Novichok Nerve Agents as Inhibitors of Acetylcholinesterase-In Silico Study of Their Non-Covalent Binding Affinity.

In silico studies were performed to assess the binding affinity of selected organophosphorus compounds toward the acetylcholinesterase enzyme (AChE). Quantum mechanical calculations, molecular docking, and molecular dynamics (MD) with molecular mechanics Generalized-Born surface area (MM/GBSA) were applied to assess quantitatively differences between the binding energies of acetylcholine (ACh; the natural agonist of AChE) and neurotoxic, synthetic correlatives (so-called "Novichoks", and selected compounds from the G- and V-series). Several additional quantitative descriptors like root-mean-square fluctuation (RMSF) and the solvent accessible surface area (SASA) were briefly discussed to give-to the best of our knowledge-the first quantitative in silico description of AChE-Novichok non-covalent binding process and thus facilitate the search for an efficient and effective treatment for Novichok intoxication and in a broader sense-intoxication with other warfare nerve agents as well.

Nucleophilic Substitution at Tricoordinate Sulfur-Alkaline Hydrolysis of Optically Active Dialkoxysulfonium Salts: Stereochemistry, Mechanism and Reaction Energetics.

Optically active dialkoxyisopropylsulfonium salts were obtained by methylation (ethylation) of optically active alkyl isopropanesulfinates using methyl (ethyl) trifluoromethanesulfonate. Alkaline hydrolysis of a series of methoxy(alkoxy)sulfonium salts afforded the two sulfinate products methyl isopropanesulfinate and alkyl isopropanesulfinate, both formed with a slightly prevailing inversion of configuration at the sulfur atom. DFT calculations revealed that this substitution reaction proceeded stepwise according to an addition-elimination (A-E) mechanism involving the formation of high tetracoordinate S sulfurane intermediates.

Self-Restructuring of Polyhydromethylsiloxanes by the Hydride Transfer Process: A New Approach to the Cross-Linking of Polysiloxanes and to the Fabrication of Thin Polysiloxane Coatings.

The branching and cross-linking of siloxane polymers are important processes in silicone technology. A new type of such a process has been developed, which is a self-restructuring of linear polyhydromethylsiloxane (PHMS). This process involves the reorganization of the PHMS to form a highly branched siloxane polymer or finally a cross-linked siloxane network.

Correction: Mikołajczyk et al. Nucleophilic Substitution at Heteroatoms-Identity Substitution Reactions at Phosphorus and Sulfur Centers: Do They Proceed in a Concerted (SN2) or Stepwise (A-E) Way? 2022, , 599.

(1) The authors would like to correct mistakes in the title paper [...

Nucleophilic Substitution at Heteroatoms-Identity Substitution Reactions at Phosphorus and Sulfur Centers: Do They Proceed in a Concerted (S2) or Stepwise (A-E) Way?

The mechanisms of three selected identity substitution reactions at phosphorus and sulfur occurring with stereospecific inversion have been investigated using density functional theory (DFT). The first identity reaction between methoxyl anion and methyl ethylphenylphosphinate reported in 1963 has been shown to proceed in a stepwise fashion according to the addition-elimination (A-E) mechanism involving formation of a pentacoordinate phosphorus intermediate (TBI-). In contrast, the results of DFT studies of the identity chloride exchange reaction in (ethoxy)ethylphosphonochloridothionate in acetone solution provided evidence that it proceeds synchronously according to the classical Ingold's S2-P mechanism.

Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric - and -2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies.

Geometrical - and - isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of corresponding cyclic P-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen-halogen exchange at P-halogenide. Their conformation and configuration at the C-ring carbon and phosphorus stereocentres were studied by NMR (H, P) methods, X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reactions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown to depend on the nature of halogen.

Reactions of Zirconium (IV) n-Propoxide with SiH-Functional Polysiloxanes as a Route to Siloxane-Zirconium Hybrid Materials with Enhanced Refractive Index.

The reaction of poly(hydromethylsiloxane-co-methylphenylsiloxane) with zirconium (IV) n-propoxide in dry toluene leads to extensive scission of the siloxane chain and conversion of Si-H groups. These processes produce oligomeric siloxanes and organosilanes containing moisture sensitive propoxy and siloxy-zirconate groups. The obtained post-reaction solution of zirconium containing heterosiloxane oligomers is stable under anhydrous conditions for several weeks.

Effect of temperature on B(CF)-catalysed reduction of germanium alkoxides by hydrosilanes - a new route to germanium nanoparticles.

