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.

Is acriflavine an efficient co-drug in chemotherapy?

Cancer is a global health problem being the second worldwide cause of deaths right after cardiovascular diseases. The main methods of cancer treatment involve surgery, radiation and chemotherapy with an emphasis on the latter. Thus development of nanochemistry and nanomedicine in a search for more effective and safer cancer treatment is an important area of current research. Below, we present interaction of doxorubicin and acriflavine and the cytotoxicity of these drug nano-complexes towards cervical cancer (HeLa) cells. Experimental results obtained from NMR measurements and fluorescence spectroscopy show that the drugs' interaction was due to van der Waals forces, formation of hydrogen bonds and π-π stacking. Quantum molecular simulations confirmed the experimental results with regard to existing π-π stacking. Additionally it was shown that, at the level of theory applied (DFT, triple zeta basis set), the stacking interactions comprise the most preferable interactions (the lowest ΔG ca. -12 kcal mol-1) both between the molecules forming the acriflavine system and between the other component - another drug (doxorubicin) dimer. Biological tests performed on HeLa cells showed high cytotoxicity of the complexes, comparable to free drugs (ACF and DOX), both after 24 and 48 hours of incubation. For non-cancerous cells, a statistically significant difference in the cytotoxicity of drugs and complexes was observed in the case of a short incubation period. The results of the uptake study showed significantly more efficient cellular uptake of acriflavine than doxorubicin, whether administered alone or in combination with an anthracycline. The mechanism determining the selective uptake of acriflavine and ACF : DOX complexes towards non-cancer and cancer cells should be better understood in the future, as it may be of key importance in the design of complexes with toxic anti-cancer drugs.

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.

Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches.

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of ß,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties.

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.

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.

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.

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.