Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.
- MeSH
- Acetylcholinesterase chemistry metabolism MeSH
- Antidotes chemistry pharmacology therapeutic use MeSH
- Cholinesterase Inhibitors chemistry toxicity MeSH
- Catalytic Domain MeSH
- Protein Conformation MeSH
- Humans MeSH
- Ligands MeSH
- Molecular Conformation MeSH
- Molecular Structure MeSH
- Nerve Agents chemistry toxicity MeSH
- Organophosphorus Compounds antagonists & inhibitors toxicity MeSH
- Organophosphate Poisoning drug therapy etiology metabolism MeSH
- Pesticides antagonists & inhibitors toxicity MeSH
- Pyridinium Compounds chemistry pharmacology MeSH
- Drug Design * MeSH
- Cholinesterase Reactivators chemistry pharmacology therapeutic use MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
PURPOSE: With the increasing use of proton therapy, there is a growing emphasis on including radiation quality, often quantified by linear energy transfer, as a treatment plan optimization factor. The Timepix detectors offer energy-sensitive particle tracking useful for the characterization of proton linear energy transfer. To improve the detector's performance in mixed radiation fields produced in proton therapy, we customized the detector settings and performed the per-pixel energy calibration. METHODS: The detection threshold and per-pixel signal shaping time (IKrum current) were customized, and energy calibration was performed for MiniPIX Timepix3. The detector calibration was verified using α source and clinical proton beams, as well as Monte Carlo simulations. The effects on the detector's performance, in terms of spectral saturation and pixel occupancy, were evaluated. RESULTS: Measurements with proton beams showed a good agreement with simulations. With the customized settings, the measurable energy range in the detector data-driven mode was extended, and the signal duration time was reduced by 80%, while the yield of pixel time occupancy reduction depends on the number of occupied pixels. For performed measurements with proton beams, the number of occupied pixels was further reduced up to 40% due to the increased threshold. CONCLUSIONS: Customized detector configuration of the Timepix3 detector allowed for reduced pixel occupancy and mitigation of signal saturation in a data-driven mode without significantly interfering with the energy deposition measurement. The presented approach enables the extension of the operational range, including higher intensities and mixed-radiation fields in particle radiotherapy environments.
- MeSH
- Calibration MeSH
- Linear Energy Transfer MeSH
- Monte Carlo Method * MeSH
- Proton Therapy * instrumentation MeSH
- Publication type
- Journal Article MeSH
Ab initio and molecular simulation methods were used in calculations of the neutral individual betulin molecule, and molecular simulations were used to optimize the betulin molecule immersed in various amounts of water. Individual betulin was optimized in different force fields to find the one exhibiting best agreement with ab initio calculations obtained in the Gaussian03 program. Dihedral torsions of active groups of betulin were determined for both procedures, and related calculated structures were compared successfully. The selected force field was used for subsequent optimization of betulin in a water environment, and a conformational search was performed using quench molecular dynamics. The total energies of betulin and its interactions in water bulk were calculated, and the influence of water on betulin structure was investigated.
An aminoborane side product from the nicergoline manufacture process was identified by single-crystal X-ray diffraction. As boranes of pharmaceutical molecules are quite rare, the binding potential of the BH3 group was investigated and compared with similar compounds using Cambridge Structural Database (CSD). Surprisingly, the packing was stabilized by a dihydrogen bond, which triggered a false alert for too-short contact of hydrogen atoms in IUCR checkCIF. As the dihydrogen bond concept is not widely known, such an alert might mislead crystallographers to force -CH3 optimal geometry to -BH3 groups. The B-H distances equal to or less than 1.0 Å (17% of the CSD structures) are substantially biased when analyzing the structures of aminoborane complexes in CSD. To conduct proper searching, B-H bond length normalization should be applied in the CSD search.
Capillary electrophoresis (CE) can provide high separation efficiency with very simple instrumentation, but has yet to be explored regarding oxysterols/cholesterol. Cholesterol and 25-hydroxycholesterol (both are 4-ene-3-ketosteroids) were quantitatively transformed into hydrazones using Girard P reagent after enzymatic oxidation by cholesterol oxidase. Separation was achieved using non-aqueous capillary electrophoresis with UV detection at 280nm; the "charge-tagging" Girard P reagent ensured both charge and chromophore (which are requirements for CE-UV). Excess reagent was also separated from the two analytes, eliminating the need for removal prior to the analysis. The compounds were separated in less than 5min with excellent separation efficiency, using separation electrolytes fully compatible with mass spectrometry. The CE-UV method was used to optimize steps for charge-tagging, revealing that the procedure is affected by the analyte/reagent ratio and reaction time, but also the analyte structure.
- MeSH
- Betaine analogs & derivatives chemistry MeSH
- Cholesterol Oxidase chemistry metabolism MeSH
- Cholesterol chemistry isolation & purification metabolism MeSH
- Electrophoresis, Capillary MeSH
- Hydroxycholesterols chemistry isolation & purification metabolism MeSH
- Molecular Conformation MeSH
- Spectrophotometry, Ultraviolet MeSH
- Publication type
- Journal Article MeSH
This study deals with the nonaqueous capillary electrophoretic separation of dextromethorphan and its metabolites using a methanolic background electrolyte. The optimization of separation conditions was performed in terms of the resolution of dextromethorphan and dextrorphan and the effect of separation temperature, voltage, and the characteristics of the background electrolyte were studied. Complete separation of all analytes was achieved in 40 mM ammonium acetate dissolved in methanol. Hydrodynamic injection was performed at 3 kPa for 4 s. The separation voltage was 20 kV accompanied by a low electric current. The ultraviolet detection was performed at 214 nm, the temperature of the capillary was 25°C. These conditions enabled the separation of four analytes plus the internal standard within 9 min. Further, the developed method was validated in terms of linearity, sensitivity, and repeatability. Rat liver perfusate samples were subjected to the nonaqueous capillary electrophoretic method to illustrate its applicability.
- MeSH
- Dextromethorphan chemistry isolation & purification metabolism MeSH
- Electrophoresis, Capillary MeSH
- Electrolytes chemistry MeSH
- Liver chemistry metabolism MeSH
- Rats MeSH
- Methanol chemistry MeSH
- Molecular Conformation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
The aim of this work was to find an optimal ester group for preparation of lupane derivatives connecting high cytotoxicity with good chemical and pharmacological properties. Activities of methyl-, pivaloyloxymethyl- (Pom-), and acetoxymethyl- (Acm-) esters were compared with the activity of free acids. Although the methyl- and Pom-esters were generally less active than free acids, some Acm-esters had cytotoxicity similar to or even better than the starting compounds. Cytotoxic activity was measured in five cancer cell lines.
- MeSH
- Esterification MeSH
- Financing, Organized MeSH
- Quantitative Structure-Activity Relationship MeSH
- Carboxylic Acids pharmacology chemical synthesis MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Cell Line, Tumor MeSH
- Cell Proliferation drug effects MeSH
- Drug Screening Assays, Antitumor MeSH
- Triterpenes pharmacology chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
In this work, we investigate the mode of binding of all nine hydrogen-bonded structures of the adenine...thymine base pair. The planar H-bonded structures were optimized at the MP2/cc-pVTZ level, and the respective interaction energies, corrected for the basis set superposition error, were determined with the aug-cc-pVDZ basis set. The energy components were obtained from the DFT-SAPT procedure using the aug-cc-pVDZ basis set. The charge-transfer character of the single structures was estimated using NBO characteristics. It was established that dipole-dipole interaction itself cannot explain the preferred structure of the pair. Of the various energy components, first-order electrostatic energy plays the most important role. Second-order energy (the sum of induction and dispersion energies) amounts to about 56% of the electrostatic energy. The delta(HF) term covering among others the charge-transfer energy is rather large. The importance of delta(HF) is reflected by the NBO characteristics and especially by the NBO charge-transfer energy. The sum of the second-order energy and the delta(HF) term is only slightly smaller than the electrostatic energy (75-77%), which reflects the importance of the nonelectrostatic terms even in the case of strong H-bonded complexes. The WC structure, which exists in DNA, represents the seventh local minimum, while the three most stable structures utilize the N9-H proton donor group of the five-membered ring.
