Dioxygen Binding in the Active Site of Histone Demethylase JMJD2A and the Role of the Protein Environment

JMJD2A catalyses the demethylation of di‐ and trimethylated lysine residues in histone tails and is a target for the development of new anticancer medicines. Mechanistic details of demethylation are yet to be elucidated and are important for the understanding of epigenetic processes. We have evaluated the initial step of histone demethylation by JMJD2A and demonstrate the dramatic effect of the protein environment upon oxygen binding using quantum mechanics/molecular mechanics (QM/MM) calculations. The changes in electronic structure have been studied for possible spin states and different conformations of O₂, using a combination of quantum and classical simulations. O₂ binding to this histone demethylase is computed to occur preferentially as an end‐on superoxo radical bound to a high‐spin ferric centre, yielding an overall quintet ground state. The favourability of binding is strongly influenced by the surrounding protein: we have quantified this effect using an energy decomposition scheme into electrostatic and dispersion contributions. His182 and the methylated lysine assist while Glu184 and the oxoglutarate cofactor are deleterious for O₂ binding. Charge separation in the superoxo‐intermediate benefits from the electrostatic stabilization provided by the surrounding residues, stabilizing the binding process significantly. This work demonstrates the importance of the extended protein environment in oxygen binding, and the role of energy decomposition in understanding the physical origin of binding/recognition.     

A Mononuclear Uranium(IV) Single‐Molecule Magnet with an Azobenzene Radical Ligand

A tetravalent uranium compound with a radical azobenzene ligand, namely, [{(SiMe₂NPh)₃‐tacn}U^IV(η²‐N₂Ph₂^.)] ( 2 ), was obtained by one‐electron reduction of azobenzene by the trivalent uranium compound [U^III{(SiMe₂NPh)₃‐tacn}] ( 1 ). Compound 2 was characterized by single‐crystal X‐ray diffraction and ¹H NMR, IR, and UV/Vis/NIR spectroscopy. The magnetic properties of 2 and precursor 1 were studied by static magnetization and ac susceptibility measurements, which for the former revealed single‐molecule magnet behaviour for the first time in a mononuclear U^IV compound, whereas trivalent uranium compound 1 does not exhibit slow relaxation of the magnetization at low temperatures. A first approximation to the magnetic behaviour of these compounds was attempted by combining an effective electrostatic model with a phenomenological approach using the full single‐ion Hamiltonian.     

High Sensitive Microsensor Based on Organic‐Inorganic Composite for Two‐Dimensional Mapping of H2O2 by SECM

The present work describes the development of a selective, sensitive and stable sensing microsensor for scanning electrochemical microscopy (SECM) to measure H₂O₂ during electrochemical reduction of oxygen. The microsensor is based on graphene and Poly(3,4‐ethylenedioxythiophene) composite as support to iron (III) hexacyanoferrate (II) (PEDOT/graphene/Fe^III₄[Fe^II(CN)₆]₃ microsensor). The electrochemical properties of the PEDOT/graphene/Fe^III₄[Fe^II(CN)₆]₃ microsensor were investigated by cyclic voltammetry (CV) and scanning electrochemical microscopy (SECM). The PEDOT/graphene/Fe^III₄[Fe^II(CN)₆]₃ microsensor showed an excellent electrocatalytic activity toward hydrogen peroxide (H₂O₂) reduction with a diminution of the overpotential of about 500 mV in comparison to the process at a bare gold microelectrode. The microsensor presented excellent performance for two dimensional mapping of H₂O₂ by SECM in 0.1 mol L^?1 phosphate buffer solution (pH 7.0). Under optimized conditions, a linear response range from 1 up to 1000 µmol L^?1 was obtained with a sensitivity of 0.08 nA L µmol^?1 and limit of detection of 0.5 µmol L^?1.     

