Crystal structure of GTPase YsxC from Staphylococcus aureus.

The YsxC protein from Staphylococcus aureus is a GTP-binding protein from the TRAFAC superfamily of the TrmE-Era-EngA-EngB-Septin-like GTPase class, EngB family of GTPases. Recent structural and biochemical studies of YsxC function show that it is an integral part of the pathogenic microorganism life cycle, as it is involved in the assembly of the large 50S ribosomal subunit. Structural studies of this protein with its specific functional features make it an attractive target for further development of new selective antimicrobials. In this study, we cloned the ysxC protein gene from S. aureus, overexpressed the protein in E. coli, and subsequently purified and crystallized it. Protein crystals were successfully grown using the vapor diffusion method, yielding diffraction data with a resolution of up to 2 Å. Comparative analysis of the structure of SaYsxC with known three-dimensional structures of homologs from other microorganisms showed the presence of structural differences for the apo form.

α-Umpolung/Michael Addition/Quaternization Tandem Reaction to provide α-Imido-ß-phosphonium Propanoates with Broad Spectrum of Biological Activity.

This paper has been supported by the Kazan Federal University Strategic Academic Leadership Program ('PRIORITY-2030'). HRMS data were obtained in the CSF-SAC FRC KSC RAS by support of the State Assignment of the Federal Research Center "Kazan Scientific Center", Russian Academy of Sciences. A.D.V, conducted studies of anticancer activity with financial support form the government assignment for FRC Kazan Scientific Center of RAS.

Emission and Luminescent Vapochromism Control of Octahedral Cu4 I4 Complexes by Conformationally Restricted P,N Ligands.

A conformationally restricted P,N-ligand capable of the design of polynuclear copper(I) complexes was synthesized via the reaction of primary pyridylphosphine, paraformaldehyde, and benzhydrylamine. The reaction of the ligand with copper(I) iodide leads to the tetranuclear copper(I) complex with the octahedral type of copper-iodide core. Different orientation of coordination bonds of the ligands relative to the P,N2 -heterocyclic fragments and to the Cu4 I4 cores leads to the existence of two types of conformers of the complex with "compact" or "stretched" geometry of the Cu4 I4 cluster. This lability of the complex allowed for obtaining two crystalline phases displaying green or red luminescence. The TDDFT computations along with XRD structural analysis gave a strong interpretation of the green emission belonging to the "compact" form of the complex and belonging of the red emission to the "stretched" form. Moreover, both crystalline phases demonstrate the strong vapochromic responses of luminescence on the vapors of wide range of solvents.

Stereoelectronic Effect in the Reaction of α-Methylene Lactones with Tertiary Phosphines and Its Application in Organocatalysis.

The kinetic data indicate that the addition of tertiary phosphines to α-methylene lactones in acetic acid is strongly accelerated in comparison to the reactions of related open-chain esters. Six-membered α-methylene-δ-valerolactone exhibited a more pronounced rate increase than five-membered α-methylene-γ-butyrolactone. The use of α-methylene-γ-butyrolactam as a nitrogen analogue of α-methylene-γ-butyrolactone resulted in a total loss of the reaction acceleration. The observed reactivities were rationalized by DFT calculations at the RwB97XD/6-31+G(d,p) level of theory, showing that the intramolecular interaction between phosphonium and enolate oxygen centers provided by the locked s-cis-geometry of the heterocycles plays an important role in the stabilization of intermediate zwitterions. The reactivity is also controlled by the conformational flexibility of the heterocycle. The geometries of five-membered and, especially, six-membered lactone cycles are slightly changed upon the nucleophilic attack of phosphine, leading to the stabilizing stereoelectronic effect by the Ρ···Ο interaction. The addition of phosphine to α-methylene-γ-butyrolactam significantly distorts the initial geometry of the heterocycle, making the nucleophilic attack unfavorable. The application of the stereoelectronic effect to enhance the efficiency of the phosphine-catalyzed Michael and Pudovik reactions of α-methylene lactones was demonstrated.

Tuning Crystal Packing and Magnetic Properties in a Series of [Dy12] Metallocubanes Based on Azobenzene Derivatives of Salicylic Acid.

