A series of triterpenoids of the lupane, taraxastane, friedelane and baccharane type were oxidized using selenium dioxide (SeO2) and benzeneseleninic anhydride (BSA) under various conditions. Depending on the reaction conditions, different reaction pathways were observed, including dehydrogenation, allylic oxidation, and 1,2-diketone formation. In this way, derivatives functionalized in the triterpene core (especially in rings A, D, and E), difficult to obtain by other methods, can be easily prepared. In some cases, rarely observed α-phenylseleno-ketones were isolated. An unexpected reaction involving the cleavage of the carbon-carbon double bond was observed in the presence of stoichiometric amounts of osmium tetroxide. Further transformations of selected intermediates facilitated the synthesis of new, functionally enriched derivatives. The key reaction pathways were investigated using density functional theory (DFT), focusing on bond length variations and transition states, revealing energetically favored pathways and critical transition structures, including covalent and noncovalent interactions. Solvent and isomerization equilibrium effects were proposed to explain the experimentally observed discrepancies. Cytotoxic activity of selected derivatives was investigated. Derivatives 4 and 38 showed strongest cytotoxicity in cancer cells and fibroblasts (IC50 2.6-26.4 μM); some compounds were selective for G-361 or HeLa cells. These results suggest that they may find application in pharmaceuticals.
- MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Oxidation-Reduction MeSH
- Pentacyclic Triterpenes MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor MeSH
- Selenium * chemistry MeSH
- Density Functional Theory MeSH
- Triterpenes * chemistry pharmacology chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
In polarizable materials, electronic charge carriers interact with the surrounding ions, leading to quasiparticle behavior. The resulting polarons play a central role in many materials properties including electrical transport, interaction with light, surface reactivity, and magnetoresistance, and polarons are typically investigated indirectly through these macroscopic characteristics. Here, noncontact atomic force microscopy (nc-AFM) is used to directly image polarons in Fe2O3 at the single quasiparticle limit. A combination of Kelvin probe force microscopy (KPFM) and kinetic Monte Carlo (KMC) simulations shows that the mobility of electron polarons can be markedly increased by Ti doping. Density functional theory (DFT) calculations indicate that a transition from polaronic to metastable free-carrier states can play a key role in migration of electron polarons. In contrast, hole polarons are significantly less mobile, and their hopping is hampered further by trapping centers.
- Publication type
- Journal Article MeSH
This study presents an exploration of the chemical space around derivatives of 3-benzamidopyrazine-2-carboxamides, previously identified as potent antimycobacterial compounds with predicted binding to mycobacterial prolyl-transfer RNA synthetase. New urea derivatives (Series-1) were generally inactive, probably due to their preference for cis-trans conformation (confirmed by density functional theory calculations and experimentally by nuclear overhauser effect spectroscopy NMR). Series-2 (3-benzamidopyrazine-2-carboxamides with disubstituted benzene ring) demonstrated that substituents larger than fluorine are not tolerated in the ortho position of the benzene ring. This series brought two new compounds (21: R = 2-F, 4-Cl and 22: R = 2-F, 4-Br) with in vitro activity against Mycobacterium tuberculosis H37Rv as well as multidrug-resistant clinical isolates, with minimum inhibitory concentration ranging from 6.25 to 25 μg/mL. The lactone-type derivatives 4H-pyrazino[2,3-d][1,3]oxazin-4-ones (Series-3) were inactive, but solvent stability studies of compound 29 indicated that they might be developed to usable lactone prodrugs of inhibitors of mycobacterial aspartate decarboxylase (PanD).
- MeSH
- Amino Acyl-tRNA Synthetases antagonists & inhibitors metabolism MeSH
- Antitubercular Agents * pharmacology chemistry chemical synthesis MeSH
- Enzyme Inhibitors pharmacology chemistry chemical synthesis MeSH
- Microbial Sensitivity Tests * MeSH
- Molecular Structure MeSH
- Mycobacterium tuberculosis * drug effects enzymology MeSH
- Pyrazines pharmacology chemistry chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
In this study, we delve into the electronic structure, spectroscopic, and optical properties of five benzo derivatives of pyridine, namely, 5-(4-chlorophenyl)-2-fluoropyridine (1), 2-fluoro-5-(4-fluorophenyl)pyridine (2), 4-(2-fluoropyridin-5-yl)phenol (3), 5-(2,3-dichlorophenyl)-2-fluoropyridine (4), and 5-(5-bromo-2-methoxyphenyl)-2-fluoropyridine (5). Utilizing quantum chemical density functional theory calculations at the B3LYP and Perdew-Burke-Ernzerhof levels of theory combined with the 6-311G(d,p) and 6-311++G(d,p) basis sets, we investigated the electronic and optical characteristics of these compounds. Band structure calculations were conducted for their crystalline structures, revealing a direct band gap varying from 3.018 to 3.558 eV, with the valence band maximum and conduction band minimum located at the G point in the Brillouin zone. The optical properties were analyzed, including the dielectric functions, reflectivity, and refractive index. Notably, reflectivity was found to be minimal in the photon energy range of 0.0-3.0 eV, and the static refractive index, n(0), ranged from 1.55 to 1.70. The research also involved assessing the reactivity of the compounds through calculation of the frontier orbital energy gaps (ΔE), indicating a significant charge transfer and high reactivity. Additionally, we performed frequency analysis to unveil the Fourier-transform infrared spectra of compounds 1-5 at room temperature. Molecular electrostatic potential surfaces of the optimized structures were employed to map the electrophilic and nucleophilic regions of the compounds. This investigation provides a comprehensive understanding of the electronic and optical properties of these pyridine derivatives, shedding light on their potential applications in optoelectronics.