Novel and Stereospecific Synthesis of (2S)‐3‐(2,4,5‐Trifluorophenyl)propane‐1,2‐diol from D‐Mannitol

A stereospecific synthesis of (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol from D ‐mannitol has been developed. The reaction of 2,3‐O‐isopropylidene‐D ‐glyceraldehyde with 2,4,5‐trifluorophenylmagnesium bromide gave [(4R)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl](2,4,5‐trifluorophenyl)methanol in 65% yield as a mixture of diastereoisomers (1 : 1). The Ph₃P catalyzed reaction of the latter with C₂Cl₆ followed by reduction with Pd/C‐catalyzed hydrogenation gave (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol with >99% ee and 65% yield.     

New fatty acid derivatives based on barbiturates and other cyclic β-dicarbonyl compounds and an acyl migration

The use of DCC, triethylamine and 4-dimethylaminopyridine in dichloromethane provides a general and standard one-pot procedure for the O-acylation of cyclic β-dicarbonyl compound derivatives (1) with palmitic and stearic acids which have long hydrocarbon tails, to synthesis of new type of fatty acid derivative in good to excellent yields. Structure elucidation was carried out by FT-IR, ¹H NMR and ¹³C NMR spectroscopy techniques. The acyl migration was also found in results and the corresponding structure was characterized by X-ray crystallography. A proposed mechanism was discussed for the formation of products.     

Thermal properties and kinetics of new-generation posterior bulk fill composite cured light-emitting diodes

In this study, the thermal behavior in terms of glass transition (T _g), degradation, and thermal stability of four commercial new-generation posterior bulk fill composites (Surefill SDR, Dentsply; Quixfill, Dentsply; Xtrabase, Voco; and Xtrafill, Voco) activated by light-emitting diodes (LEDs) was analyzed by thermogravimetric analysis (TG), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). The activation energies (E _a) for the decomposition of the dental resins were calculated based on the Kissinger and Doyle kinetic models from the peaks of the endothermic curves obtained when the specimens were heated at four different temperatures (5, 10, 15, and 20 °C min^?1) during DSC. The results show that the Xtrabase composite displayed the highest T _g (120 °C at a 5 °C min^?1 heating rate) and E _a (157.64 kJ mol^?1) values associated with thermal degradation from the main chain of the polymer.     

Antiplasmodial Drugs in the Gas Phase: A CID and DFT Study of Quinolon-4(1H)-Imine Derivatives

The gas-phase behavior of 12 quinolon-4(1H)-imine derivatives with antiplasmodial activity was investigated using electrospray ionization tandem mass spectrometry together with collision induced dissociation and density functional theory (DFT) calculations. The most probable protonation site was predicted by calculating the proton affinity (PA) values for each possible protonation site and it was found to be the imine nitrogen for all compounds under study. Fragmentation pathways of the protonated molecules were proposed and the assignment of product ion structures was performed taking into account theoretical calculations. The nature of the quinoline substituent was found to influence the gas-phase behavior of the compounds under study. The data acquired allowed to bracket the proton affinity of the quinolin-4-imine scaffold, which can be a useful starting point to choose appropriate references for determining PA values of this scaffold. Figure

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Synthesis of New Chlorin e6 Trimethyl and Protoporphyrin IX Dimethyl Ester Derivatives and Their Photophysical and Electrochemical Characterizations

In view of increasing demands for efficient photosensitizers for photodynamic therapy (PDT), we herein report the synthesis and photophysical characterizations of new chlorin e₆ trimethyl ester and protoporphyrin IX dimethyl ester dyads as free bases and Zn^II complexes. The synthesis of these molecules linked at the β‐pyrrolic positions to pyrano[3,2‐c]coumarin, pyrano[3,2‐c]quinolinone, and pyrano[3,2‐c]naphthoquinone moieties was performed by using the domino Knoevenagel hetero Diels–Alder reaction. The α‐methylenechromanes, α‐methylenequinoline, and ortho‐quinone methides were generated in situ from a Knoevenagel reaction of 4‐hydroxycoumarin, 4‐hydroxy‐6‐methylcoumarin, 4‐hydroxy‐N‐methylquinolinone, and 2‐hydroxy‐1,4‐naphthoquinone, respectively, with paraformaldehyde in dioxane. All the dyads as free bases and as Zn^II complexes were obtained in high yields. All new compounds were fully characterized by 1D and 2D NMR techniques, UV/Vis spectroscopy, and HRMS. Their photophysical properties were evaluated by measuring the fluorescence quantum yield, the singlet oxygen quantum yield by luminescence detection, and also the triplet lifetimes were correlated by flash photolysis and intersystem crossing (ISC) rates. The fluorescence lifetimes were measured by a time‐correlated single photon count (TCSPC) method, fluorescence decay associated spectra (FDAS), and anisotropy measurements. Magnetic circular dichroism (MCD) and circular dichroism (CD) spectra were recorded for one Zn^II complex in order to obtain information, respectively, on the electronic and conformational states, and interpretation of these spectra was enhanced by molecular orbital (MO) calculations. Electrochemical studies of the Zn^II complexes were also carried out to gain insights into their behavior for such applications.     