A series of four new Dy12 dodecanuclear clusters based on azobenzene derivative ligands of salicylic acid (L1-L4) has been synthesized and characterized in the crystalline phase using X-ray diffraction on single crystal and powder, IR spectroscopy, elemental analysis, and DSC-TGA methods. It was revealed that all obtained clusters exhibit the formation of the similar metallic cluster nodes, as vertex-sharing heterocubanes, obtained from four Dy3+ cations, three bridging hydroxyl groups, and O atoms from the salicylic ligands. The coordination geometry around the Dy(III) centers has been carefully analyzed. Whereas Dy12-L1 and Dy12-L2 with L1 and L2 containing Me and OMe groups in para positions of the phenyl rings, respectively, form similar porous 3D diamond-like molecular networks due to CH-π interactions, for Dy12-L3 with L3 bearing NO2-electron-withdrawing group, the generation of 2D molecular grids assembled by π-π staking is observed, and for Dy12-L4 with L4 bearing phenyl substituent, 3D hexagonal channels have been generated. The complexes Dy12-L1, Dy12-L2, and Dy12-L3 exhibit a zero-field slow magnetic relaxation effect. After UV irradiation of Dy12-L1, a decrease of the magnetic anisotropy energy barrier displaying the possibility of control over magnetic properties by the external stimulus has been observed.

Linkage of the Dinuclear Gold(I) Complex Luminescence and Origin of Endocyclic Amino Group of Cyclic P2N2-Bridging Ligands.

Gold(I) complexes of LAu2Cl2 composition based on P2N2 ligands, namely 1,5-diaza-3,7-diphosphacyclooctanes, containing ethylpyridyl substituents at the phosphorus atoms and sp2- or sp3-hybridized endocyclic nitrogen atoms were synthesized. The SCXRD analysis indicated the strong impact of the geometry of the nitrogen atom on the structure and conformational flexibility of the complexes. The N-aryl substituted ligand with the planar endocyclic nitrogen atom provides higher flexibility of the complex and an ability to bind the solvent molecules in the "host-guest" mode, whereas that kind of behavior is forbidden for the complex with an N-alkyl substituted ligand with a pyramidal nitrogen atom. The substituents at nitrogen atoms also control the origin of the emission, which is phosphorescence for the N-aryl substituted complex and fluorescence for the N-alkylaryl substituted complex. The phosphorescent gold(I) complex displays high cytotoxicity without selectivity toward the m-HeLa and normal cells, but the core-shell nanoparticles formed on the base of the complex demonstrate reduced cytotoxicity. The luminescence of the NPs allows tracking the complexes in the cell samples.

Chemical and Electrochemical Reductions of Monoiminoacenaphthenes.

Redox properties of monoiminoacenaphthenes (MIANs) were studied using various electrochemical techniques. The potential values obtained were used for calculating the electrochemical gap value and corresponding frontier orbital difference energy. The first-peak-potential reduction of the MIANs was performed. As a result of controlled potential electrolysis, two-electron one-proton addition products were obtained. Additionally, the MIANs were exposed to one-electron chemical reduction by sodium and NaBH4. Structures of three new sodium complexes, three products of electrochemical reduction, and one product of the reduction by NaBH4 were studied using single-crystal X-ray diffraction. The MIANs reduced electrochemically by NaBH4 represent salts, in which the protonated MIAN skeleton acts as an anion and Bu4N+ or Na+ as a cation. In the case of sodium complexes, the anion radicals of MIANs are coordinated with sodium cations into tetranuclear complexes. The photophysical and electrochemical properties of all reduced MIAN products, as well as neutral forms, were studied both experimentally and quantum-chemically.

(2-Hydroxy-3-Methoxybenzylidene)thiazolo[3,2-a]pyrimidines: Synthesis, Self-Assembly in the Crystalline Phase and Cytotoxic Activity.

