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.

• Keywords
• BSA oxidation, Cytotoxic activity, Cytotoxicity of O-Mesylates, DFT calculations, Oxidation of triterpenoids, SeO(2) oxidation, α-phenylseleno-ketone,
• MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Oxidation-Reduction 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
• Names of Substances
• lupane MeSH Browser
• Pentacyclic Triterpenes MeSH
• Antineoplastic Agents * MeSH
• Selenium * MeSH
• Triterpenes * MeSH

Classical structure-activity relationships for square-planar Pt(II) anticancer complexes were based on the activity of cis-[PtCl2(NH3)2] (cisplatin) and inactivity of the trans isomer. Many other families of cis-diamine complexes and analogous octahedral Pt(IV) prodrugs are active. Here, we report the chemical and biological activities of isomeric photoactivatable cis,trans,cis- and all-trans-[Pt(N3)2(OH)2(MNZ)2] complexes (MNZ = metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole). While both are relatively nontoxic in the ground state, only the all-trans isomer is cytotoxic toward bladder cancer cells on excitation with visible light and under hypoxia. Studies of DNA interstrand cross-links and photocytotoxicity toward wild-type and nucleotide-excision-repair deficient cells suggest that, unlike cisplatin, DNA is not the major target site of these isomers. Differences in photoactivation pathways were also explored using time-dependent DFT calculations. The key differences between the isomers on irradiation are the more rapid photoactivation of the all-trans complex, generation of azidyl radicals, retention of its metronidazole ligands, higher accumulation in cancer cells, binding to DNA, RNA, and proteins, and induction of apoptosis and mitochondrial membrane damages. These findings provide a basis for the design of future photochemotherapeutic platinum anticancer prodrugs.

• MeSH
• Diamines * chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds * chemistry   pharmacology   chemical synthesis   MeSH
• Antineoplastic Agents * chemistry   pharmacology   chemical synthesis   MeSH
• Drug Screening Assays, Antitumor MeSH
• Density Functional Theory MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Diamines * MeSH
• Organoplatinum Compounds * MeSH
• Antineoplastic Agents * MeSH

This study provides a comprehensive investigation of the structural and vibrational properties of protonated cytosine monomers and dimers. Experimental IRPD spectroscopy, combined with theoretical calculations, revealed distinct behaviors for monomers and dimers. We find that protonated cytosine monomers predominantly adopt the enol form in the gas phase, with a contribution from the keto form between 25% and 33%. For dimers, our computations predict a keto-enol configuration to be more stable than the keto-keto form by 1.5 kcal mol-1. However, experimentally, the keto-keto form emerged as the dominant structure. The theoretically most stable keto-enol configuration undergoes a structural reorganization in MD simulations with explicit methanol, forming the dynamically unstable neutral-keto-protonated-keto complex. This reorganization highlights the role of environmental factors in modulating tautomer populations.

• MeSH
• Cytosine * chemistry   MeSH
• Dimerization MeSH
• DNA * chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Spectrophotometry, Infrared MeSH
• Density Functional Theory MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cytosine * MeSH
• DNA * MeSH

This study explores the structural and electronic factors affecting the absorption spectra of 5-carboxy-tetramethylrhodamine (TAMRA) in water, a widely used fluorophore in imaging and molecular labeling in biophysical studies. Through molecular dynamics (MD) simulations and density functional theory (DFT) calculations, we examine TAMRA UV absorption spectra together with TAMRA-labeled peptides (Arg9, Arg4, Lys9). We found that DFT calculations with different functionals underestimate TAMRA maximum UV absorption peak by ~100 nm, resulting in the maximum at ca. 450 nm instead of the experimental value of ca. 550 nm. However, incorporating MD simulation snapshots of TAMRA in water, the UV maximum peak shifts and is in close agreement with the experimental results due to the rotation of TAMRA N(CH3)2 groups, effectively captured in MD simulations. The method is used to estimate the UV absorption spectra of TAMRA-labeled peptides, matching experimental values.

