The study of acute and chronic toxicity of the sodium-, calcium-, iron-polygalacturonate pharmacological substance in rabbits.

The purpose of this study is the assessment of the acute and chronic toxicity of pharmacological substance sodium, calcium, iron-polygalacturonate (PG Na,Ca,Fe) in rabbits as one of the stages of preclinical studies. We studied an acute and chronic oral toxicity of PG Na,Ca,Fe, which stimulates the process of hemopoiesis, in male and female rabbits of the "Chinchilla". According to the results of the study of acute toxicity of PG Na,Ca,Fe, treating with it the rabbits of both sexes in doses of 0.

Water structure changes in oxime-mediated reactivation process of phosphorylated human acetylcholinesterase.

The role of water in oxime-mediated reactivation of phosphylated cholinesterases (ChEs) has been asked with recurrence. To investigate oximate water structure changes in this reaction, reactivation of paraoxon-inhibited human acetylcholinesterase (AChE) was performed by the oxime asoxime (HI-6) at different pH in the presence and absence of lyotropic salts: a neutral salt (NaCl), a strong chaotropic salt (LiSCN) and strong kosmotropic salts (ammonium sulphate and phosphate HPO). At the same time, molecular dynamic (MD) simulations of enzyme reactivation under the same conditions were performed over 100 ns.

Synthesis and Antimicrobial Study of Novel 1-Benzylated Water-Soluble Isatin-3-hydrazones.

A high-yield synthesis of some novel isatin-3-acylhydrazones on the base of 5-ethylisatin derivatives and Girard's reagent T is described. Antimicrobial activity preliminary SAR study of both 1-benzylated isatins and water-soluble hydrazones was established. The most active against Staphylococcus aureus and Bacillus cereus are ammonium salts bearing 3,4-dichloro- or 4-CF substituents in benzyl fragment.

Resolving the Singlet Excited State Manifold of Benzophenone by First-Principles Simulations and Ultrafast Spectroscopy.

Accurate characterization of the high-lying excited state manifolds of organic molecules is of fundamental importance for the interpretation of the rich response detected in time-resolved nonlinear electronic spectroscopies. Here, we have characterized the singlet excited state manifold of benzophenone (BP), a versatile organic photoinitiator and a well-known DNA photosensitizer. Benchmarks of various multiconfigurational/multireference (RASSCF/PT2) and time-dependent density functional theory (TD-DFT) approaches allowed assignments of experimental linear absorption signals of BP in the ultraviolet (UV) region, with unprecedented characterization of ground state absorptions in the far UV.

Sulfur-Containing Monoterpenoids as Potential Antithrombotic Drugs: Research in the Molecular Mechanism of Coagulation Activity Using Pinanyl Sulfoxide as an Example.

In this article we present the synthesis of enantiomerically pure sulfoxide and study the influence of this compound on hemostasis. Detailed NMR studies and molecular dynamics simulations using sodium dodecyl sulfate (SDS) membrane models indicated that the bicyclic fragment of sulfoxide was embedded into the SDS micelle whereas the -SO(CH)OH fragment remained on the surface of the micelle and was in contact with the solvent. We also found that the pro-coagulative activity of sulfoxide was due to its ability to inhibit platelet activation and inhibited the catalytic activity of phospholipid surface which was involved in formation of coagulation clotting factor complexes.

Silica nanoparticles with Tb(III)-centered luminescence decorated by Ag as efficient cellular contrast agent with anticancer effect.

The present work introduces composite luminescent nanoparticles (Ag-Tb-SNs), where ultra-small nanosilver (4 ± 2 nm) is deposited onto amino-modified silica nanoparticles (35±6 nm) doped by green luminescent Tb(III) complexes. Ag-Tb-SNs are able to image cancer (Hep-2) cells in confocal microscopy measurements due to efficient cell internalization, which is confirmed by TEM images of the Hep-2 cells exposed by Ag-Tb-SNs. Comparative analysis of the cytotoxicity of normal fibroblasts (DK-4) and cancer cells (Hep-2) incubated with various concentrations of Ag-Tb-SNs revealed the concentration range where the toxic effect on the cancer cells is significant, while it is insignificant towards the nonmalignant fibroblasts cells.

Water-soluble polyol-methanofullerenes as mitochondria-targeted antioxidants: Mechanism of action.

The mechanism of an antioxidant action of water-soluble polyol - methanofullerenes C[CHO(OH)] and C[CHO(OH)] as the mild uncouplers of an oxidative phosphorylation and respiration is postulated. According to this mechanism, hydroxyl group of methanofullerenols can be protonated under excess of protons in the intermembrane space of hyperpolarized mitochondria. Protonation of fullerene derivatives is confirmed by the decrease in their negative Zeta potential in the pH below 5.

Amido Ca and Yb(II) Complexes Coordinated by Amidine-Amidopyridinate Ligands for Catalytic Intermolecular Olefin Hydrophosphination.