A series of new 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with different aryl substituents at the 5 position are synthesized and characterized by 1H/ 13C NMR and IR-spectroscopy and mass-spectrometry, as well as single crystal X-ray diffraction (SCXRD). It was demonstrated that the type of hydrogen bonding can play a key role in the chiral discrimination of these compounds in the crystalline phase. The hydrogen bond of the O-H...N type leads to 1D supramolecular heterochiral chains or conglomerate crystallization in the case of the formation of homochiral chains. The hydrogen bond of O-H...O type gave racemic dimers, which are packed into 2D supramolecular layers with a parallel or angular dimers arrangement. Halogen bonding of the N...Br or O...Br type brings a new motif into supramolecular self-assembly in the crystalline phase: the formation of 1D supramolecular homochiral chains instead 2D supramolecular layers. The study of cytotoxicity against various tumor cells in vitro was carried out. It was found that 2-hydroxy-3-methoxybenzylidenethiazolo[3,2-a]pyrimidines with 3-nitrophenyl substituent at C5 carbon atom demonstrated a high efficiency against M-HeLa (cervical adenocarcinoma) and low cytotoxicity against normal liver cells.

Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis.

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

An Unusual Rearrangement of Pyrazole Nitrene and Coarctate Ring-Opening/Recyclization Cascade: Formal CH-Acetoxylation and Azide/Amine Conversion without External Oxidants and Reductants.

We report an unusual transformation where the transient formation of a nitrene moiety initiates a sequence of steps leading to remote oxidative C-H functionalization (R-CH3 to R-CH2OC(O)R') and the concomitant reduction of the nitrene into an amino group. No external oxidants or reductants are needed for this formal molecular comproportionation. Detected and isolated intermediates and computational analysis suggest that the process occurs with pyrazole ring opening and recyclization.

Deep-Blue Emissive Copper(I) Complexes Based on P-Thiophenylethyl-Substituted Cyclic Bisphosphines Displaying Photoinduced Structural Transformations of the Excited States.

A synthetic method for a primary 2-(thiophen-2'-yl)ethylphosphine was developed. The reaction of thiophenylethylphosphine with paraformaldehyde and primary arylamines leads to the formation of cyclic bisphosphines, namely, 1,5-di(aryl)-3,7-bis(thiophenylethyl)-1,5-diaza-3,7-diphosphacyclooctane (aryl = phenyl, p-tolyl). The obtained bisphosphines form cationic bis-P,P-chelate complexes with copper(I) tetrafluoroborate, which were structurally characterized by NMR spectroscopy, mass spectrometry, and elemental and XRD analyses. Surprisingly, the copper(I) complexes display a multiband emission in the solid state with maxima at 355-360, 425-430, and 480-490 nm and nanosecond lifetimes (1.2-1.4 ns) upon a 335 nm excitation. The excitation of the complexes at 360 nm at room temperature results in a deep-blue emission at 425-430 nm and a tail at 460-490 nm. A temperature decrease leads to an increased intensity of the emission band at 480 nm, while the luminescence lifetimes insignificantly increased up to 14 ns. Quantum chemical calculations explain the observed unusual luminescent behavior by the existence of "undistorted" and "flattened" singlet excited states of copper(I) complexes at room temperature and at 77 K, respectively.

Synthesis, biological evaluation and structure-activity relationship of 2-(2-hydroxyaryl)alkenylphosphonium salts with potency as anti-MRSA agents.

Here we report the synthesis, in vitro antimicrobial activity, preliminary toxicity and mechanism study of a new series of 2-(2-hydroxyaryl)alkenylphosphonium salts with the variation of phosphonium moiety obtained by a two-step synthetic method from phosphine oxides. The salts showed pronounced activity against Gram-positive bacteria, including MRSA strains, and some fungi. Mechanism of action against S. aureus was studied by CV test, TEM and proteomic assay. No cell wall integrity loss was observed while proteomic assay results suggested interference in different metabolic processes of S. aureus. For this series, lipophilicity was determined as a key factor for the inhibition of Gram-positive bacteria growth and S. aureus killing. Biological properties of methylated derivatives were notably different with manifested action against Gram-negative bacteria.

Thiacalixarenes with Sulfur Functionalities at Lower Rim: Heavy Metal Ion Binding in Solution and 2D-Confined Space.