Reduction of Ge(OBu)4 with PhMe2SiH catalyzed by B(C6F5)3 at ambient temperature leads to GeH4. We discovered that a higher temperature (above 100 °C) completely changes the reaction course by producing germanium nanoparticles (Ge NPs) in high yield. This process provides a simple one-pot method for Ge NPs synthesis from readily available substrates under mild conditions.

C5-Substituted 2-Selenouridines Ensure Efficient Base Pairing with Guanosine; Consequences for Reading the NNG-3' Synonymous mRNA Codons.

5-Substituted 2-selenouridines (R5Se2U) are post-transcriptional modifications present in the first anticodon position of transfer RNA. Their functional role in the regulation of gene expression is elusive. Here, we present efficient syntheses of 5-methylaminomethyl-2-selenouridine (, mnm5Se2U), 5-carboxymethylaminomethyl-2-selenouridine (, cmnm5Se2U), and Se2U () alongside the crystal structure of the latter nucleoside.

Reasons for enhanced activity of doxorubicin on co-delivery with octa(3-aminopropyl)silsesquioxane.

This paper presents results of spectroscopic (NMR, FTIR, fluorescence), Q-TOF mass spectrometry and -potential analyses of interactions between octa(3-aminopropyl)silsesquioxane hydrochloride (POSS-NH·HCl) and anticancer drug - doxorubicin hydrochloride. These studies aimed at explanation of the enhanced activity of doxorubicin on co-delivery with POSS-NH. The results point to the formation of active complexes ionic interactions between the ammonium chloride groups of silsesquioxane and the drug, and not, as suggested earlier, NH⋯N hydrogen bonding.

Nucleophilic Substitution at Tetracoordinate Sulfur. Kinetics and Mechanism of the Chloride-Chloride Exchange Reaction in Arenesulfonyl Chlorides: Counterintuitive Acceleration of Substitution at Sulfonyl Sulfur by -Alkyl Groups and Its Origin.

The chloride-chloride exchange reaction in arenesulfonyl chlorides was investigated experimentally and theoretically by density functional theory (DFT) calculations. The second order rate constants and activation parameters of this identity reaction were determined for 22 variously substituted arenesulfonyl chlorides using radio-labeled EtNCl. The chloride exchange rates of 11 sulfonyl chlorides bearing -and -substituents (σ constants from -0.

1-(Acylamino)alkylphosphonic Acids-Alkaline Deacylation.

The alkaline deacylation of a representative series of 1-(acylamino)alkylphosphonic acids [(AC)-AA: (AC) = Ac, TFA, Bz; AA = Gly, Ala, Val, Pgl and Phe] in an aqueous solution of KOH (2M) was investigated. The results suggested a two-stage reaction mechanism with a quick interaction of the hydroxyl ion on the carbonyl function of the amide R-C(O)-N(H)- group in the first stage, which leads to instant formation of the intermediary acyl-hydroxyl adducts of R-C(O)₂-N(H)-, visible in the P NMR spectra. In the second stage, these intermediates decompose slowly by splitting of the RC(O)₂-N(H)- function with the subsequent formation of 1-aminoalkylphosphonate and carboxylate ions.

C5-substituents of uridines and 2-thiouridines present at the wobble position of tRNA determine the formation of their keto-enol or zwitterionic forms - a factor important for accuracy of reading of guanosine at the 3΄-end of the mRNA codons.

Modified nucleosides present in the wobble position of the tRNA anticodons regulate protein translation through tuning the reading of mRNA codons. Among 40 of such nucleosides, there are modified uridines containing either a sulfur atom at the C2 position and/or a substituent at the C5 position of the nucleobase ring. It is already evidenced that tRNAs with 2-thiouridines at the wobble position preferentially read NNA codons, while the reading mode of the NNG codons by R5U/R5S2U-containing anticodons is still elusive.

Computational benchmark for calculation of silane and siloxane thermochemistry.

Geometries of model chlorosilanes, R3SiCl, silanols, R3SiOH, and disiloxanes, (R3Si)2O, R = H, Me, as well as the thermochemistry of the reactions involving these species were modeled using 11 common density functionals in combination with five basis sets to examine the accuracy and applicability of various theoretical methods in organosilicon chemistry. As the model reactions, the proton affinities of silanols and siloxanes, hydrolysis of chlorosilanes and condensation of silanols to siloxanes were considered. As the reference values, experimental bonding parameters and reaction enthalpies were used wherever available.

2-Thiouracil deprived of thiocarbonyl function preferentially base pairs with guanine rather than adenine in RNA and DNA duplexes.

