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Rationale: Cytosine and its conjugates are prone to form protonated, triply‐bonded dimers. Therefore, the nucleic‐acid cytosine‐rich sequence forms the four‐stranded noncanonical secondary structure known as the intercalated motif (i‐motif). This process has resulted in studies on cytosine protonated dimers. This communication focuses on the protonated dimers of cytosine and its nucleoside using the survival yield (SY) method and quantum mechanics calculations. Methods: To obtain the precursor ion fragmentation curve, the plot of SY against Ecomδ, the product ion spectra of the protonated dimers were obtained using a Waters/Micromass Q‐TOF Premier mass spectrometer. Quantum mechanics calculations were performed using GAUSSIAN 16, and full geometry optimizations and energy calculations were performed within the density functional theory framework at B3LYP/6‐31G(d,p). Results: The precursor ion fragmentation curve allowed the rating of the gas‐phase stabilities of the analyzed protonated dimers. Substitution of sugar moiety at N1 cytosine atom decreased the gas‐phase stabilities of the protonated dimers. The deoxycytidine dimer was found to be more stable than the cytidine dimer and cytidine–deoxycytidine dimer. Quantum chemical calculations indicated that cytosine aminohydroxy tautomer may be involved in the formation of protonated cytosine–cytosine nucleoside dimers but not in the formation of cytosine dimers. Conclusions: The results obtained for nucleoside dimers indicated that the SY method may reflect the i‐motif stabilities observed under physiological conditions. Therefore, the analysis of other protonated dimers of variously substituted cytosine–cytosine nucleoside using the SY method may be important to study the effect of cytosine substitution on the i‐motif stabilities. Cytosine tautomer containing C2‐OH... N(2H)‐C4 moiety may be involved in the formation of protonated cytosine–cytosine nucleoside dimers. [ABSTRACT FROM AUTHOR]

Herein, we present the application of fluorinated carbohydrate-derived building blocks for α-hydroxy β-fluoro/β-trifluoromethyl and unsaturated phosphonates synthesis. Pudovik and Horner–Wadsworth–Emmons reactions were applied to achieve this goal. The proposed pathway of the key reactions is supported by the experimental results, as well as quantum chemical calculations. The structure of the products was established by spectroscopic (1D, 2D NMR) and spectrometric (MS) techniques. Based on our data received, we claim that the progress of the Pudovik and HWE reactions is significantly influenced by the acidic protons present in the molecules as assessed by pKa values of the reagent. [ABSTRACT FROM AUTHOR]

Colchicine is a tropolone alkaloid from Colchicinum autumnale. It shows antifibrotic, antimitotic, and anti-inflammatory activities, and is used to treat gout and Mediterranean fever. In this work, complexes of colchicine with zinc(II) nitrate were synthesized and investigated using DFT, H and C NMR, FT IR, and ESI MS. The counterpoise-corrected and uncorrected interaction energies of these complexes were calculated. We also calculated their H, C NMR, and IR spectra and compared them with the corresponding experimentally obtained data. According to the ESI MS mass spectra, colchicine forms stable complexes with zinc(II) nitrate that have various stoichiometries: 2:1, 1:1:1, and 2:1:1 with respect to colchichine, Zn(II), and nitrate ion. All of the complexes were investigated using the quantum theory of atoms in molecules (QTAIM). The calculated and the measured spectra showed differences before and after the complexation process. Calculated electron densities and bond critical points indicated the presence of bonds between the ligands and the central cation in the investigated complexes that satisfied the quantum theory of atoms in molecules. [ABSTRACT FROM AUTHOR]

• interactions between the molecule of a plasticizer and organic peroxide have significant directional character of a hydrogen bonding. • plasticizer molecules not only dilute an organic peroxide but also provide additional stabilization, whose energy is ca -15 kcal/mol. • organic peroxide molecule has two hydrogen bond donors so the favorable plasticizer should possesses two hydrogen bond acceptors. • alternatives to phthalate plasticizers are likely to be found amongst di- or poly- esters. In this paper we would present our studies how organic peroxides are being stabilized by plasticizers used in manufacturing of organic peroxides as polymerization initiators etc. As an exemplary system, interactions between 2,2-dihydroperoxybutane and dimethyl phthalate (system already approved for commercial use) has been studied. The quantum chemical study protocol was to investigate for the first time the interactions between a plasticizer and the peroxide – indicating that the interaction energy of about -15 kcal/mol favors the formation of a supramolecular system. [Display omitted] [ABSTRACT FROM AUTHOR]

Reactions of zinc(II) chloride with ( S )-(−)-nicotine (Nic), cotinine, thionicotine and selenonicotine in 1:1 molar ratio yielded new metal complexes, which were characterized by elemental analysis, infrared, 13 C and 1 H NMR spectral methods. Single crystal X-ray diffraction studies of ZnCl 2 complexes with thionicotine and selenonicotine revealed that the two complexes form isostructural crystals build of 1D coordination polymers (CP) and that coordination to metal centers alters the conformation of the parent organic ligand from syn to anti . Quantum chemical calculations indicate that in the isolated state the anti conformation of the uncoordinated chalcogen nicotine lactams is slightly more preferred energetically and it does not undergo substantial changes upon coordination to the metal center. The preference for the syn conformation in crystals of thio- and selenolactams of nicotine might be ascribed to their involvement in columnar stacking interactions, which do not operate in the isolated state and are also absent in crystals of their adducts with ZnCl 2 . This study has provided useful information regarding functionalization of ( S )-(−)-nicotine molecule as a mixed-donor-atom ligand to enforce formation of 1D coordination polymers. [ABSTRACT FROM AUTHOR]

CrkL is a key signaling protein that mediates the leukemogenic activity of Bcr-Abl. CrkL is thought to adopt a structure that is similar to that of its CrkII homolog. The two proteins share high sequence identity and indistinguishable ligand binding preferences, yet they have distinct physiological roles. Here we show that the structures of CrkL and phosphorylated CrkL are markedly different than the corresponding structures of CrkII. As a result, the binding activities of the Src homology 2 and Src homology 3 domains in the two proteins are regulated in a distinct manner and to a different extent. The different structural architecture of CrkL and CrkII may account for their distinct functional roles. The data show that CrkL forms a constitutive complex with Abl, thus explaining the strong preference of Bcr-Abl for CrkL. The results also highlight how the structural organization of the modular domains in adaptor proteins can control signaling outcome. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the study was to assess the influence that the shape of low frequency magnetic field may have on catalase and superoxide dismutase activity, malondialdehyde concentration and free radicals generation in human blood platelets. Materials and methods: The suspension of human blood platelets was exposed for 15 min to 50 Hz magnetic field of different shape, and flux density of 10 mT. Results: The determinations of free radicals, malondialdehyde and catalase showed increased values compared with the initial level, regardless of the shape of the magnetic field applied. In contrast, superoxide dismutase activity was lower than at the onset of the experiment. Conclusions: The findings indicate that the oxidative stress resulting from exposure to 50 Hz magnetic field of 10 mT induction may produce a number of adverse effects within the cell and thus may lead to systemic disturbances in the human body. [ABSTRACT FROM AUTHOR]

Gas-phase decompositions of magnesium complexes with adenosine-5′-triphosphate (ATP) and adenosine-5′-diphosphate (ADP) were studied by using electrospray ionization-collision-induced dissociation-tandem mass spectrometry, in the negative ion mode. The loss of internal ribose residue was observed and was found to occur directly from the [ADP-3H+Mg]− ion. The occurrence of this process indicates the presence of a strong phosphate-Mg-adenine interaction. The performed quantum mechanics calculations confirmed the occurrence of this interaction in the [ADP-3H+Mg]− ion, namely the presence of Mg–N7 bond and hydrogen bond between the phosphate oxygen atom and amino group. Although the finding concerns the gas phase, it indicates that phosphate-Mg-adenine interaction may be also of importance for biological processes. The loss of an internal ribose residue was also observed for calcium and zinc complexes with ATP/ADP as well as for magnesium complexes with guanosine-5′-triphosphate (GTP) or guanosine-5′-diphosphate (GDP). Therefore, it is reasonable to conclude that the presence of the phosphate-metal-nucleobase interaction is a feature of gas phase [NDP-3H+metal]− ion (NDP, nucleoside-5′-diphosphate) and may also be important for biological processes. [ABSTRACT FROM AUTHOR]

Thrombin generation (TG) and fibrin clot formation represent the central process of blood coagulation. Up to 95% of thrombin is considered to be generated after the clot is formed. However, this was not investigated in depth. In this study, we conducted a quantitative analysis of the Thrombin at Clot Time (TCT) parameter in 5758 simultaneously recorded TG and clot formation assays using frozen plasma samples from commercial sources under various conditions of activation. These samples were supplemented with clotting factor concentrates, procoagulant lipid vesicles and a fluorogenic substrate and triggered with tissue factor (TF). We found that TCT is often close to a 10% of thrombin peak height (TPH) yet it can be larger or smaller depending on whether the sample has low or high TPH value. In general, the samples with high TPH are associated with elevated TCT. TCT appeared more sensitive to some procoagulant phenotypes than other commonly used parameters such as clotting time, TPH or Thrombin Production Rate (TPR). In a minority of cases, TCT were not predicted from TG parameters. For example, elevated TCT (above 15% of TPH) was associated with either very low or very high TPR values. We conclude that clotting and TG assays may provide complementary information about the plasma sample, and that the TCT parameter may serve as an additional marker for the procoagulant potential in plasma sample. [ABSTRACT FROM AUTHOR]

Reliable and reproducible monitoring of the conformational state of therapeutic protein products remains an unmet technological need. This need is amplified by the increasing number of biosimilars entering the drug development pipeline as many branded biologics are reaching the end of their market exclusivity period. Availability of methods to better characterize protein conformation may improve detection of counterfit and unlicensed therapeutic proteins. In this study, we report the use of a set of modified DNA aptamers with enhanced chemical diversity to probe the conformational state of 12 recombinant human erythropoietin (rHuEPO) therapeutic protein products; one FDA-licensed rHuEPO originator biological product, three rHuEPO products that are approved for marketing in the US or EU as biosimilars, and eight rHuEPO products that are not approved for marketing in the US or EU. We show that several of these modified aptamers are able to distinguish rHuEPO reference products or approved biosimilars from non-licensed rHuEPO products on the basis of differences in binding kinetics and equilibrium affinity constants. These reagents exhibit sensitivity to the conformational integrity of various forms of rHuEPO and as such represent powerful, simple-to-use analytical tools to monitor the conformational integrity of therapeutic-proteins during manufacture and to screen for and identify both substandard and counterfeit products. [ABSTRACT FROM AUTHOR]

For thousands years Ephedrae herba has been used in traditional Chinese herbal medicine. Its main bioactive constituents are ephedrine and pseudoephedrine. Nowadays, these alkaloids have found application in various clinical treatments, as sports-enhancing drugs and for the illicit production of amphetamine-like drugs. Ephedrine and pseudoephedrine are diastereomers, and because of their high polarity and similar pK a values, their chromatographic separation may be a challenge. In this study a possible application of direct infusion mass spectrometry and direct infusion tandem mass spectrometry has been proposed for differentiation of ephedrine and pseudoephedrine as well as the relative determination of the contents of these compounds in a mixture. At low collision energy condition, the ratio of relative abundances of ions [M+H–H 2 O]+ and [M+H]+ permit distinction of the analyzed diastereomers, and enable evaluation of their relative content in a mixture with no need of chromatographic separation. The performed quantum chemical calculation have shown that protonated pseudoephedrine contains stronger hydrogen bond than protonated ephedrine, which can justify the observed higher relative abundance of ion [M+H–H 2 O]+ in the mass spectrum of pseudoephedrine, in comparison to that of ephedrine. [Display omitted] • MS methods has been proposed for differentiation of ephedrine and pseudoephedrine. • Abundances of ions [M+H–H 2 O]+ and [M+H]+ permit distinction of the compounds. • Evaluation of their relative content in a mixture is possible. • There is no need of chromatographic separation. • Formation of ions [M+H–H 2 O]+ has been studied by quantum chemical calculations. [ABSTRACT FROM AUTHOR]

In the conditions of electrospray ionization, a diclofenac‐gold complex, namely the ion [DIC−H+AuCl3]− (DIC stands for diclofenac), was generated. According to the calculations, the most stable is the O−Au bond‐containing structure. By subjecting the anion [DIC−H+AuCl3]− to the collision‐induced dissociation, the loss of [DIC]. radical occurred and the open shell anion [AuCl3]− was formed with the unprecedentedly high efficiency. The observed gas‐phase behavior of the Au(III)‐diclofenac complex was analogical to that of the diclofenac complexes with metals (Fe(III) and Cu(II)), which are easily reduced in the gas phase, although the process Au(III)→Au(II) is rather unusual. [ABSTRACT FROM AUTHOR]

A series of new di- and polyamine-caffeine analogues were synthesised and characterised by NMR, FT-IR, and MS spectroscopic methods. To access the stability of the investigated caffeine analogues, molecular dynamic simulations were performed in NAMD 2.9 assuming CHARMM36 force field. To evaluate the antioxidant capacity of new compounds, three different antioxidant assays were used, namely 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH•) scavenging activity, ferrous ions (Fe2+) chelating activity, and Fe3+→Fe2+reducing ability. In vitro, the ability of new derivatives to protect human erythrocytes against oxidative haemolysis induced by free radical from 2,2′-azobis(2-methylpropionamidine) dihydrochloride (AAPH) was estimated. The cytotoxic activity was tested using MCF-7 breast cancer cells and human erythrocytes. All compounds showed the antioxidant capacity depending mostly on their ferrous ions chelating activity. In the presence of AAPH, some derivatives were able to effectively inhibit the oxidative haemolysis. Two derivatives, namely 8-(methyl(2-(methylamino)ethyl)-amino)caffeine and 8-(methyl(3-(methylamino)propyl)amino)caffeine, showed cytotoxic activity against MCF-7 breast cancer cells but not against human erythrocytes. Therefore, it is concluded that the selected di- and polyamine caffeine analogues, depending on their chemical structure, were able to minimise the oxidative stress and to inhibit the tumour cell growth. The confirmed antioxidant and cytotoxic properties of some caffeine derivatives make them attractive for potential applications in food or pharmaceutical industries. [ABSTRACT FROM AUTHOR]

The crystal structure of the title compound, benzamide–2,3,4,5,6-penta­fluoro­benzoic acid (2/1), 2C7H7NO·C7HF5O2, consists of centrosymmetric hexa­meric supermolecules composed of four amide and two carboxylic acid mol­ecules connected via O—H⋯O and N—H⋯O hydrogen bonds. No phen­yl–perfluoro­phenyl π–π stacking inter­actions are observed in this cocrystal. [ABSTRACT FROM AUTHOR]

The emergence of the novel SARS-CoV-2 virus is the most important public-health issue of our time. Understanding the diverse clinical presentations of the ensuing disease, COVID-19, remains a critical unmet need. Here we present a comprehensive listing of the diverse clinical indications associated with COVID-19. We explore the theory that anti-SARS-CoV-2 antibodies could cross-react with endogenous human proteins driving some of the pathologies associated with COVID-19. We describe a novel computational approach to estimate structural homology between SARS-CoV-2 proteins and human proteins. Antibodies are more likely to interrogate 3D-structural epitopes than continuous linear epitopes. This computational workflow identified 346 human proteins containing a domain with high structural homology to a SARS-CoV-2 Wuhan strain protein. Of these, 102 proteins exhibit functions that could contribute to COVID-19 clinical pathologies. We present a testable hypothesis to delineate unexplained clinical observations vis-à-vis COVID-19 and a tool to evaluate the safety-risk profile of potential COVID-19 therapies. [ABSTRACT FROM AUTHOR]

Anabasine copper(II) and zinc(II) complexes have been studied using experimental methods and quantum-chemical studies. Preferred coordination centers and possible structures of the complexes have been determined. It has been revealed, that the main coordination center for anabasine complexes with both Cu(II) and Zn(II) ions is the piperidine nitrogen atom, while in zinc complexes also the nitrogen atom from the pyridine residue of anabasine is engaged to some small degree. In both systems investigated preferable formation of hydroxo-complexes was observed. [ABSTRACT FROM AUTHOR]

Earlier studies have revealed that wood treated with caffeine was effectively protected against decay fungi and molds. However, there is a need to establish how the caffeine molecule behaves after wood impregnation and how it can protect wood. The objective of the research was to characterize the interaction between caffeine and Scots pine (Pinus sylvestris L.) wood as well as to assess the stability of the alkaloid molecule in lignocellulosic material. For this purpose, an elementary analyzer was used to assess the nitrogen concentration in the treated wood. The results showed that caffeine is easily removed from the wood structure through large amounts of water. The changes occurring in the wood structure after impregnation were evaluated with regard to the results obtained by Fourier transform infrared (FTIR) spectroscopy of two model mixtures with caffeine and cellulose or lignin for the purpose of conducting a comparison with the spectrum of impregnated and non-impregnated samples. The observed changes in FTIR spectra involve the intensity of the C=O(6) caffeine carbonyl group and signals from guaiacyl units. It might indicate favorable interactions between caffeine and lignin. Additionally, molecular simulation of the caffeine's interaction with the guaiacyl β-O-4 lignin model compound characteristic for the lignin structure using computational studies was performed. Consequently, all analyses confirmed that caffeine may interact with the methylene group derived from the aromatic rings of the guaiacyl group of lignin. In summary, scanning electron microscope (SEM) observations suggest that caffeine was accumulated in the lignin-rich areas of the primary walls. [ABSTRACT FROM AUTHOR]

Gas phase decompositions of protonated methyl benzoate and its conjugates have been studied by using electrospray ionization-collision induced dissociation-tandem mass spectrometry. Loss of CO2 molecule, thus transfer of methyl group, has been observed. In order to better understand this process, the theoretical calculations have been performed. For methyl benzoate conjugates, it has been found that position of substituent affects the loss of CO2 molecule, not the electron donor/withdrawing properties of the substituent. Therefore, electrospray ionization-mass spectrometry in positive ion mode may be useful for differentiation of isomers of methyl benzoate conjugates. [ABSTRACT FROM AUTHOR]

The ability to design proteins with high affinity and selectivity for any given small molecule is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition. Attempts to rationally design ligand-binding proteins have met with little success, however, and the computational design of protein-small-molecule interfaces remains an unsolved problem. Current approaches for designing ligand-binding proteins for medical and biotechnological uses rely on raising antibodies against a target antigen in immunized animals and/or performing laboratory-directed evolution of proteins with an existing low affinity for the desired ligand, neither of which allows complete control over the interactions involved in binding. Here we describe a general computational method for designing pre-organized and shape complementary small-molecule-binding sites, and use it to generate protein binders to the steroid digoxigenin (DIG). Of seventeen experimentally characterized designs, two bind DIG; the model of the higher affinity binder has the most energetically favourable and pre-organized interface in the design set. A comprehensive binding-fitness landscape of this design, generated by library selections and deep sequencing, was used to optimize its binding affinity to a picomolar level, and X-ray co-crystal structures of two variants show atomic-level agreement with the corresponding computational models. The optimized binder is selective for DIG over the related steroids digitoxigenin, progesterone and β-oestradiol, and this steroid binding preference can be reprogrammed by manipulation of explicitly designed hydrogen-bonding interactions. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics and diagnostics. [ABSTRACT FROM AUTHOR]

The vicarious nucleophilic substitution in some nitroindazole and nitrobenzotriazole derivatives with tertiary carbanions leads almost exclusively to products substituted para to the nitro group. As results from the theoretical calculations and structural evidences, such reaction outcome is due mainly to the stereoelectronic reasons in combination with the considerable shortening of the Cortho-CNO2 bond. The presence of the chiral and prochiral centres (the methine and N-methylene groups, respectively) often gives rise to additional splitting of the methylene protons signal that is transmitted on a long distance provided there is no pyridinic nitrogen in the pathway of coupling. [ABSTRACT FROM AUTHOR]

It is clear that in the former case we dealt with the product ion spectra of [M + H] SP + sp ions, and in the latter case we dealt with the product ion spectra of [M(D) + D] SP + sp ions. We also obtained the product ion spectra of [M + H - H SB 2 sb O] SP + sp ions. Figure shows the product ion spectrum of the [M + H - H SB 2 sb O] SP + sp ion of buphedrone (as a representative example), whereas Figure S8 (supporting information) shows the spectra of other [M + H-H SB 2 sb O] SP + sp ions. As a consequence the SP 13 sp C-containing fragment ions were more abundant in the product ion spectra of [M(D) + D] SP + sp than in the product ion spectra of [M + H] SP + sp . [Extracted from the article]