Sulfur-containing groups preorganized on macrocyclic scaffolds are well suited for liquid-phase complexation of soft metal ions; however, their binding potential was not extensively studied at the air-water interface, and the effect of thioether topology on metal ion binding mechanisms under various conditions was not considered. Herein, we report the interface receptor characteristics of topologically varied thiacalixarene thioethers (linear bis-(methylthio)ethoxy derivative L2, O2S2-thiacrown-ether L3, and O2S2-bridged thiacalixtube L4). The study was conducted in bulk liquid phase and Langmuir monolayers. For all compounds, the highest liquid-phase extraction selectivity was revealed for Ag+ and Hg2+ ions vs. other soft metal ions. In thioether L2 and thiacalixtube L4, metal ion binding was evidenced by a blue shift of the band at 303 nm (for Ag+ species) and the appearance of ligand-to-metal charge transfer bands at 330-340 nm (for Hg2+ species). Theoretical calculations for thioether L2 and its Ag and Hg complexes are consistent with experimental data of UV/Vis, nuclear magnetic resonance (NMR) spectroscopy, and single-crystal X-ray diffractometry of Ag-thioether L2 complexes and Hg-thiacalixtube L4 complex for the case of coordination around the metal center involving two alkyl sulfide groups (Hg2+) or sulfur atoms on the lower rim and bridging unit (Ag+). In thiacrown L3, Ag and Hg binding by alkyl sulfide groups was suggested from changes in NMR spectra upon the addition of corresponding salts. In spite of the low ability of the thioethers to form stable Langmuir monolayers on deionized water, one might argue that the monolayers significantly expand in the presence of Hg salts in the water subphase. Hg2+ ion uptake by the Langmuir-Blodgett (LB) films of ligand L3 was proved by X-ray photoelectron spectroscopy (XPS). Together, these results demonstrate the potential of sulfide groups on the calixarene platform as receptor unit towards Hg2+ ions, which could be useful in the development of Hg2+-selective water purification systems or thin-film sensor devices.

Calix[4]arene Polyamine Triazoles: Synthesis, Aggregation and DNA Binding.

Artificial gene delivery systems are in great demand from both scientific and practical biomedical points of view. In this paper, we present the synthesis of a new click chemistry calix[4]arene precursor with free lower rim and new water-soluble calixarene triazoles with 12 amino-groups on the upper rim (one with free phenol hydroxyl groups and two another containing four butyl or tetradecyl fragments). Aggregation in the series of amino-triazole calixarenes of different lipophilicity (calixarene with free phenol hydroxyl groups or butyl and tetradecyl fragments on the lower rim) was studied using dynamic light scattering and fluorescent pyrene probe. It was found that calix[4]arene with a free lower rim, like alkyl-substituted butyl calix[4]arene, forms stable submicron aggregates 150-200 nm in size, while the more lipophilic tetradecyl -substituted calix[4]arene forms micellar aggregates19 nm in size. Using UV-Vis spectroscopy, fluorimetry and CD, it was shown that amino-triazole calix[4]arenes bind to calf thymus DNA by classical intercalation. According to DLS and TEM data, all studied macrocycles cause significant DNA compaction, forming stable nanoparticles 50-20 nm in size. Among all studied calix[4]arenes the most lipophilic tetradecyl one proved to be the best for both binding and compaction of DNA.

Thermodynamic vs. Kinetic Control in Synthesis of O-Donor 2,5-Substituted Furan and 3,5-Substituted Pyrazole from Heteropropargyl Precursor.

Elaboration of a convenient route towards donor-substituted pyrazoles from heteropropargyl precursors is challenging due to a number of thermodynamically favorable side reactions (e.g., acetylene-allene isomerization and Glaser homocoupling). In this work, Sonogashira cross-coupling conditions of 4-tert-butylphenyl propargyl ether with benzoyl chloride followed by tandem Michael addition/cyclocondensation with hydrazine into 3,5-disubstituted pyrazole (kinetic control), as well as cycloisomerization conditions of ketoacetylene intermediate into 2,5-disubstituted furan (thermodynamic control), were established through a variation of the catalyst loading, solvent polarity, excess of triethylamine, and time of reaction. During the optimization of process parameters, a number of by-products represented by a monophosphine binuclear complex (PPh3PdI2)2 with two bridging iodine atoms and diyne were identified and isolated in the pure form. The quantum-chemical calculations and solution-state 1H/13C NMR spectroscopy suggested that the 5(3)-(4-tert-butylphenyloxy)methoxy-3(5)-phenyl-1H-pyrazole exists in the tautomeric equilibrium in a polar methanol solvent and that individual tautomers could be characterized in case aprotic solvents employed. The pyrazole features a unique tetramer motif in the crystal phase formed by alternating 3(5)-phenyl-1H-pyrazole tautomers, which was stabilized by N-H···N bonds and stacking interactions of pyrazole rings, whereas pyrazole dimers were identified in the gas phase.