A series of amido Ca and Yb(II) complexes LM[N(SiMe)](THF) (1Yb, 1-4Ca) coordinated by amidine-amidopyridinate ligands L were synthesized via a transamination reaction between proligands LH and bisamido complexes M[N(SiMe)](THF) (M = Yb, Ca). The reactions of Yb[N(SiMe)](THF) with proligands LH-LH containing CF and CHF fragments do not allow for preparing the target Yb(II) complexes, while the Ca analogues were synthesized in good yields. Complexes 1Yb and 1-4Ca were evaluated as precatalysts for hydrophosphination of styrene, p-substituted styrenes, α-Me-styrene, and 2,3-dimethylbutadiene with various primary and secondary phosphines (PhPH, 2,4,6-MeCHPH, 2-CNHPH, PhPH, CyPH).

The supramolecular polymer complexes with oppositely charged calixresorcinarene: hydrophobic domain formation and synergistic binding modes.

The association of branched polyethyleneimine (PEI) with a series of octacarboxy-calixresorcinarenes bearing different low-rim substituents leads to the formation of nanosized supramolecular complexes. The PEI-macrocycle complexes have fine-tunable sizes regulated by variations in the self-association capacity of the calixresorcinarenes. In the supramolecular complexes, hydrophobic fragments of the polymer and calixresorcinarenes form cooperative hydrophobic domains which provide synergistic enhancement of guest molecule binding.

Luminescent nanoparticles for rapid monitoring of endogenous acetylcholine release in mice atria.

The present work introduces for the first time a nanoparticulate approach for ex vivo monitoring of acetylcholinesterase-catalyzed hydrolysis of endogenous acetylcholine released from nerve varicosities in mice atria. Amino-modified 20-nm size silica nanoparticles (SNs) doped by luminescent Tb(III) complexes were applied as the nanosensors. Their sensing capacity results from the decreased intensity of Tb(III)-centred luminescence due to the quenching effect of acetic acid derived from acetylcholinesterase-catalyzed hydrolysis of acetylcholine.

Vibrational spectroscopic study of cationic phosphorus dendrimers with aminoethylpiperidine terminal groups.

Two generations of phosphoric dendrimers with piperidine functional groups were synthesized for use in biology and medicine. Neutral samples are soluble in organic solvents but after protonation these dendrimers become water soluble and can be used for biological experiments. The FTIR and FT Raman spectra of two generations of dendrimers G constructed from the cyclotriphosphazene core, repeating units OCHCHNN(CH)P(S)< and aminoethylpiperidine end groups NH(CH)CNH were recorded.

Synthesis of 2-d-acrylamide.

2-d-Acrylamide was synthesized via the 2-step procedure starting from acrylonitrile and deuterium oxide. This procedure affords 2-d-acrylamide in 99.9% chemical purity and 98.

Specific inhibition of acetylcholinesterase as an approach to decrease muscarinic side effects during myasthenia gravis treatment.

Non-selective inhibitors of cholinesterases (ChEs) are clinically used for treatment of myasthenia gravis (MG). While being generally safe, they cause numerous adverse effects including induction of hyperactivity of urinary bladder and intestines affecting quality of patients life. In this study we have compared two ChEs inhibitors, a newly synthesized compound C547 and clinically used pyridostigmine bromide, by their efficiency to reduce muscle weakness symptoms and ability to activate contractions of urinary bladder in a rat model of autoimmune MG.

C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies.

C-547, a potent slow-binding inhibitor of acetylcholinesterase (AChE) was intravenously administered to rat (0.05 mg/kg). Pharmacokinetic profiles were determined in blood and different organs: extensor digitorum longus muscle, heart, liver, lungs and kidneys as a function of time.

External oxidant-free cross-coupling: electrochemically induced aromatic C-H phosphonation of azoles with dialkyl-H-phosphonates under silver catalysis.

A convenient external oxidant-free method of phosphorylation of azole derivatives (benzo-1,3-azoles, 3-methylindole, 4-methyl-2-acetylthiazole) by using dialkyl-H-phosphonates through the catalytic oxidation of their mixture under electrochemical mild conditions (room temperature, normal pressure) in the presence of silver salts or oxide (1%) is proposed. This method allows us to obtain the desired azole dialkylphosphonates with good yield (up to 75%). The transformations of silver and phosphorus precursors and intermediates using cyclic voltammetry, ESR, and NMR spectroscopy were investigated, and a radical process mechanism was proposed.

Tuning magnetic relaxation properties of "hard cores" in core-shell colloids by modification of "soft shell".

The present work introduces an impact of polyelectrolyte-based hydrophilic shell on magnetic relaxivity and luminescence of hard cores built from isostructural complexes of Tb(III) and Gd(III) in the core-shell aqueous colloids. Microscopic and scattering techniques reveal "plum pudding" morphology of the colloids, where polyelectrolyte-coated ultrasmall (<5nm) hard cores form aggregates in aqueous solutions. Interaction of bovine serum albumin (BSA) with the colloids provides a tool to modify the polyelectrolyte-based shell, which is the reason for the improvement in both aggregation behavior of the colloids and their relaxivity.

Controlled and Reversible Stepwise Growth of Linear Copper(I) Chains Enabled by Dynamic Ligand Scaffolds.