- Publication type
- Journal Article MeSH
We designed 0D, 1D, and 2D supramolecular assemblies made of diaryliodonium salts (functioning as double σ-hole donors) and carboxylates (as σ-hole acceptors). The association was based on two charge-supported halogen bonds (XB), which occurred between IIII sites of the iodonium cations and the carboxylate anions. The sequential introduction of the carboxylic groups in the aryl ring of the benzoic acid added a dimension to the 0D supramolecular organization of the benzoate, which furnished 1D-chained and 2D-layered structures when terephthalate and trimesate anions, correspondingly, were applied as XB acceptors. The structure-directing XB were studied using DFT calculations under periodic boundary conditions and were followed by the one-electron-potential analysis and the Bader atoms-in-molecules topological analysis of electron density. These theoretical methods confirmed the existence of the XB and verified the philicities of the interaction partners in the designed solid-state structures.
- MeSH
- Anions MeSH
- Halogens * chemistry MeSH
- Benzoic Acid MeSH
- Carboxylic Acids * MeSH
- Density Functional Theory MeSH
- Publication type
- Journal Article MeSH
CONTEXT: Chlordecone (CLD) and β-hexachlorocyclohexane (β-HCH) are chlorinated pesticides that coexist as persistent organic pollutants in the groundwater of several countries in the Caribbean, being an environmental issue. This work evaluates theoretically the competitive formation of host-guest complexes pesticides@cyclodextrines (CDs) as an alternative for water purification and selective separation of pesticides. METHODS: Quantum mechanical calculations based on density functional theory (DFT) and classical molecular dynamics (MD) simulations were used to achieve information on geometries, energies, structure, and dynamics of guest-host complexes in the gas phase, implicit solvent medium, and in aqueous solutions. RESULTS: DFT studies showed that interactions of both pesticides with CDs are mediated by steric factors and guided by maximization of the hydrophobic interactions either with the other pesticide or with the CD cavity's inner atoms. MD results corroborate the formation of stable complexes of both pesticides with the studied CDs. α-CD exhibited a preference for the smaller β-HCH molecule over the CLD that could not perturb the formed complex. CONCLUSIONS: The simulation of competitive formation with γ-CD illustrated that this molecule could accommodate both pesticides inside its cavity. These results suggest that CDs with smaller cavity sizes such as α-CD could be used for selective separation of β-HCH from CLD in water bodies, while γ-CD could be used for methods that aim to remove both pesticides at the same time.
- Publication type
- Journal Article MeSH
Microvascular integrity is disrupted following spinal cord injury (SCI) by both primary and secondary insults. Changes to neuronal structures are well documented, but little is known about how the capillaries change and recover following injury. Spatiotemporal morphological information is required to explore potential treatments targeting the microvasculature post-SCI to improve functional recovery. Sprague-Dawley rats were given a T10 moderate/severe (200 kDyn) contusion injury and were perfuse-fixed at days 2, 5, 15, and 45 post-injury. Unbiased stereology following immunohistochemistry in four areas (ventral and dorsal grey and white matter) across seven spinal segments (n = 4 for each group) was used to calculate microvessel density, surface area, and areal density. In intact sham spinal cords, average microvessel density across the thoracic spinal cord was: ventral grey matter: 571 ± 45 mm-2, dorsal grey matter: 484 ± 33 mm-2, ventral white matter: 90 ± 8 mm-2, dorsal white matter: 88 ± 7 mm-2. Post-SCI, acute microvascular disruption was evident, particularly at the injury epicentre, and spreading three spinal segments rostrally and caudally. Damage was most severe in grey matter at the injury epicentre (T10) and T11. Reductions in all morphological parameters (95-99% at day 2 post-SCI) implied vessel regression and/or collapse acutely. Transmission electron microscopy (TEM) revealed disturbed aspects of neurovascular unit fine structure at day 2 post-SCI (n = 2 per group) at T10 and T11. TEM demonstrated a more diffuse and disrupted basement membrane and wider intercellular clefts at day 2, suggesting a more permeable blood spinal cord barrier and microvessel remodelling. Some evidence of angiogenesis was seen during recovery from days 2 to 45, indicated by increased vessel density, surface area, and areal density at day 45. These novel results show that the spinal cord microvasculature is highly adaptive following SCI, even at chronic stages and up to three spinal segments from the injury epicentre. Multiple measures of gross and fine capillary structure from acute to chronic time points provide insight into microvascular remodelling post-SCI. We have identified key vascular treatment targets, namely stabilising damaged capillaries and replacing destroyed vessels, which may be used to improve functional outcomes following SCI in the future.
- Publication type
- Journal Article MeSH
Nonaqueous capillary electrophoresis (NACE) using methanol (MeOH) as a solvent of the BGEs and quantum mechanical density functional theory (DFT) have been applied to determine the thermodynamic acidity (ionization) constants (pKa ) of mono- and diaza[5]helicenes, mono- and diaza[6]helicenes, and their dibenzo derivatives in MeOH and water. First, the mixed acidity constants, pKa,MeOHmix${\rm{p}}K_{{\rm{a,MeOH}}}^{{\rm{mix}}}$ , of ionogenic pyridinium groups of azahelicenes and their derivatives in MeOH were obtained by nonlinear regression analysis of pH dependence of their effective electrophoretic mobilities. The effective mobilities were measured by NACE in a large series of methanolic BGEs within a wide conventional pH range (pHMeOH 1.6-12.0) and at ambient temperature (21-26°C) in a home-made CE device. Prior to mixed acidity constant calculation, the effective mobilities were corrected to reference temperature (25°C) and constant ionic strength (25 mM). Then, the mixed acidity constants were recalculated to the thermodynamic acidity constants pKa,MeOH by the Debye-Hückel theory of nonideality of electrolyte solutions. Finally, from the methanolic thermodynamic pKa,MeOH values, the aqueous thermodynamic pKa,H2O${\rm{p}}{K_{{\rm{a,}}{{\rm{H}}_{\rm{2}}}{\rm{O}}}}$ constants were estimated using the empirical relations between methanolic and aqueous acidity constants derived for structurally related pyridine derivatives. Depending on the number and position of the nitrogen atoms in their molecules, the analyzed azahelicenes were found to be weak to moderate bases with methanolic pKa,MeOH in the range 2.01-8.75 and with aqueous pKa,H2O${\rm{p}}{K_{{\rm{a,}}{{\rm{H}}_{\rm{2}}}{\rm{O}}}}$ in the range 1.67-8.28. The thermodynamic pKa,MeOH obtained by the DFT calculations were in a good agreement with those determined experimentally by NACE.
This work extends the multi-scale computational scheme for the quantum mechanics (QM) calculations of Nuclear Magnetic Resonance (NMR) chemical shifts (CSs) in proteins that lack a well-defined 3D structure. The scheme couples the sampling of an intrinsically disordered protein (IDP) by classical molecular dynamics (MD) with protein fragmentation using the adjustable density matrix assembler (ADMA) and density functional theory (DFT) calculations. In contrast to our early investigation on IDPs (Pavlíková Přecechtělová et al., J. Chem. Theory Comput., 2019, 15, 5642-5658) and the state-of-the art NMR calculations for structured proteins, a partial re-optimization was implemented on the raw MD geometries in vibrational normal mode coordinates to enhance the accuracy of the MD/ADMA/DFT computational scheme. In addition, machine-learning based cluster analysis was performed on the scheme to explore its potential in producing protein structure ensembles (CLUSTER ensembles) that yield accurate CSs at a reduced computational cost. The performance of the cluster-based calculations is validated against results obtained with conventional structural ensembles consisting of MD snapshots extracted from the MD trajectory at regular time intervals (REGULAR ensembles). CS calculations performed with the refined MD/ADMA/DFT framework employed the 6-311++G(d,p) basis set that outperformed IGLO-III calculations with the same density functional approximation (B3LYP) and both explicit and implicit solvation. The partial geometry optimization did not universally improve the agreement of computed CSs with the experiment but substantially decreased errors associated with the ensemble averaging. A CLUSTER ensemble with 50 structures yielded ensemble averages close to those obtained with a REGULAR ensemble consisting of 500 MD frames. The cluster based calculations thus required only a fraction of the computational time.
The non-invasive determination of the vasculature volume would be very useful in many fields of medicine such as oncology and implantation. The purpose of this research was, therefore, to develop a methodology to investigate vascularisation in phantoms using microcomputed tomography (μCT) without having to visualise the single vessels. Epoxy resin and cotton candy were used to form the phantoms with microchannels. The size of the channels was measured via microscopy and the proportion of the void volume (PVV) was calculated. The phantoms were placed in contrast agent solutions of different concentrations and scanned in μCT. The mean CT numbers of the phantoms were calculated with the Amira software and displayed as a function of the determined PVV and the contrast agent concentration (CAC). The fabricated microchannels had the size of biological capillaries (diameter: 5 μm to 15 μm) and the phantoms showed a microchannel density of 5 to15 microchannels per mm2. With an increasing CAC, the CT numbers increased significantly. Additionally, the phantoms with a higher PVV also had a higher CT number. The CT numbers and the PVV correlated moderately together, but significantly. The slope of the regression line increased with an increasing CAC.
