xa and anti-IIa assays, UFH exhibited partial neutralization whereas enoxaparin and fondaparinux did not show any neutralization. All agents produced varying degrees of the inhibition of thrombin generation, which were differentially neutralized by andexanet alfa. These results indicate that andexanet alfa is capable of differentially neutralizing anticoagulant and antiprotease effects of UFH and enoxaparin in an assay-dependent manner. However, andexanet alfa is incapable of neutralizing the anti-Xa effects of fondaparinux.

The apple pectin influence on biochemical and hematological parameters in animals with chronic alcohol intoxication

Enterosorbents and prebiotics are included in treatment protocols for somatic disorders in chronic alcohol intoxication. Considering on relevant properties of pectin, the purpose of the study was to investigate its effect on biochemical and hematological parameters of experimental animals in chronic alcoholic intoxication. The study was conducted on 30 white outbred rats (males) weighing 180-200 g, which injected 30% ethanol into the stomach (control), animals in experimental groups after 30 minutes, got apple pectin at a dose of 0.2 g/100 g of body weight and reference preparations — activated charcoal and silicon dioxide — by 0.25 g and 0.05 g, respectively for 11 days. The statistical analysis was performed by Microsoft Exel and Statistica 5.5 (Multiple Regression) software using variation statistics methods. Research results. Changes in lipid metabolism were manifested by an increase in serum cholesterol of alcoholic animals without treatment by 29.8% compared with intact (p˂0.05). The use of pectin and reference drugs significantly reduced cholesterol levels. In the group with the use of pectin, this indicator was 36% lower, activated charcoal — by 19%, silicon dioxide — by 26.4% (p˂0,05) compared to untreated animals, at the same time, practically did not differ from intact animals. The level of triacylglycerols increased in all experimental groups and, although, it significantly differed from the intact, at the same time, it was essentially lower in all groups of treated animals than in non-treated ones (p˂0.05). A normalizing effect of pectin and silicon dioxide on the number of erythrocytes and hemoglobin levels comparing to alcoholated and treated activated charcoal animals also were shown (p˂0.05). The apple pectin curative effect on lipid and protein metabolism, as well as on the content of erythrocytes and hemoglobin in the blood of animals with chronic alcohol intoxication, practically equaled to standard enterosorbents, and on some indicators exceeds their effect, which may also be due to partial neutralization of ethanol.

A Decision Framework for Managing the Risk of Terrorist Threats at Rail Stations Interconnected with Airports

This paper highlights a risk-based decision-making framework on a basis of probabilistic risk assessment (PRA). Its aim is to enable stakeholders of transport infrastructures to systematically and effectively allocate their limited resources and consequently improve resilience when facing the potential risk of a terrorist attack. The potential risk of a terrorist attack affects the inter-operation of transportation infrastructures including airports and rail stations, the regional economy, and imposes additional costs of security or any countermeasures. This novel framework is thus established in order to model the security system, to consider a multitude of threat scenarios, and to assess the decisions and choices taken by the aggressors during various stages of their attack. The framework has capability to identify the state of partial neutralization, which reveals the losses incurred when the terrorist could not reach the primary target. In this study, an underground railway station interconnected to an international airport has been used as a case study to demonstrate the effectiveness of this novel framework. By the rigorous assessment of potential losses during a variety of threat scenarios, four countermeasures that could minimise losses are proposed: screening of passengers by observation techniques (SPOT), a surveillance system, increase of the cargo screening rate, and blast-resistant cargo containers. The cost and efficiency assessment is employed to determine the most suitable countermeasures when the value of the security measures equal their cost. Note that ongoing research is still needed to establish better countermeasures since there is no end to the creativity of terrorists. The new technology, such as wireless sensors, will play an important role in the security system in the future. In particular, this study will help insurance and rail industries to model and manage risk profiles at critical infrastructure.

Functional Stability of HIV-1 Envelope Trimer Affects Accessibility to Broadly Neutralizing Antibodies at Its Apex

