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 SIV sulfurane intermediates. In addition, the DFT calculations showed that recombination of the hydroxy anion with the methoxy(alkoxy)sulfonium cation-leading to the parallel formation of the two most stable primary sulfuranes, with the hydroxy and alkoxy groups in apical positions and their direct decomposition-is the most energetically favorable pathway.

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. It occurs through the transfer of a hydride ion between silicon atoms catalyzed by tris(pentafluoromethyl)borane. Its advantage over existing branching and cross-linking reactions is that it runs at room temperature without a low-molecular-weight cross-linker in the absence of water, silanol groups, or other protic compounds and it does not use metal catalysts. The study of this process was carried out in toluene solution. Its course was followed by 1H NMR, 29Si NMR and FTIR, SEC, and gas chromatography. A general mechanism of this new self-restructuring process supported by quantum calculations is proposed. It has been shown that a linear PHMS self-restructured to a highly branched polymer can serve as a pure methylsiloxane film precursor.

Correction: Mikolajczyk 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? Molecules 2022, 27, 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 (SN2) 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 1 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-1). In contrast, the results of DFT studies of the identity chloride exchange reaction in (ethoxy)ethylphosphonochloridothionate 3 in acetone solution provided evidence that it proceeds synchronously according to the classical Ingold's SN2-P mechanism. DFT calculations of the methoxyl-methoxy exchange reaction at sulfur in methyl p-toluenesulfinate 4 catalyzed by trifluoroacetic acid in methanol revealed that it proceeds stepwise (A-E mechanism), involving the formation of the high-coordinate sulfurane intermediate. In both identity transesterification reactions, 1 and 4, the transiently formed trigonal bipyramidal intermediates with the two methoxyl groups occupying apical positions (TBI-1 and TBI-4) have higher free energy barriers for the Berry-type pseudorotation than those for direct decomposition to starting phosphinate and sulfinate ensuring stereospecific inversion of configuration at the phosphinyl and sulfinyl centers. Thus, the DFT method proved its usefulness in the distinction between both mechanisms that are often indistinguishable by kinetic measurements.

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

Geometrical cis- and trans- 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 PIII-halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus pentachloride and (c) halogen-halogen exchange at PIV-halogenide. Their conformation and configuration at the C4-ring carbon and phosphorus stereocentres were studied by NMR (1H, 31P) 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. Cyclic cis- and trans-isomers of chlorides and bromides react with nucleophiles (HO-, CH3O-, Me2NH) with inversion of configuration at phosphorus. DFT calculations provided evidence that alkaline hydrolysis of cyclic thiophosphoryl chlorides proceeds according to the SN2-P mechanism with a single transition state according to the potential energy surface (PES) observed. The alkaline hydrolysis reaction of cis- and trans-fluorides afforded the same mixture of the corresponding cyclic thiophosphoric acids with the thermodynamically more stable major product. Similar DFT calculations revealed that substitution at phosphorus in fluorides proceeds stepwise according to the A-E mechanism with formation of a pentacoordinate intermediate since a PES with two transition states was observed.

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. However, its exposure to moisture initiates the hydrolytic condensation of the reactive groups leading to cross-linking and the formation of a siloxane-zirconium composite. Spin coating of the siloxane-zirconium prepolymer followed by exposure to moisture produces thin films with excellent light transparency and increased refractive index. The final coatings are characterized by ellipsometry, UV-Vis, IR, and 29 Si MAS NMR spectroscopies.

Effect of temperature on B(C6F5)3-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 (1, mnm5Se2U), 5-carboxymethylaminomethyl-2-selenouridine (2, cmnm5Se2U), and Se2U (3) alongside the crystal structure of the latter nucleoside. By using pH-dependent potentiometric titration, pKa values for the N3H groups of 1-3 were assessed to be significantly lower compared to their 2-thio- and 2-oxo-congeners. At physiological conditions (pH 7.4), Se2-uridines 1 and 2 preferentially adopted the zwitterionic form (ZI, ca. 90%), with the positive charge located at the amino alkyl side chain and the negative charge at the Se2-N3-O4 edge. As shown by density functional theory (DFT) calculations, this ZI form efficiently bound to guanine, forming the so-called "new wobble base pair", which was accepted by the ribosome architecture. These data suggest that the tRNA anticodons with wobble R5Se2Us may preferentially read the 5'-NNG-3' synonymous codons, unlike their 2-thio- and 2-oxo-precursors, which preferentially read the 5'-NNA-3' codons. Thus, the interplay between the levels of U-, S2U- and Se2U-tRNA may have a dominant role in the epitranscriptomic regulation of gene expression via reading of the synonymous 3'-A- and 3'-G-ending codons.

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 ortho-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 Et4N36Cl. The chloride exchange rates of 11 sulfonyl chlorides bearing para-and meta-substituents (σ constants from -0.66 to +0.43) in the aromatic ring followed the Hammett equation with a ρ-value of +2.02. The mono- and di-ortho-alkyl substituted sulfonyl chlorides exhibit an enhanced reactivity although both inductive and steric effects lower the reaction rate. The DFT calculations of their structures together with X-ray data showed that an increased reactivity is mainly due to a peculiar, rigid, strongly compressed and sterically congested structure. The DFT studies of the title reaction revealed that it proceeds via a single transition state according to the SN2 mechanism. The analogous fluoride exchange reaction occurs according to the addition-elimination mechanism (A-E) and formation of a difluorosulfurandioxide intermediate. The reliability of the calculations performed was supported by the fact that the calculated relative rate constants and activation parameters correlate well with the experimental kinetic data.