• Keywords
• UV absorption spectra, fluorescent probes, molecular dynamics simulations, time‐dependent density functional theory,
• MeSH
• Fluorescent Dyes * chemistry   MeSH
• Peptides * chemistry   MeSH
• Rhodamines * chemistry   MeSH
• Molecular Dynamics Simulation * MeSH
• Spectrophotometry, Ultraviolet MeSH
• Density Functional Theory * MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fluorescent Dyes * MeSH
• Peptides * MeSH
• Rhodamines * MeSH
• tetramethylrhodamine MeSH Browser

In this study, a functionalized graphene oxide-cerium oxide nanocatalysts (FGCe) with varying graphene oxide (GO) contents were prepared using an in-situ reflux method. The prepared nanocatalysts showcased improvement in the crystallinity and BET surface area values with increasing GO contents. The efficacies of prepared catalysts were investigated towards oxidative pyrolysis of alkali lignin in an ethanol-water system. Among various nanocatalyst samples, the best lignin conversion (93 %) and bio-oil yield (86 %) were achieved using 50 mg FGCe nanocatalyst (0.5 wt% GO) at 423 K and 60 min. GC-MS and 1HNMR analyses were used to identify significant lignin conversion products, including 2-pentanone-4-hydroxy-4-methyl, 2-methoxyphenol, nonylcyclopropane, vanillin, apocynin, homovanollic acid, and benzoic acid. Kinetic studies revealed that the activation energy for lignin conversion was 24.36 kJ/mol at 423 K. Mechanistic investigations by density functional theory analysis revealed that the lignin breakdown occurred at oxygen bonds producing aromatic.

• Keywords
• Alkali lignin, Cerium oxide, Density functional theory, Functionalized graphene oxide, Pyrolysis,
• MeSH
• Alkalies * chemistry   MeSH
• Cerium * chemistry   MeSH
• Nitrogen * chemistry   MeSH
• Graphite * chemistry   MeSH
• Catalysis MeSH
• Kinetics MeSH
• Lignin * chemistry   MeSH
• Oxidation-Reduction MeSH
• Gas Chromatography-Mass Spectrometry MeSH
• Pyrolysis * MeSH
• Density Functional Theory MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkalies * MeSH
• Bio-Oil MeSH Browser
• Cerium * MeSH
• ceric oxide MeSH Browser
• Nitrogen * MeSH
• Graphite * MeSH
• graphene oxide MeSH Browser
• Lignin * MeSH
• Plant Oils MeSH
• Polyphenols MeSH

Poor aqueous solubility of crystalline active pharmaceutical ingredients (APIs) restricts their bioavailability. Amorphous solid dispersions with biocompatible polymer excipients offer a solution to overcome this problem, potentially enabling a broader use of many drug candidate molecules. This work addresses various aspects of the in silico design of a suitable combination of an API and a polymer to form such a binary solid dispersion. Molecular interactions in such bulk systems are tracked at full atomic resolution within molecular-dynamics (MD) simulations, enabling to identify API-polymer pairs that exhibit the most beneficial interactions. Importance of these interactions is manifold: increasing the mutual miscibility, kinetic stabilization of their amorphous dispersions and impedance of the spurious recrystallization of the API component. MD tools are used to investigate the structural and cohesive properties of pure compounds and mixtures, with a special emphasis on molecular interactions, microscopic structures and internal dynamics. This analysis is then accompanied by a macroscopic image of the energetic compatibility and vitrification tendency of the mixtures in terms of their excess enthalpies and glass transition temperatures. Density-functional theory (DFT) and non-covalent interaction (NCI) analysis fortify our computational conclusions and enable us to map the intensities of particular NCI among the individual target materials and relevant molecular sites therein. Three archetypal polymer excipients and four API molecules are included in this study. The results of our computational analysis of molecular interactions in bulk systems agree with the experimentally observed trends of solubility of the given API in polymers. Our calculations confirm PVP as the most potent acceptor of hydrogen bonding among the three considered polymer excipients, whereas ibuprofen molecules are predicted to be the most efficient hydrogen bond donors among our four target APIs. Our simulations also suggest that carbamazepine does not exhibit particularly strong interactions with the considered polymer excipients. Although current MD cannot offer quantitative accuracy of many of the discussed descriptors, current computational models focusing on NCI of APIs with polymer excipients contribute to understanding of the behavior of these materials at the molecular level, and thus also to the rational design of novel efficient drug formulations.

• MeSH
• Ibuprofen chemistry   MeSH
• Kinetics MeSH
• Crystallization MeSH
• Pharmaceutical Preparations * chemistry   MeSH
• Polymers chemistry   MeSH
• Excipients chemistry   MeSH
• Solubility MeSH
• Molecular Dynamics Simulation MeSH
• Density Functional Theory MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Ibuprofen MeSH
• Pharmaceutical Preparations * MeSH
• Polymers MeSH
• Excipients MeSH

Cytochrome b562 is a small redox-active heme protein that has served as an important model system for understanding biological electron transfer processes. Here, we present a comprehensive theoretical study of electron transport mechanisms in protein-metal junctions incorporating cytochrome b562 using a multi-scale computational approach. Employing molecular dynamics (MD) simulations, we generated junction geometries for both vacuum-dried and solvated conditions, with the protein covalently bound to gold contacts in various configurations. Coherent tunneling, described by the Landauer-Buttiker formalism within the density functional theory (DFT) framework, is compared to the incoherent hopping charge transport mechanism captured by the semi-classical Marcus theory. The tunneling was identified as the dominant mechanism explaining the experimental data measured on the cytochrome b562 junctions, exhibiting exponential yet very shallow distance dependence. While the structural orientations and protein contacts with the electrodes influence the junction conductance significantly, the solvation effects are relatively small, affecting the electronic properties mostly via the adsorption arrangement. On the other hand, the considerable temperature dependence of the conductance was found strong only for hopping, while the tunneling current magnitudes remain practically unaffected and are a good indicator of the coherent mechanism in this case.

• MeSH
• Cytochrome b Group chemistry   metabolism   MeSH
• Escherichia coli Proteins MeSH
• Solvents * chemistry   MeSH
• Molecular Dynamics Simulation * MeSH
• Density Functional Theory MeSH
• Temperature * MeSH
• Electron Transport MeSH
• Gold chemistry   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• cytochrome b562, E coli MeSH Browser
• Cytochrome b Group MeSH
• Escherichia coli Proteins MeSH
• Solvents * MeSH
• Gold MeSH

In this study, we investigated the potential of long-range fluorine-carbon J-coupling for determining the structures of deoxyfluorinated disaccharides. Three disaccharides, previously synthesized as potential galectin inhibitors, exhibited through-space fluorine-carbon J-couplings. In our independent conformational analysis of these disaccharide derivatives, we employed a combination of density functional theory (DFT) calculations and nuclear magnetic resonance (NMR) experiments. By comparing the calculated nuclear shieldings with the experimental carbon chemical shifts, we were able to identify the most probable conformers for each compound. A model comprising fluoromethane and methane molecules was used to study the relationship between molecular arrangements and intermolecular through-space J-coupling. Our study demonstrates the important effect of internuclear distance and molecular orientation on the magnitude of fluorine-carbon coupling. The experimental values for the fluorine-carbon through-space couplings (TSCs) of the disaccharides corresponded with values calculated for the most probable conformers identified by the conformational analysis. These results unlock the broader application of fluorine-carbon TSCs as powerful tools for conformational analysis of flexible molecules, offering valuable insights for future structural investigations.

• Keywords
• Conformation, DFT calculations, Fluorine, NMR spectroscopy, Saccharides,
• MeSH
• Disaccharides * chemistry   MeSH
• Fluorine * chemistry   MeSH
• Carbohydrate Conformation MeSH
• Magnetic Resonance Spectroscopy * MeSH
• Molecular Conformation MeSH
• Density Functional Theory * MeSH
• Carbon chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Cyclic dinucleotides (CDNs) are important second messengers in bacteria and eukaryotes. Detailed characterization of their physicochemical properties is a prerequisite for understanding their biological functions. Herein, we examine acid-base and electromigration properties of selected CDNs employing capillary electrophoresis (CE), density functional theory (DFT), and nuclear magnetic resonance (NMR) spectroscopy to provide benchmark pKa values, as well as to unambiguously determine the protonation sites. Acidity constants (pKa) of the NH+ moieties of adenine and guanine bases and actual and limiting ionic mobilities of CDNs were determined by nonlinear regression analysis of the pH dependence of their effective electrophoretic mobilities measured by CE in aqueous background electrolytes in a wide pH range (0.98-11.48), at constant temperature (25°C), and constant ionic strength (25 mM). The thermodynamic pKa values were found to be in the range 3.31-4.56 for adenine and 2.28-3.61 for guanine bases, whereas the pKa of enol group of guanine base was in the range 10.21-10.40. Except for systematic shifts of ∼2 pKa, the pKa values calculated by the DFT-D3//COSMO-RS composite protocol that included large-scale conformational sampling and "cross-morphing" were in a relatively good agreement with the pKas determined by CE and predict N1 atom of adenine and N7 atom of guanine as the protonation sites. The protonation of the N1 atom of adenine and N7 atom of guanine in acidic background electrolytes (BGEs) and the dissociation of the enol group of guanine in alkaline BGEs was confirmed also by NMR spectroscopy.

• Keywords
• DFT calculations, NMR spectroscopy, acidity constant, capillary electrophoresis, cyclic dinucleotides,
• MeSH
• Dinucleoside Phosphates chemistry   MeSH
• Electrophoresis, Capillary * methods   MeSH
• Hydrogen-Ion Concentration MeSH
• Magnetic Resonance Spectroscopy * methods   MeSH
• Protons * MeSH
• Density Functional Theory MeSH
• Thermodynamics MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dinucleoside Phosphates MeSH
• Protons * MeSH

Adsorption of cell-penetrating peptides (CPPs) at cellular membranes is the first and necessary step for their subsequent translocation across cellular membranes into the cytosol. It has been experimentally shown that CPPs rich in arginine (Arg) amino acid penetrate across phospholipid bilayers more effectively than their lysine (Lys) rich counterparts. In this work, we aim to understand the differences in the first translocation step, adsorption of Arg9 and Lys9 peptides at fully hydrated neutral phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipid bilayers and evaluate in detail the energetics of the process using molecular dynamics (MD) simulations and free energy calculations of adsorption of the single peptide. We show that the adsorption of Arg9 is energetically feasible, with the free energy of adsorption being ∼-5.0 kcal mol-1 at PC and ∼-5.5 kcal mol-1 at PE bilayers. In contrast, adsorption of Lys9 is not observed at PC bilayers, and their adsorption at PE bilayers is very weak, being ∼-0.5 kcal mol-1. We show by energy decomposition and analysis of peptide hydration along the membrane that significantly stronger electrostatic interactions of Arg9 with lipid phosphate groups, together with the greater loss of peptide hydration (and in turn stronger hydrophobic interactions) along the membrane translocation path, are the main driving factors governing the adsorption of Arg-rich peptides at neutral lipid bilayers in contrast to Lys-rich peptides. Finally, we also compare the energetics in lipid/bilayer systems with the density functional theory (DFT) calculations of the corresponding model systems in the continuum water model and reveal the energetic differences in different environments.

• MeSH
• Phosphatidylcholines chemistry   MeSH
• Phospholipids MeSH
• Lipid Bilayers chemistry   MeSH
• Cell-Penetrating Peptides * chemistry   MeSH
• Polylysine * MeSH
• Molecular Dynamics Simulation MeSH
• Density Functional Theory MeSH
• Thermodynamics MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phosphatidylcholines MeSH
• Phospholipids MeSH
• Lipid Bilayers MeSH
• Cell-Penetrating Peptides * MeSH
• polyarginine MeSH Browser
• Polylysine * MeSH