ABSTRACT The trimeric envelope glycoprotein spike (Env) of HIV-1 is the target of vaccine development to elicit broadly neutralizing antibodies (bnAbs). Env trimer instability and heterogeneity in principle make subunit interfaces inconsistent targets for the immune response. Here, we investigate how functional stability of Env relates to neutralization sensitivity to V2 bnAbs and V3 crown antibodies that engage subunit interfaces upon binding to unliganded Env. Env heterogeneity was inferred when antibodies neutralized a mutant Env with a plateau of less than 100% neutralization. A statistically significant correlation was found between the stability of mutant Envs and the MPN of V2 bnAb, PG9, as well as an inverse correlation between stability of Env and neutralization by V3 crown antibody, 447-52D. A number of Env-stabilizing mutations and V2 bnAb-enhancing mutations were identified in Env, but they did not always overlap, indicating distinct requirements of functional stabilization versus antibody recognition. Blocking complex glycosylation of Env affected V2 bnAb recognition, as previously described, but also notably increased functional stability of Env. This study shows how instability and heterogeneity affect antibody sensitivity of HIV-1 Env, which is relevant to vaccine design involving its dynamic apex. IMPORTANCE The Env trimer is the only viral protein on the surface of HIV-1 and is the target of neutralizing antibodies that reduce viral infectivity. Quaternary epitopes at the apex of the spike are recognized by some of the most potent and broadly neutralizing antibodies to date. Being that their glycan-protein hybrid epitopes are at subunit interfaces, the resulting heterogeneity can lead to partial neutralization. Here, we screened for mutations in Env that allowed for complete neutralization by the bnAbs. We found that when mutations outside V2 increased V2 bnAb recognition, they often also increased Env stability-of-function and decreased binding by narrowly neutralizing antibodies to the V3 crown. Three mutations together increased neutralization by V2 bnAb and eliminated binding by V3 crown antibodies. These results may aid the design of immunogens that elicit antibodies to the trimer apex.

Crystal structure of sodium dihydrogen arsenate

Single crystals of the title compound, Na(H2AsO4), were obtained by partial neutralization of arsenic acid with sodium hydroxide in aqueous solution. The crystal structure of Na(H2AsO4) is isotypic with the phosphate analogue and the asymmetric unit consists of two sodium cations and two tetrahedral H2AsO4−anions. Each of the sodium cations is surrounded by six O atoms of five H2AsO4−groups, defining distorted octahedral coordination spheres. In the extended structure, the sodium cations and dihydrogen arsenate anions are arranged in the form of layers lying parallel to (010). Strong hydrogen bonds [range of O...O distances 2.500 (3)–2.643 (3) Å] between adjacent H2AsO4−anions are observed within and perpendicular to the layers. The isotypic structure of Na(H2PO4) is comparatively discussed.

SYNTHESIS AND REACTIVITY OF 4-NITRO-3-(TETRAZOL-5-YL) FURAZAN WITH N- AND O-NUCLEOPHILES

A rational four-stages scheme for the synthesis of 4-nitro-3-(tetrazol-5-yl)furazane is proposed. The synthesis starts from the stage of 3-amino-4-(1,2,4-oxadiazol-3-yl)-furazan preparation by condensation of amidoxime of 4-aminofurazan-3-carboxylic acid with triethyl orthoformate, further reductive ring opening of 1,2,4-oxadiazole cycle. The action of hydrazine results in amidrazone of 4-aminofurazan-3-carboxylic acid formation. On the next step the diazotization of the resulting compound with sodium nitrite in acetic acid gives 3-amino-4-(tetrazol-5-yl)furazane. At last stage the titled 4-nitro-3-(tetrazol-5-yl)furazan was synthesized by oxidation of the amino group of 3-amino-4-(tetrazol-5-yl)furazan by a solution of 30% hydrogen peroxide in concentrated sulfuric acid with 85% yield. The increase in the oxidative activity of the H2O2/H2SO4 system by carrying out the oxidation stage at an elevated temperature made possible to substantially reduce the consumption of hydrogen peroxide and sulfuric acid. The desired 4-nitro-3-(tetrazol-5-yl)furazan was isolated by partial neutralization of the reaction mixture with sodium orthophosphate, followed by extraction with ethyl acetate. The total yield of 4-nitro-3-(tetrazol-5-yl)furazane in terms of the starting amidoxime of 4-aminofurazan-3-carboxylic acid was 42-48%. It was shown that the reaction of 4-nitro-3-(tetrazol-5-yl)furazan with a number of N- and O-nucleophilic agents (sodium azide, high-basic amines, hydrazine, sodium hydroxide, methanol in the presence of potassium carbonate) resulted in the substitution of the nitro group of the selected compound by a nucleophile and formation of corresponding 4-R-3-(tetrazol-5-yl)furazane derivatives (R = N3, substituted amino group, NHNH2, OH, OMe). Some chemical properties of thereby obtained compounds are considered. Thus [3 + 2] cycloaddition reaction of 4-azido-3-(tetrazol-5-yl)furazane (R = N3) with propargyl alcohol was used at the synthesis of 4- (4-hydroxy-methyl-1,2,3-triazol-1-yl)-3-(tetrazol-5-yl)furazane. The condensation of 3-hydrazino-4-(tetrazol-5-yl)furazane (R = NHNH2) with carbonyl compounds in the case of reaction with benzaldehyde leads to the corresponding hydrazone, with β-dicarbonyl compounds (malonaldehyde, acetylacetone) pyrazole derivatives were obtained. The synthesized compounds are characterized by 1H and 13C nuclear magnetic resonance spectra, by IR and mass spectroscopy. For citation:Stepanova E.V., Stepanov A.I. Obtaining and Reactivity of 4-nitro-3-(tetrazol-5-yl) furazan with N- and O-nucleophiles. Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol. 2017. V. 60. N 5. P. 21-29