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 Z-potential analyses of interactions between octa(3-aminopropyl)silsesquioxane hydrochloride (POSS-NH2·HCl) and anticancer drug - doxorubicin hydrochloride. These studies aimed at explanation of the enhanced activity of doxorubicin on co-delivery with POSS-NH2. The results point to the formation of active complexes via ionic interactions between the ammonium chloride groups of silsesquioxane and the drug, and not, as suggested earlier, via NH⋯N hydrogen bonding. It has also been shown that the main driving force for the formation of the complexes can be strengthened by π-π stacking and hydrogen bonds. The experimental results are supported by quantum mechanical calculations. This work has proven that co-delivery with POSS offers a potentially advantageous and simple approach for improved efficacy in chemotherapy, avoiding often complicated synthesis of conjugates, involving covalent bonding between drug, nanocarrier and targeting agents.

1-(Acylamino)alkylphosphonic Acids-Alkaline Deacylation.

The alkaline deacylation of a representative series of 1-(acylamino)alkylphosphonic acids [(AC)-AAP: (AC) = Ac, TFA, Bz; AAP = GlyP, AlaP, ValP, PglP and PheP] 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 31P 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. For a series of 18 modified uridines and 2-thiouridines, we determined the pKa values and demonstrated that both modifying elements alter the electron density of the uracil ring and modulate the acidity of their N3H proton. In aqueous solutions at physiological pH the 2-thiouridines containing aminoalkyl C5-substituents are ionized in ca. 50%. The results, confirmed also by theoretical calculations, indicate that the preferential binding of the modified units bearing non-ionizable 5-substituents to guanosine in the NNG codons may obey the alternative C-G-like (Watson-Crick) mode, while binding of those bearing aminoalkyl C5-substituents (protonated under physiological conditions) and especially those with a sulfur atom at the C2 position, adopt a zwitterionic form and interact with guanosine via a 'new wobble' pattern.

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. Where there are no experimental data, W1 and CBS-QB3 values were used instead. For the gas phase conditions, excellent agreement between theoretical CBS-QB3 and W1 and experimental thermochemical values was observed. All DFT methods also give acceptable values and the precision of various functionals used was comparable. No significant advantage of newer more advanced functionals over 'classical' B3LYP and PBEPBE ones was noted. The accuracy of the results was improved significantly when triple-zeta basis sets were used for energy calculations, instead of double-zeta ones. The accuracy of calculations for the reactions in water solution within the SCRF model was inferior compared to the gas phase. However, by careful estimation of corrections to the ΔHsolv and ΔGsolv of H(+) and HCl, reasonable values of thermodynamic quantities for the discussed reactions can be obtained.

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. Recently, we have demonstrated that 2-thiouridine (alone or within an RNA chain) is predominantly transformed under oxidative stress conditions to 4-pyrimidinone riboside (H2U) and not to uridine. Due to the important biological functions and various biotechnological applications for sulfur-containing nucleic acids, we compared the thermodynamic stabilities of duplexes containing desulfured products with those of 2-thiouracil-modified RNA and DNA duplexes. Differential scanning calorimetry experiments and theoretical calculations demonstrate that upon 2-thiouracil desulfuration to 4-pyrimidinone, the preferred base pairing of S2U with adenosine is lost, with preferred base pairing with guanosine observed instead. Therefore, biological processes and in vitro assays in which oxidative desulfuration of 2-thiouracil-containing components occurs may be altered. Moreover, we propose that the H2U-G base pair is a suitable model for investigation of the preferred recognition of 3'-G-ending versus A-ending codons by tRNA wobble nucleosides, which may adopt a 4-pyrimidinone-type structural motif.

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. The structures of the transition states and product ions were optimized using the density functional theory (DFT), and free energy calculations confirmed the observed differences in the formation and relative intensities of specific fragment ions.

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. The latter is explained in terms of a smaller energy difference between complexes of CAL-B and particular enantiomers of the P-borane in comparison with those of the phosphine oxide, resulting from the steric effect of the BH3 group. The results helped to revise the previously published erroneous conclusions concerning absolute configuration of the phosphine-borane complex.

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. It has been demonstrated that the primary products of this catalytic reaction are halogeno P(III) structures R'R''PX and silyl ethers ROSiMe(3) and that they subsequently react to give the corresponding phosphorus silyl esters-Me(3)SiOPR'R''-and alkyl halides RX. At higher temperatures these intermediates then react to form R'R''P(O)R compounds. This paper also features the surprising observation that when esters Ph(2)POR and halotrimethylsilanes Me(3)SiX (X = Br, I) are used in 2:1 ratio, phosphonium salts Ph(2)R(2)P(+)X(-) and trimethylsilyl diphenylphosphinate--Ph(2)P(O)OSiMe(3)--are formed as the major products. Experimental evidence indicates that the mechanisms of both reactions are fundamentally different from that of the Michaelis-Arbuzov reaction. Me(3)SiCl is not reactive and this paper explains why.

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. Density functional theory (DFT) calculations confirmed high efficiency of the isotopic exchange, which is predicted to proceed via a pentacoordinate siliconate intermediate dissociating immediately to form the radiolabeled [ (18)F]SiFA-A.