Reversible stepwise chain growth in linear Cu assemblies can be achieved by using the dynamic, unsymmetric naphthyridinone-based ligand scaffolds L1 and L2. With the same ligand scaffolds, the length of the linear copper chain can be varied from two to three and four copper atoms, and the nuclearity of the complex is easily controlled by the stepwise addition of a Cu precursor to gradually increase the chain length, or by the reductive removal of Cu atoms to decrease the chain length. This represents a rare example of a stepwise controlled chain growth in extended metal atom chains (EMACs).

Hydration number: crucial role in nuclear magnetic relaxivity of Gd(III) chelate-based nanoparticles.

Today, nanostructure-based contrast agents (CA) are emerging in the field of magnetic resonance imaging (MRI). Their sensitivity is reported as greatly improved in comparison to commercially used chelate-based ones. The present work is aimed at revealing the factors governing the efficiency of longitudinal magnetic relaxivity (r) in aqueous colloids of core-shell Gd(III)-based nanoparticles.

Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol.

Mitochondria play a crucial role in the cell fate; in particular, reducing the accumulation of calcium in the mitochondrial matrix offers cardioprotection. This affect is achieved by a mild depolarization of the mitochondrial membrane potential, which prevents the assembly and opening of the mitochondrial permeability transition pore. For this reason, mitochondria are an attractive target for pharmacological interventions that prevent ischaemia/reperfusion injury.

Covalent self-assembly of the specific RSSR isomer of 14-membered tetrakisphosphine.

The first representative of the specific RSSR isomer of 14-membered tetrakisphosphine has been obtained instead of the RRRR/SSSS isomer predicted according to the empirical rule formulated recently. The geometry of the obtained 14-PN is preorganized for the dicopper complex formation with the unique coordination mode in the row of PN corands.

Ytterbium and Europium Complexes of Redox-Active Ligands: Searching for Redox Isomerism.

The reaction of (dpp-Bian)Eu(dme) (3) (dpp-Bian is dianion of 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene; dme is 1,2-dimethoxyethane) with 2,2'-bipyridine (bipy) in toluene proceeds with replacement of the coordinated solvent molecules with neutral bipy ligands and affords europium(II) complex (dpp-Bian)Eu(bipy) (9). In contrast the reaction of related ytterbium complex (dpp-Bian)Yb(dme) (4) with bipy in dme proceeds with the electron transfer from the metal to bipy and results in (dpp-Bian)Yb(bipy)(bipẏ) (10) - ytterbium(III) derivative containing both neutral and radical-anionic bipy ligands. Noteworthy, in both cases dianionic dpp-Bian ligands retain its reduction state.

Design, Synthesis, and Cancer Cell Growth Inhibitory Activity of Triphenylphosphonium Derivatives of the Triterpenoid Betulin.

A series of new triphenylphosphonium (TPP) derivatives of the triterpenoid betulin (1, 3-lup-20(29)-ene-3β,28-diol) have been synthesized and evaluated for cytotoxic effects against human breast cancer (MCF-7), prostate adenocarcinoma (PC-3), vinblastine-resistant human breast cancer (MCF-7/Vinb), and human skin fibroblast (HSF) cells. The TPP moiety was applied as a carrier group through the acyl linker at the 28- or 3- and 28-positions of betulin to promote cellular and mitochondrial accumulation of the resultant compounds. A structure-activity relationship study has revealed the essential role of the TPP group in the biological properties of the betulin derivatives produced.

Leaching from Palladium Nanoparticles in an Ionic Liquid Leads to the Formation of Ionic Monometallic Species.

Molecular dynamics simulations and DFT calculations suggest that leaching of palladium species from Pd nanoparticles in ionic liquids does not involve "naked" Pd(0) atoms or neutral ArPdX species formed by oxidative addition of arylhalides. Instead, the ionic liquid contributes largely to leaching of ionic PdX or PdAr species.

The isomeric structure of pentacoordinate chiral spirophosphoranes in solution by the combined use of NMR experiments and GIAO DFT calculations of NMR parameters.

The interplay of NMR experiments and DFT calculations of NMR parameters is a reliable method for determining the relative configurations of pentacoordinate chiral spirophosphoranes bearing two six- or five-membered rings at the phosphorus atom in solution. The major product of the Betti based derivatives corresponds to the isomers with both substituents at chiral carbons being opposite to the P-H proton. The next populated product corresponds to the isomer with different chiralities at carbons.

Nanoparticle-Delivered 2-PAM for Rat Brain Protection against Paraoxon Central Toxicity.

Solid lipid nanoparticles (SLNs) are among the most promising nanocarriers to target the blood-brain barrier (BBB) for drug delivery to the central nervous system (CNS). Encapsulation of the acetylcholinesterase reactivator, pralidoxime chloride (2-PAM), in SLNs appears to be a suitable strategy for protection against poisoning by organophosphorus agents (OPs) and postexposure treatment. 2-PAM-loaded SLNs were developed for brain targeting and delivery via intravenous (iv) administration.