2-Thiouracil-containing nucleosides are essential modified units of natural and synthetic nucleic acids. In particular, the 5-substituted-2-thiouridines (S2Us) present in tRNA play an important role in tuning the translation process through codon-anticodon interactions. The enhanced thermodynamic stability of S2U-containing RNA duplexes and the preferred S2U-A versus S2U-G base pairing are appreciated characteristics of S2U-modified molecular probes.

Differentiation of diastereoisomers of protected 1,2-diaminoalkylphosphonic acids by EI mass spectrometry and density functional theory.

Electron ionization mass spectrometry and density functional theory (DFT) calculations have been used to study the fragmentation of diastereoisomers of protected 1,2-diaminoalkylphosphonic acids. The loss of a diethoxyphosphoryl group and the elimination of diethyl phosphonate were found to be competitive fragmentation processes, which can be used to differentiate both stereoisomers. Selective deuterated analogs and product- and precursor-ion mass spectra allowed the elucidation of the fragmentation mechanisms.

Molecular modeling of the lipase-catalyzed hydrolysis of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue.

The molecular modeling of the CAL-B-promoted hydrolysis reactions of acetoxymethyl(i-propoxy)phenylphosphine oxide and its P-borane analogue, acetoxymethyl(i-propoxy)-phenylphosphine P-borane, confirms that the reactions proceed with the same stereochemistry and in both cases the (S)-enantiomers are preferentially transformed by the enzyme. Molecular mechanics calculations show that the main reason for the particular stereoselectivity of the substrates is the steric effect of the phenyl group which causes a remarkable hindrance when placed inside the active site. The replacement of the oxygen by a borane group at the phosphorus stereogenic center does not nullify the stereorecognition by the enzyme, although for the P-borane a lower stereoselectivity is observed.

Studies on the efficient generation of phosphorus-carbon bonds via a rearrangement of P(III) esters catalysed by trimethylhalosilanes.

Halotrimethylsilanes Me(3)SiX (X = Br, I) catalyse rearrangements of tricoordinate phosphorus esters R'R''P-OR into the corresponding phosphoryl systems R'R''P(O)R. This provides a simple and efficient route to a variety of structures containing phosphorus-carbon bonds, under mild conditions and with good yields. The reaction mechanism was investigated in detail by (31)P NMR spectroscopy and independent synthesis of the reaction intermediates.

Synthesis of p-(di-tert-butyl[(18)F]fluorosilyl)benzaldehyde ([(18)F]SiFA-A) with high specific activity by isotopic exchange: a convenient labeling synthon for the (18)F-labeling of N-amino-oxy derivatized peptides.

The syntheses of different (18)F-labeled peptides using the highly effective labeling synthon p-(di- tert-butylfluorosilyl) benzaldehyde ([ (18)F]SiFA-A) for the development of (18)F-radiopharmaceuticals for oncological positron emission tomography (PET) is reported. The novel and mild labeling technique for the radiosynthesis of [ (18)F]SiFA-A, based on an unexpectedly efficient isotopic (19)F- (18)F exchange, yielded the (18)F-synthon [ (18)F]SiFA-A in almost quantitative yields in high specific activities between 225 and 680 GBq/micromol (6081-18 378 Ci/mmol) without applying HPLC purification. The [ (18)F]SiFA-A was finally used to label the N-terminal amino-oxy (N-AO) derivatized peptides AO-Tyr (3)-octreotate (AO-TATE), cyclo(fK(AO-N)RGD and N-AO-PEG 2-[D-Tyr-Gln-Trp-Ala-Val-betaAla-His-Thi-Nle-NH 2] (AO-BZH3, a bombesin derivative) in high radiochemical yields.

A novel class of DNA analogs bearing 5'-C-phosphonothymidine units: synthesis and physicochemical and biochemical properties.

S(C) and R(C) diastereomers of 5'-C-(O,O-diethyl)-phosphonylthymidine ((R)T and (S)T) were used for the synthesis of the dimers T(R)T and T(S)T, respectively. These dimers were incorporated at selected sites in oligonucleotide constructs. Melting temperature (Tm) experiments demonstrated that relative to the unmodified oligodeoxyribonucleotide, the presence of the (R)T moiety reduced the thermal stability of the duplexes by approximately 5.

Hydrolysis of fluorosilanes: a theoretical study.

Hydrolysis and condensation of simple trifluorosilanes, HSiF3 and MeSiF3, was studied by quantum mechanical methods. Hydrolysis of fluorosilanes is highly endothermic. The Gibbs free energy of the first reaction step in the gas phase is 31.