- MeSH
- Adenine chemistry MeSH
- Algorithms MeSH
- Biophysics methods MeSH
- DNA chemistry MeSH
- Financing, Organized MeSH
- Nucleic Acid Conformation MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Base Pairing MeSH
- Energy Transfer MeSH
- Spectrophotometry, Infrared methods MeSH
- Static Electricity MeSH
- Thymine chemistry MeSH
- Hydrogen Bonding MeSH
Density functional theory (DFT) studies on adsorption of several gaseous homo- and hetero-diatomic molecules (AB) including H2, O2, N2, NO and CO on external surface of H-capped pristine armchair (5, 5) single-walled carbon nanotube (SWCNT) were conducted. Structures of C70H10 and the corresponding C70H10-AB adducts were fully optimized at the B3LYP/6-311G* level of theory. Calculated HOMO/LUMO energy gaps (Eg), (13)C NMR chemical shifts and IR/Raman parameters were analyzed and critically compared with available experimental data. Significant changes of carbon NMR atom chemical shifts (up to -100 ppm) and shielding anisotropies (up to -180 ppm) at sites of addition were observed. Functionalized SWCNTs produced IR and Raman spectra different from the pristine nanotube model. The selective changes in vibrational spectra will help in assigning the topology of functionalization at the nanotube wall.
- MeSH
- Electrons MeSH
- Quantum Theory * MeSH
- Magnetic Resonance Spectroscopy MeSH
- Molecular Conformation MeSH
- Models, Molecular * MeSH
- Nanotubes, Carbon chemistry MeSH
- Spectrum Analysis, Raman * MeSH
- Spectroscopy, Fourier Transform Infrared MeSH
- Thermodynamics MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Inhibition of the human O-linked β-N-acetylglucosaminidase (hOGA, GH84) enzyme is pharmacologically relevant in several diseases such as neurodegenerative and cardiovascular disorders, type 2 diabetes, and cancer. Human lysosomal hexosaminidases (hHexA and hHexB, GH20) are mechanistically related enzymes; therefore, selective inhibition of these enzymes is crucial in terms of potential applications. In order to extend the structure-activity relationships of OGA inhibitors, a series of 2-acetamido-2-deoxy-d-glucono-1,5-lactone sulfonylhydrazones was prepared from d-glucosamine. The synthetic sequence involved condensation of N-acetyl-3,4,6-tri-O-acetyl-d-glucosamine with arenesulfonylhydrazines, followed by MnO2 oxidation to the corresponding glucono-1,5-lactone sulfonylhydrazones. Removal of the O-acetyl protecting groups by NH3/MeOH furnished the test compounds. Evaluation of these compounds by enzyme kinetic methods against hOGA and hHexB revealed potent nanomolar competitive inhibition of both enzymes, with no significant selectivity towards either. The most efficient inhibitor of hOGA was 2-acetamido-2-deoxy-d-glucono-1,5-lactone 1-naphthalenesulfonylhydrazone (5f, Ki = 27 nM). This compound had a Ki of 6.8 nM towards hHexB. To assess the binding mode of these inhibitors to hOGA, computational studies (Prime protein-ligand refinement and QM/MM optimizations) were performed, which suggested the binding preference of the glucono-1,5-lactone sulfonylhydrazones in an s-cis conformation for all test compounds.
- MeSH
- Antigens, Neoplasm chemistry metabolism MeSH
- beta-Hexosaminidase beta Chain chemistry metabolism MeSH
- Histone Acetyltransferases chemistry metabolism MeSH
- Hyaluronoglucosaminidase chemistry metabolism MeSH
- Hydrazones chemical synthesis chemistry pharmacology MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Lactones chemistry MeSH
- Humans MeSH
- Molecular Conformation MeSH
- Models, Molecular MeSH
- Oxides chemistry MeSH
- Manganese Compounds chemistry MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