A Novel pH/Light‐Triggered Surface for DNA Adsorption and Release

A simple strategy for the immobilization of Cy3‐labeled single strand DNA (Cy3‐ssDNA) on a Si(001) surface and its release under control of both light and pH stimuli is presented. In order to prepare a dual pH/light‐triggered surface, positively chargeable azobenzene molecules are self‐assembled on the Si(001) surface. The surface wettability of this substrate can be changed under influence of both light and pH conditions. The substrates can be positively charged under mildly acidic conditions. The pH‐sensitive behavior of the film allows binding of Cy3‐ssDNA on the functionalized Si(001) surface through e?ective electrostatic interactions with the negatively charged polynucleotide backbone. Moreover, irradiation of the film with UVA light induces trans–cis isomerization of the azobenzene units on the surface. As a result, the binding a?nity for DNA decreases due to the changing surface hydrophilicity. In order to understand and control the reversible photoswitchable mechanism of this surface, water contact angles are measured after UVA and visible light irradiation. The release of DNA from a dual pH/light‐sensitive sample is performed using fluorescence microscopy. The results show that irradiation of the film with UVA light induces trans–cis isomerization of the photoresponsive azobenzene units; this leads to significant changes in the surface hydrophilicity and reduces the binding affinity for DNA.     

Kinetic Modeling of α‐Hydrogen Abstractions from Unsaturated and Saturated Oxygenate Compounds by Carbon‐Centered Radicals

Hydrogen abstractions are important elementary reactions in a variety of reacting media at high temperatures in which oxygenates and hydrocarbon radicals are present. Accurate kinetic data are obtained from CBS‐QB3 ab initio (AI) calculations by using conventional transition‐state theory within the high‐pressure limit, including corrections for hindered rotation and tunneling. From the obtained results, a group‐additive (GA) model is developed that allows the Arrhenius parameters and rate coefficients for abstraction of the α‐hydrogen from a wide range of oxygenate compounds to be predicted at temperatures ranging from 300 to 1500 K. From a training set of 60 hydrogen abstractions from oxygenates by carbon‐centered radicals, 15 GA values (ΔGAV^os) are obtained for both the forward and reverse reactions. Among them, four ΔGAV^os refer to primary contributions, and the remaining 11 ΔGAV^os refer to secondary ones. The accuracy of the model is further improved by introducing seven corrections for cross‐resonance stabilization of the transition state from an additional set of 43 reactions. The determined ΔGAV^os are validated upon a test set of AI data for 17 reactions. The mean absolute deviation of the pre‐exponential factors (log A) and activation energies (E_a) for the forward reaction at 300 K are 0.238 log(m³ mol^?1 s^?1) and 1.5 kJ mol^?1, respectively, whereas the mean factor of deviation <ρ> between the GA‐predicted and the AI‐calculated rate coefficients is 1.6. In comparison with a compilation of 33 experimental rate coefficients, the <ρ> between the GA‐predicted values and these experimental values is only 2.2. Hence, the constructed GA model can be reliably used in the prediction of the kinetics of α‐hydrogen‐abstraction reactions between a broad range of oxygenates and oxygenate radicals.