Igor A. Sedov

Atmospheric and high pressure ene reaction of norbornene with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione

Thermodynamic and activation parameters (enthalpy, entropy, and volume) have been determined from the pressure and temperature dependences of the rate of the reaction of norbornene with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione in toluene, which is accompanied by Wagner-Meerwein rearrangement. The enthalpy of the reaction in 1,2-dichloroethane has been determined by calorimetry. The obtained data correspond to a weakly polar transition state.

Determination of Abraham Model Correlations for Solute Transfer into Propyl Acetate Based on Experimental Activity Coefficient and Solubility Data

Experimental infinite dilution activity coefficients, gas-to-liquid partition coefficients, and molar solubility data have been measured for numerous organic solutes dissolved in propyl acetate. Results of our experimental measurements, combined with published solubility data retrieved from the published literature, have been used to derive Abraham model correlations for describing solute transfer into propyl acetate. The derived Abraham model correlations describe the experimental data to within 0.11 log10 units. Calculation of Abraham model solute descriptors for boscalid was illustrated using our derived solute transfer correlations into propyl acetate. Predictions using the calculated solute descriptors indicate that boscalid would show significant partitioning into the skin and fat tissues in the body, and would exhibit considerable baseline toxicity towards the eight aquatic organisms (five fish species and three water flea species).

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

ABSTRACT 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. Pharmacokinetics (PK) was studied using non‐compartmental and compartmental analyses. A 3‐compartment model describes PK in blood. Most of injected C‐547 binds to albumin in the bloodstream. The steady‐state volume of distribution (3800 ml/kg) is 15 times larger than the distribution volume, indicating a good tissue distribution. C‐547 is slowly eliminated (kel = 0.17 h−1; T1/2 = 4 h) from the bloodstream. Effect of C‐547 on animal model of myasthenia gravis persists for more than 72 h, even though the drug is not analytically detectable in the blood. A PK/PD model was built to account for such a pharmacodynamical (PD) effect. Long‐lasting effect results from micro‐PD mechanisms: the slow‐binding nature of inhibition, high affinity for AChE and long residence time on target at neuromuscular junction (NMJ). In addition, NMJ spatial constraints i.e. high concentration of AChE in a small volume, and slow diffusion rate of free C‐547 out of NMJ, make possible effective rebinding of ligand. Thus, compared to other cholinesterase inhibitors used for palliative treatment of myasthenia gravis, C‐547 is the most selective drug, displays a slow pharmacokinetics, and has the longest duration of action. This makes C‐547 a promising drug leader for treatment of myasthenia gravis, and a template for development of other drugs against neurological diseases and for neuroprotection. Graphical abstract Figure. No Caption available. HighlightsC‐547, a 6‐methyluracil derivative, is a selective slow‐binding inhibitor of AChE.Administered to rat, C‐547 is slowly eliminated from bloodstream.Long lasting effect on myasthenia gravis model persists >72 h.Micropharmacodynamic mechanisms allow rebinding to neuromuscular junction AChE.Interest for palliative treatment of myasthenia gravis.

[2π + 2π]-Cycloaddition of biadamantylidene to 4-phenyl-3 H -1,2,4-triazole-3,5(4 H )-dione. Effects of temperature, high pressure, and solvent

The effects of temperature, solvent nature, and high hydrostatic pressure on the rate of the reaction of biadamantylidene with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione have been estimated. Significant shielding of the C=C double bond in biadamantylidene is responsible for the high entropy and volume of activation. Quantitative yield of the reaction in the temperature range 25‒45°C is related to its exothermicity. The rate of the [2π + 2π]-cycloaddition unexpectedly weakly depends on the solvent polarity, which makes it radically different from the [2π + 2π]-reaction with tetracyanoethylene.

Influence of the Cross-Link Density on the Rate of Crystallization of Poly(ε-Caprolactone)

Cross-linked poly(ε-caprolactone) (PCL) is a smart biocompatible polymer exhibiting two-way shape memory effect. PCL samples with different cross-link density were synthesized by heating the polymer with various amounts of radical initiator benzoyl peroxide (BPO). Non-isothermal crystallization kinetics was characterized by means of conventional differential scanning calorimetry (DSC) and fast scanning calorimetry (FSC). The latter technique was used to obtain the dependence of the degree of crystallinity on the preceding cooling rate by following the enthalpies of melting for each sample. It is shown that the cooling rate required to keep the cooled sample amorphous decreases with increasing cross-link density, i.e., crystallization process slows down monotonically. Covalent bonds between polymer chains impede the crystallization process. Consequently, FSC can be used as a rather quick and low sample consuming method to estimate the degree of cross-linking of PCL samples.

Fast scanning calorimetry of lysozyme unfolding at scanning rates from 5 K/min to 500,000 K/min

BACKGROUND Protein denaturation is often studied using differential scanning calorimetry (DSC). However, conventional instruments are limited in the temperature scanning rate available. Fast scanning calorimetry (FSC) provides an ability to study processes at much higher rates while using extremely small sample masses [ng]. This makes it a very interesting technique for protein investigation. METHODS A combination of conventional DSC and fast scanning calorimeters was used to study denaturation of lysozyme dissolved in glycerol. Glycerol was chosen as a solvent to prevent evaporation from the micro-sized samples of the fast scanning calorimeter. RESULTS The lysozyme denaturation temperatures in the range of scanning rates from 5 K/min to ca. 500,000 K/min follow the Arrhenius law. The experimental results for FSC and conventional DSC fall into two distinct clusters in a Kissinger plot, which are well approximated by two parallel straight lines. CONCLUSIONS The transition temperatures for the unfolding process measured on fast scanning calorimetry sensor are significantly lower than what could be expected from the results of conventional DSC using extrapolation to high scanning rates. Evidence for the influence of the relative surface area on the unfolding temperature was found. GENERAL SIGNIFICANCE For the first time, fast scanning calorimetry was employed to study protein denaturation with a range of temperature scanning rates of 5 orders of magnitude. Decreased thermal stability of the micro-sized samples on the fast scanning calorimeter raise caution over using bulk solution thermal stability data of proteins for applications where micro-sized dispersed protein solutions are used, e.g., spray drying.

Molecular dynamics study of unfolding of lysozyme in water and its mixtures with dimethyl sulfoxide

All-atom explicit solvent molecular dynamics was used to study the process of unfolding of hen egg white lysozyme in water and mixtures of water with dimethyl sulfoxide at different compositions. We have determined the kinetic parameters of unfolding at a constant temperature 450K. For each run, the time of disruption of the tertiary structure of lysozyme tu was defined as the moment when a certain structural criterion computed from the trajectory reaches its critical value. A good agreement is observed between the results obtained using several different criteria. The secondary structure according to DSSP calculations is found to be partially unfolded to the moment of disruption of tertiary structure, but some of its elements keep for a long time after that. The values of tu averaged over ten 30ns-long trajectories for each solvent composition are shown to decrease very rapidly with addition of dimethyl sulfoxide, and rather small amounts of dimethyl sulfoxide are found to change the pathway of unfolding. In pure water, despite the loss of tertiary contacts and disruption of secondary structure elements, the protein preserves its compact globular state at least over 130ns of simulation, while even at 5mol percents of dimethyl sulfoxide it loses its compactness within 30ns. The proposed methodology is a generally applicable tool to quantify the rate of protein unfolding in simulation studies.