PNP Ligands in Cobalt-Mediated Activation and Functionalization of White Phosphorus.

Transition-metal mediated white phosphorus activation is of high interest as an ecological alternative to P4 chlorination pathway to the practically useful phosphorus products. Herein, we report a facile approach for P4 activation, transformation and subsequent functionalization using cobalt complexes bearing PNP ligands. The use of N,N-bis(diphenylphosphino)amine as a ligand allows one to transform P4 tetrahedron into a zig-zag chain with the formation of complex [Co(Ph2 PNHP(Ph2 )PPPPP(Ph2 )NHPPh2 )]BF4 (4). The presence of organic substituent at nitrogen atom in PNP ligand enables one to obtain complexes with η1 -coordinated P4 molecule, which indicates a crucial role of N-H bond in transformation of white phosphorus tetrahedron. Additionally, complex 4 can readily be functionalized by means of the reaction with Ph2 PCl leading to the formation of a new complex bearing unique P9 -ligand. The obtained results provide opportunities for facile construction of new polyphosphorus ligands in the coordination sphere of transition metal complexes.

Comparison of crystal structure and DFT calculations of triferrocenyl trithiophosphite's conformance.

A triferrocenyl trithiophosphite was studied by X-ray single-crystal diffraction. Triferrocenyl trithiophosphite has nine axes of internal rotation: three P-S bonds, three C-S bonds and three Fe-cyclopentadienyl axes. Rotation around the P-S bonds results in a totally asymmetric structure with three ferrocenylthio groups exhibiting different orientations towards the phosphorus lone electron pair (LEP). A comparison of DFT calculations and X-ray diffraction data is presented, herein we show which conformations are preferred for a given ligand.

Composing NLO Chromophore as a Puzzle: Electrochemistry-based Approach to Design and Effectiveness.

A series of D-π-A, D-π-D'-π-A, D-π-A'-π-A nonlinear optical chromophores with vinylene π-electron bridges or bridges with π-deficient/π-excessive heterocyclic moieties along with the corresponding precursors D-vinylene, D-π-D', D'-π-A, D-π-A' and A'-π-A are synthesized and studied both experimentally and computationally. The effect of the heterocycle in the π-electron bridge on the oxidation/reduction potentials and the energy gap (ΔEel ) is investigated in detail. The properties of the D-π-A'(D')-π-A chromophores are shown to correlate with those of building blocks: the oxidation potential is determined by the D-vinylene, and the reduction potential is determined by A'(D')-π-A truncated compounds. The contribution of the acceptor to the oxidation potential of chromophores in comparison with those of the precursors was estimated and analyzed in terms of electronic communication between the end groups. A good correlation between the ΔEel and the chromophores' first hyperpolarizability is revealed.

Assembly of Heterometallic AuICu2I2 Cores on the Scaffold of NPPN-Bridging Cyclic Bisphosphine.

The row of metallocyclic dinuclear gold(I) complexes with cyclic diphosphines, namely, P-pyridylethyl-substituted 1,5-diaza-3,7-diphosphacyclooctanes, has been obtained. Further interaction of the dinuclear gold(I) complexes with copper(I) iodide gave the first examples of hexanuclear AuI/CuI complexes containing two unusual trinuclear AuICu2I2 fragments. The structures of di- and hexanuclear complexes were confirmed by NMR spectroscopy, ESI mass spectrometry, elemental analysis, and single-crystal X-ray diffraction. All of the obtained complexes are moderate emitters in the solid state. Dinuclear gold(I) complexes displayed a greenish emission with the maxima in the emission spectra at ca. 550 nm. The obtained hexanuclear heterobimetallic AuI/CuI complexes are triplet solid-state blue emitters with the maximum in the emission spectra at 463 and 484 nm. According to the TD-DFT calculations, the observed emission of all studied complexes had a triplet origin and was caused by the 3CC or 3(MLCT) T1 → S0 transitions for dinuclear and hexanuclear complexes, respectively.

Novel Hybrid Compounds Containing Benzofuroxan and Aminothiazole Scaffolds: Synthesis and Evaluation of Their Anticancer Activity.

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Tamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents.