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Marine plastic pollution caused by non-biodegradable polymers is a major worldwide concern. So-called “biodegradable” polymers should reduce plastic pollution in the environment by the safeguard of biodegradation. However, many polyesters degrade very slowly in seawater. We therefore designed a systematic library of “breaking points” that are installed into a polylactide backbone and simulated their degradation mechanisms, including internal and external SN2 mechanisms, Addition-Elimination (AE) mechanisms, and RNA-inspired mechanisms. The breaking points are composed of phosphoesters with pendant nucleophiles directly at the P-atom, or structurally similar silicones, or side-chain functional polyesters. All P-containing breaking points react via the RNA-inspired mechanism, while Si-containing linkers undergo decomposition via the A-E mechanism. For C-containing linkers, only when a long pendant chain (4 carbon atoms) is present can the reaction proceed via the RNA-inspired mechanism. In cases of shorter pendants, the Addition-Elimination (AE) mechanism is energetically favorable. We believe that these calculations will pave the way for the synthesis of exceptionally seawater-degradable polyesters in the future that can act as a safeguard to prevent microplastic formation after eventual littering.

Precision biotransformation is an envisioned strategy offering detailed insights into biotransformation pathways in real environmental settings using experimentally guided high-accuracy quantum chemistry. Emerging pollutants, whose metabolites are easily overlooked but may cause idiosyncratic toxicity, are important targets of such a strategy. We demonstrate here that complex metabolic reactions of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) catalyzed by human CYP450 enzymes can be mapped via a three-step synergy strategy: (i) screening the possible metabolites via high-throughout (moderate-accuracy) computations; (ii) analyzing the proposed metabolites in vitro by human liver microsomes and recombinant human CYP450 enzymes; and (iii) rationalizing the experimental data via precise mechanisms using high-level targeted computations. Through the bilateral dialogues from qualitative to semi-quantitative to quantitative levels, we show how TDCIPP metabolism especially by CYP3A4 generates bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) as an O-dealkylation metabolite and bis(1,3-dichloro-2-propyl) 3-chloro-1-hydroxy-2-propyl phosphate (alcoholβ-dehalogen) as a dehalogenation/reduction metabolite via the initial rate-determining H-abstraction from αC- and βC-positions. The relative yield ratio [dehalogenation/reduction]/[O-dealkylation] is derived from the relative barriers of H-abstraction at the βC- and αC-positions by CYP3A4, estimated as 0.002 to 0.23, viz., an in vitro measured ratio of 0.04. Importantly, alcoholβ-dehalogen formation points to a new mechanism involving successive oxidation and reduction functions of CYP450, with its precursor aldehydeβ-dehalogen being a key intermediate detected by trapping assays and rationalized by computations. We conclude that the proposed three-step synergy strategy may meet the increasing challenge of elucidating biotransformation mechanisms of substantial synthesized organic compounds in the future.

This review examines the existing knowledge about Ru(II)/(III) ion complexes with a potential application in medicine or pharmacy, which may offer greater potential in cancer chemotherapy than Pt(II) complexes, which are known to cause many side effects. Hence, much attention has been paid to research on cancer cell lines and clinical trials have been undertaken on ruthenium complexes. In addition to their antitumor activity, ruthenium complexes are under evaluation for other diseases, such as type 2 diabetes, Alzheimer’s disease and HIV. Attempts are also being made to evaluate ruthenium complexes as potential photosensitizers with polypyridine ligands for use in cancer chemotherapy. The review also briefly examines theoretical approaches to studying the interactions of Ru(II)/Ru(III) complexes with biological receptors, which can facilitate the rational design of ruthenium-based drugs.

Although weak intermolecular interactions are the essence of most processes of key importance in medicine, industry, environment, and life cycles, their characterization is still not sufficient. Enzymatic dehalogenations that involve chloride anion interaction within a host-guest framework is one of the many examples. Recently published experimental results on host-guest systems provided us with models suitable to assess isotopic consequences of these noncovalent interactions. Herein, we report the influence of environmental and structural variations on chlorine isotope effects. We show that these effects, although small, may obscure mechanistic interpretations, as well as analytical protocols of dehalogenation processes.

Disaccharide complexes have been shown experimentally to be useful for drug delivery or as an antifouling surface biofilm, and are promising drug-encapsulation and delivery candidates. Although such complexes are intended for medical applications, to date no studies at the molecular level have been devoted to the influence of complexation on the enzymatic decomposition of polysaccharides. A theoretical approach to this problem has been hampered by the lack of a suitable computational tool for binding such non-covalent complexes to enzymes. Herein, we combine quantum-mechanical calculations of disaccharides complexes with a nonstandard docking GaudiMM engine that can perform such a task. Our results on four different complexes show that they are mostly stabilized by electrostatic interactions and hydrogen bonds. This strong non-covalent stabilization demonstrates the studied complexes are some excellent candidates for self-assembly smart materials, useful for drug encapsulation and delivery. Their advantage lies also in their biocompatible and biodegradable character.

Bladder cancer (BC) is the most common urological malignancy and has a high incidence of recurrence. BC cells alter their nutrient uptake and metabolic pathways in order to continue the production of sufficient levels of ATP and metabolic intermediates for proliferation and survival. Changes in metabolic pathways regarding the rate of the enzymatic reaction and transport lead to differences in the content of natural isotopes (13C, 15N, 34S) between normal and cancerous tissues. The assessment of the stable isotopes of carbon, nitrogen, and sulfur in normal urothelium and bladder cancer samples was performed using Isotope Ratio Mass Spectrometry (IRMS). The natural abundance of 15N and 13C was decreased in bladder cancer samples when compared to normal urothelium. No significant correlation was observed in BC specimens depending on the tumor grade and stage. Samples derived from bladder tumors and normal urothelium had a different pattern of 15N and 13C isotope abundance. Decreased 13C natural isotopes in the normal urothelium of BC patients were significantly associated with a shorter DFS. Our results suggest that isotopic analysis of normal urothelium of BC patients can be used to predict bladder cancer recurrence.

With the advent of new experimental techniques, measurements of individual, per-position, vapor pressure isotope effects (VPIEs) became possible. Frequently, they are in opposite directions (larger and smaller than unity), leading to the cancellation when only bulk values are determined. This progress has not been yet paralleled by the theoretical description of phase change processes that would allow for computational prediction of the values of these isotope effects. Herein, we present the first computational protocol that allowed us to predict carbon VPIEs for ethanol—the molecule of great importance in authentication protocols that rely on the precise information about position-specific isotopic composition. Only the model comprising explicit treatment of the surrounding first-shell molecules provided good agreement with the measured values of isotope effects. Additionally, we find that the internal vibrations of molecules of the model to predict isotope effects work better than the entire set of normal modes of the system.

To synthesize new (bio)degradable alternatives to commodity polymers, adapting natural motives can be a promising approach. We present the synthesis and characterization of degradable polyethylene (PE)-like polyphosphoesters, which exhibit increased degradation rates due to an intra-molecular transesterification similar to RNA. An α,ω-diene monomer was synthesized in three steps starting from readily available compounds. By acyclic diene metathesis (ADMET) polymerization, PE-like polymers with molecular weights up to 38 400 g mol−1 were obtained. Post-polymerization functionalization gave fully saturated and semicrystalline polymers with a precise spacing of 20 CH2 groups between each phosphate group carrying an ethoxy hydroxyl side chain. This side chain was capable of intramolecular transesterification with the main-chain similar to RNA-hydrolysis, mimicking the 2′-OH group of ribose. Thermal properties were characterized by differential scanning calorimetry (DSC (Tmca. 85 °C)) and the crystal structure was investigated by wide-angle X-ray scattering (WAXS). Polymer films immersed in aqueous solutions at different pH values proved an accelerated degradation compared to structurally similar polyphosphoesters without pendant ethoxy hydroxyl groups. Polymer degradation proceeded also in artificial seawater (pH = 8), while the polymer was stable at physiological pH of 7.4. The degradation mechanism followed the intra-molecular “RNA-inspired” transesterification which was detected by NMR spectroscopy as well as by monitoring the hydrolysis of a polymer blend of a polyphosphoester without pendant OH-group and the RNA-inspired polymer, proving selective hydrolysis of the latter. This mechanism has been further supported by the DFT calculations. The “RNA-inspired” degradation of polymers could play an important part in accelerating the hydrolysis of polymers and plastics in natural environments, e.g. seawater., RNA-inspired degradation of polyethylene-like polyphosphoesters accelerates the backbone hydrolysis dramatically to guarantee seawater-degradable plastics.

The development of drug-resistant bacteria is currently one of the major challenges in medicine. Therefore, the discovery of novel lead structures for the design of antibacterial drugs is urgently needed. In this structure&ndash, activity relationship study, a library of ortho-, meta-, and para-fluorobenzoylthiosemicarbazides, and their cyclic analogues with 1,2,4-triazole scaffold, was created and tested for antibacterial activity against Gram-positive bacteria strains. While all tested 1,2,4-triazoles were devoid of potent activity, the antibacterial response of the thiosemicarbazides was highly dependent on substitution pattern at the N4 aryl position. The optimum activity for these compounds was found for trifluoromethyl derivatives such as 15a, 15b, and 16b, which were active against both the reference strains panel, and pathogenic methicillin-sensitive and methicillin-resistant Staphylococcus aureus clinical isolates at minimal inhibitory concentrations (MICs) ranging from 7.82 to 31.25 &mu, g/mL. Based on the binding affinities obtained from docking, the conclusion can be reached that fluorobenzoylthiosemicarbazides can be considered as potential allosteric d-alanyl-d-alanine ligase inhibitors.

Two distinct intracellular pathogens, namely Mycobacterium tuberculosis (Mtb) and Toxoplasma gondii (Tg), cause major public health problems worldwide. In addition, serious and challenging health problems of co-infections of Tg with Mtb have been recorded, especially in developing countries. Due to this fact, as well as the frequent cases of resistance to the current drugs, novel anti-infectious therapeutics, especially those with dual (anti-Tg and anti-Mtb) modes of action, are needed. To address this issue, we explored the anti-Tg potential of thiazolidinedione-based (TZD-based) hybrid molecules with proven anti-Mtb potency. Several TZD hybrids with pyridine-4-carbohydrazone (PCH) or thiosemicarbazone (TSC) structural scaffolds were more effective and more selective than sulfadiazine (SDZ) and trimethoprim (TRI). Furthermore, all of these molecules were more selective than pyrimethamine (PYR). Further studies for the most potent TZD-TSC hybrids 7, 8 and 10 and TZD-PCH hybrid molecule 2 proved that these compounds are non-cytotoxic, non-genotoxic and non-hemolytic. Moreover, they could cross the blood–brain barrier (BBB), which is a critical factor linked with ideal anti-Tg drug development. Finally, since a possible link between Tg infection and the risk of glioblastoma has recently been reported, the cytotoxic potential of TZD hybrids against human glioblastoma cells was also evaluated. TZD-PCH hybrid molecule 2 was found to be the most effective, with an IC50 of 19.36 ± 1.13 µg/mL against T98G cells.

Marine plastic pollution is a worldwide challenge making advances in the field of biodegradable polymer materials necessary. Polylactide (PLA) is a promising biodegradable polymer used in various applications; however, it has a very slow seawater degradability. Herein, we present the first library of PLA derivatives with incorporated “breaking points” to vary the speed of degradation in artificial seawater from years to weeks. Inspired by the fast hydrolysis of ribonucleic acid (RNA) by intramolecular transesterification, we installed phosphoester breaking points with similar hydroxyethoxy side groups into the PLA backbone to accelerate chain scission. Sequence-controlled anionic ring-opening copolymerization of lactide and a cyclic phosphate allowed PLA to be prepared with controlled distances of the breaking points along the backbone. This general concept could be translated to other slowly degrading polymers and thereby be able to prevent additional marine pollution in the future.

BACKGROUND: Quantitative determination with site‐specific natural isotope fractionation nuclear magnetic resonance (SNIF‐NMR) has been exploited widely in detecting adulteration and for the classification of natural products by their geographical origin. RESULTS: We compared isotopic parameters such as deuterium / hydrogen (D/H) site specific ratios and the R parameter for alcoholic beverages, obtained using (i) a 500 MHz spectrometer equipped with a dedicated probe for isotopic measurements, and (ii) a 700 MHz spectrometer equipped with a standard probe. The factors affecting the accuracy and precision of quantitative NMR with the second instrument have been explored. CONCLUSIONS: It has been demonstrated that, in laboratories with a spectrometer that is not equipped with a specific deuterium probe, the selection of the appropriate experimental parameters enables measurements with a similar precision and accuracy as in the case of the official method adopted by the International Organisation of Vine and Wine. © 2019 Society of Chemical Industry

Three half-sandwich organometallic ruthenium(II) complexes containing purine analogs such as triazolopyrimidines of general formula [(η6-p-cym)Ru(L)Cl2], where p-cym represents p-cymene and L is 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp for 1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for 2) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO for 3), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (1H, 13C, 15N), and single-crystal X-ray diffraction (for 1 and 2). All these complexes have been thoroughly screened for their in vitro cytotoxicity against MCF-7 and HeLa cell lines as well as L929 murine fibroblast cells, indicating [(η6-p-cym)Ru(HmtpO)Cl2] (3) as the most active representative against the HeLa cell line and simultaneously being 64-fold less toxic to normal L929 murine fibroblast cells than cisplatin. At the same time, 3 has shown antimetastatic activity comparable to NAMI-A against HeLa cells both after 24 and 48 h of treatment in a wound healing assay. In order to better understand the mechanism of anticancer action and differences in the cytotoxic activity of 1–3, the studies were expanded to determining their lipophilicity, the kinetic stability at pH 6.5–8, the effect on reactive oxygen species (ROS) production in HeLa cells and interactions with significant biomolecules (DNA and albumin) by using molecular docking and circular dichroism (CD) experiments. Furthermore, antiparasitic studies against L. braziliensis, L. infantum and T. cruzi reveal that the newly synthesized complexes 1–3 are very promising candidates which can compete with commercial antiparasitic drugs. Complex 3 in particular, on top of exhibiting a high antiparasitic effect (IC50 1000.

Compounds targeting bacterial topoisomerases are of interest for the development of antibacterial agents. Our previous studies culminated in the synthesis and characterization of small-molecular weight thiosemicarbazides as the initial prototypes of a novel class of gyrase and topoisomerase IV inhibitors. To expand these findings with further details on the mode of action of the most potent compounds, enzymatic studies combined with a molecular docking approach were carried out, the results of which are presented herein. The biochemical assay for 1-(indol-2-oyl)-4-(4-nitrophenyl) thiosemicarbazide (4) and 4-benzoyl-1-(indol-2-oyl) thiosemicarbazide (7), showing strong inhibitory activity against Staphylococcus aureus topoisomerase IV, confirmed that these compounds reduce the ability of the ParE subunit to hydrolyze ATP rather than act by stabilizing the cleavage complex. Compound 7 showed better antibacterial activity than compound 4 against clinical strains of S. aureus and representatives of the Mycobacterium genus. In vivo studies using time-lapse microfluidic microscopy, which allowed for the monitoring of fluorescently labelled replisomes, revealed that compound 7 caused an extension of the replication process duration in Mycobacterium smegmatis, as well as the growth arrest of bacterial cells. Despite some similarities to the mechanism of action of novobiocin, these compounds show additional, unique properties, and can thus be considered a novel group of inhibitors of the ATPase activity of bacterial type IIA topoisomerases.

Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.

We present an overview of the theory behind isotope effects, explaining how to predict them using modern computational techniques, and how the knowledge coming from computations can be used in the analysis of the behavior of various systems ranging from chemical to enzymatic processes. We illustrate current applications of theoretically predicted kinetic isotope effects using the example of oxidation and hydrogen abstraction reactions taking place in aqueous solution. We demonstrate the use of different computational QM/MM protocols in studies of enzymatic reactions such as dehalogenation, oxygenation, and hydroxylation. Finally, we discuss our ability to predict equilibrium isotope effects, such as vapor pressure isotope effects, using the example of the evaporation of pure-phase organic solvents, binding isotope effects, and isotope effects on the adsorption on graphene.

International audience; Position-specific isotope analysis by Nuclear Magnetic Resonance spectrometry was employed to study the 13C intramolecular isotopic fractionation associated with the migration of organic substrates through different stationary phases chromatography columns. Liquid chromatography is often used to isolate compounds prior to their isotope analysis and this purification step potentially alters the isotopic composition of target compounds introducing a bias in the later measured data. Moreover, results from liquid chromatography can yield the sorption parameters needed in reactive transport models that predict the transport and fate of organic contaminants to in the environment. The aim of this study was to use intramolecular isotope analysis to study both 13C and 15N isotope effects associated with the elution of paracetamol (acetaminophen) through different stationary phases and to compare them to effects observed previously for vanillin. Results showed very different intramolecular isotope fractionation profiles depending on the chemical structure of the stationary phase. The data also demonstrate that both the amplitude and the distribution of measured isotope effects depend on the nature of the non-covalent interactions involved in the migration process. Results provided by theoretical calculation performed during this study also confirmed the direct link between observed intramolecular isotope fractionation and the nature of involved intermolecular interactions. It is concluded that the nature of the stationary phase through which the substrate passes has a major impact on the intramolecular isotopic composition of organic compounds isolated by chromatography methods..

Docking of over 160 aminothiourea derivatives at the SARS-CoV-2 S-protein&ndash, human ACE2 receptor interface, whose structure became available recently, has been evaluated for its complex stabilizing potency and subsequently subjected to quantitative structure&ndash, activity relationship (QSAR) analysis. The structural variety of the studied compounds, that include 3 different forms of the N&ndash, N&ndash, C(S)&ndash, N skeleton and combinations of 13 different substituents alongside the extensive length of the interface, resulted in the failure of the QSAR analysis, since different molecules were binding to different parts of the interface. Subsequently, absorption, distribution, metabolism, and excretion (ADME) analysis on all studied compounds, followed by a toxicity analysis using statistical models for selected compounds, was carried out to evaluate their potential use as lead compounds for drug design. Combined, these studies highlighted two molecules among the studied compounds, i.e., 5-(pyrrol-2-yl)-2-(2-methoxyphenylamino)-1,3,4-thiadiazole and 1-(cyclopentanoyl)-4-(3-iodophenyl)-thiosemicarbazide, as the best candidates for the development of future drugs.

Binding of over 20 approved drugs proposed for the repurposing for COVID-19 treatment and over 160 aminothioureas derivatives to SARS-CoV-2 enzymes which structures became available very recently have been evaluated using a few docking algorithms. These studies support potential effectiveness of homobarringtonine, chloroquine, rimcazole, and benserazine. From among studied aminothioureas thiadiazoles with pyrrol-derived substituents at the carbon atom, and ortho-hydroxyphenyl at the nitrogen atom are potential lead compounds for future drugs development.

The production of 'Polish Vodka' is restricted by law to the ethyl alcohol of agricultural origins obtained from rye, wheat, barley, oat, triticale and potatoes grown on the territory of the Republic of Poland. The current labeling system should guarantee that the spirit is authentic and of good quality but not all producers are honest. Unfortunately, authentic 'Polish Vodka' is the most often counterfeited by the addition of cheaper and more accessible maize spirits. These illegal practices significantly reduce costs of the spirit production. Therefore, determination of the botanical origin of alcohol in Poland is highly relevant. RESULTS Quantitative 2H nuclear magnetic resonance and isotope ratio mass spectrometry were used to investigate the authenticity of 30 samples of Polish spirits. Several isotopic parameters were used to determine the botanical origin of 10 unknown samples. Both approaches led to the same conclusions regarding the percentage of maize-derived ethanol addition. CONCLUSIONS Applied techniques are a valuable tool in the fight against counterfeiting of products. ? 2018 Society of Chemical Industry

GPR119 receptor has been proposed as a metabolic regulator playing a pivotal role in the modulation of glucose homeostasis in type 2 diabetes. GPR119 was identified on pancreatic β cells and its ligands have the ability to enhance glucose-stimulated insulin secretion (GSIS). Lysophosphatidylcholine (LPC) was shown to potentiate GSIS and our present studies indicate that 2-methoxy-lysophosphatidylcholine (2-OMe-LPC) analogues, unable to undergo 1 → 2 acyl migration, stimulate GSIS from murine βTC-3 pancreatic cells even more efficiently. Moreover, biological assays in engineered Tango™ GPR119-bla U2OS cells were carried out to ascertain the agonist activity of 2-OMe-LPC at GPR119. 2-OMe-LPC possessing in sn-1 position the residues of myristic, palmitic, stearic and oleic acid were also evaluated as factors regulating [Ca2 +]i mobilization and cAMP levels. Extension of these studies to R- and S-enantiomers of 14:0 2-OMe-LPC revealed that the overall impact on GSIS does not depend on chirality, however, the intracellular calcium mobilization data show that the R enantiomer is significantly more active than S one. Taking into account differences in chemical structure between various native LPCs and their 2-methoxy counterparts the possible binding mode of 2-OMe-LPC to the GPR119 receptor was determined using molecular modeling approach.

The current pandemic outbreak clearly indicated the urgent need for tools allowing fast predictions of bioactivity of a large number of compounds, either available or at least synthesizable. In the computational chemistry toolbox, several such tools are available, with the main ones being docking and structure-activity relationship modeling either by classical linear QSAR or Machine Learning techniques. In this contribution, we focus on the comparison of the results obtained using different docking protocols on the example of the search for bioactivity of compounds containing N-N-C(S)-N scaffold at the S-protein of SARS-CoV-2 virus with ACE2 human receptor interface. Based on over 1800 structures in the training set we have predicted binding properties of the complete set of nearly 600000 structures from the same class using the Machine Learning Random Forest Regressor approach.

Binding isotope effects (BIEs) associated with binding of four triazole-based ligands to HIV-1 reverse transcriptase have been calculated at the QM/MM MD level of theory. Two main binding sites: allosteric cavity and RNase H active site, as well as three other sites reported in the literature (the Knuckles, the NNRTI Adjacent, and Incoming Nucleotide Binding) have been considered. The interactions between inhibitors and these protein sites have been quantified by binding free energies obtained from free energy perturbation (FEP) calculations, supported by interaction energy analysis. It has been shown that binding in the allosteric cavity can be distinguished from binding to other sites based on BIEs as it is associated with normal 18O-BIEs of the carbonyl oxygen atom while binding to RNase H active site is characterized by inverse binding isotope effect (18O-BIE

We have performed calculations of possible oxidation pathways of 4-nitrotoluene (4NT) by permanganate anion and evaluated relative contributions of oxidation of the methyl group and aromatic ring. Although a few theory levels matched the experimental results obtained by compound specific isotope analysis (CSIA) for 4NT, they failed in reproducing results for other nitrotoluene derivatives studied previously [Wijker, R.S.; Adamczyk, P.; Bolotin, J.; Paneth, P.; Hofstetter, T.B. Environ. Sci. Technol., 2013, 47, 13459-13468]. This discrepancy prompted us to reevaluate the experimental isotopic fractionation of carbon and hydrogen for 4NT on which the relative contributions of the oxidation channels has been based. Using position specific isotope analysis (PSIA) for hydrogen isotopic fractionation we have found that the previously determined value was incorrect. Reexamination of theory levels that are in agreement with these new findings indicated that while a better agreement for this particular case can be reached, overall, the previously used B3LYP functional expressed in the 6-31+G(d,p) basis set with inclusion of the polarized continuum model (PCM) of aqueous solution remains the theoretical level of choice in modeling oxidation of nitrotoluene derivatives by permanganate.

This paper examines the cytotoxic effect of nine compounds with spiropyrazoline structures, and determines the reaction mechanism between diazomethane and selected benzylideneflavanones, their lipophilicity, and their binding ability to human serum albumin. The cytotoxic effect was determined on two human leukaemia cell lines (HL-60 and NALM-6) and melanoma WM-115 cells, as well as on normal human umbilical vein endothelial cells (HUVEC). The highest cytotoxicity was exhibited by compound B7: it was found to have an IC50 of less than 10 μM for all three cancer cell lines, with five to 12-fold lower sensitivity against normal cells (HUVEC). All the compounds exhibit comparable affinity energy in human serum albumin binding (from −8.1 to −8.6 kcal mol−1) but vary in their binding sites depending on the substituent. X-ray crystallography of two derivatives confirmed their synthetic pathway, and their structures were carefully examined.

Fusarium oxysporum laccase was functionally expressed in Saccharomyces cerevisiae and engineered towards higher expression levels and higher reactivity towards 2,6-dimethoxyphenol, that could be used as a mediator for lignin modification. A combination of classical culture optimization and protein engineering led to around 30 times higher activity in the culture supernatant. The winner mutant exhibited three times lower Km, four times higher kcat and ten times higher catalytic efficiency than the parental enzyme. The strategy for laccase engineering was composed of a combination of random methods with a rational approach based on QM/MM MD studies of the enzyme complex with 2,6-dimethoxyphenol. Laccase mediator system with 2,6-dimethoxyphenol caused fulvic acids release from biosolubilized coal.

Due to its importance in chemistry and biology, mechanisms of reactions involving phosphates are of central interest. However, only recently, quantum-chemical modeling of these reactions has become possible. With the advent of DFT calculations on phosphate-containing molecules, we have, therefore, investigated theoretically the mechanism of thiol-thione isomerization of a monothiopyrophosphate, which has been for a long time a subject of controversy. The calculations indicate that the reaction proceeds via concerted intramolecular mechanisms.

The contribution of C, N and S, as well as the isotopic composition of C and N of atmospheric pollutants, are assumed to be reflected in the organic compounds inbuilt into the lichen thallus. The chemical and isotopic analyses were carried out on lichen Hypogymnia physodes samples gathered from Picea abies and Larix decidua, collected in 13 sampling points located in Karkonoski National Park and its closest vicinity in 2011. The results for %C, %N and %S varied from 43.44 to 46.79%, from 0.86 to 1.85% and from 0.07 to 0.27 %, respectively. The δ13C values ranged from −26.6 to −24.6‰, whereas δ15N values varied from −13.0 to −6.8‰. The ranges in isotope composition suggest different sources of C and N for Karpacz compared to the remaining sampling sites. For Karpacz, the δ13C values suggest (in case the fractionation product-substrate does not exist and Δ=0) that the dominant sources are coal combustion processes, whereas for remaining sampling points, the δ13C values are ambiguous and are masked by many mixed natural and anthropogenic processes. With the same assumption that Δ=0, the δ15N values suggest that transport is not a dominant source of nitrogen within Karpacz city. Moreover, in this study we tested the possible fractionation (Δ) for carbon and nitrogen, assuming that within the investigated area, the source of carbon is probably CO2 and/or DIC (HCO3 −) dissolved in precipitation, while the source of nitrogen is NOx and/or NO3 − ion. The calculated fractionation factors were: (i) for gaseous carbon compounds ΔCO2-Corg value from −13.4 to −11.4‰, whereas for the ions form ΔHCO3 −-Corg value from −16.6 to −14.6‰, (ii) for nitrogen gaseous compounds ΔNOx-Norg value between apx. −17 and −5‰, whereas for the ions form ΔNO3 −-Norg value between −9.9 and −3.7‰.

Introduction: Hepatoblastoma is the most common primary liver tumor in children. However, it occurs rarely, with an incidence of 0.5-1.5 cases per million children. There is no clear explanation of the relationship between clinicopathologic features, therapy, and outcome in hepatoblastoma cases, so far. One of the most widely accepted prognostic factors in hepatoblastoma is histology of the tumor. The aim of the study was to determine the potential differences in biology of hepatoblastoma histological subtypes at the atomic level using the unique method of isotope ratio mass spectrometry, which is especially valuable in examination of small groups of biological samples. Material/Methods: Twenty-four measurements of nitrogen stable isotope ratio, carbon stable isotope ratio and total carbon to nitrogen mass ratio in fetal and embryonal hepatoblastoma tissue were performed using a Sercon 20-22 Continuous Flow Isotope Ratio Mass Spectrometer (CF-IRMS) coupled with a Sercon SL elemental analyzer for simultaneous carbon-nitrogen-sulfur (NCS) analysis. Results: A difference of about 1.781 parts per thousand in stable nitrogen isotope N-15/N-14 ratio was found between examined hepatoblastoma histological subtypes. Conclusions: The prognosis in liver tumors cases in children may be challenging particularly because of the lack of versatile methods of its evaluation. Isotope ratio mass spectrometry allows one to determine the difference between hepatoblastoma histological subtypes and clearly indicates the cases with the best outcome.