Computational insights into factor affecting the potency of diaryl sulfone analogs as Escherichia coli dihydropteroate synthase inhibitors

Dihydropteroate synthase (DHPS) is an alluring target for designing novel drug candidates to prevent infections caused by pathogenic Escherichia coli strains. Diaryl Sulfone (SO) compounds are found to inhibit DHPS competitively with respect to the substrate pABA (p-aminobenzoate). The extra aromatic ring of diaryl sulfone compounds found to stabilize them in highly flexible pABA binding loops. In this present study, a statistically significant 3D-QSAR model was developed using a data set of diaryl sulfone compounds. The favourable and unfavourable contributions of substitutions in sulfone compounds were illustrated by contour plot obtained from the developed 3D-QSAR model. Molecular docking calculations were performed to investigate the putative binding mode of diaryl sulfone compounds at the catalytic pocket. DFT calculations were carried out using SCF approach, B3LYP- 6-31 G (d) basis set to compute the HOMO, LUMO energies and their respective location at pABA binding pocket. Further, the developed model was validated by FEP (Free Energy Perturbation) calculations. The calculated relative free energy of binding between the highly potent and less potent sulfone compound was found to be −3.78 kcal/ mol which is comparable to the experimental value of −5.85 kcal/mol. A 10 ns molecular dynamics simulation of inhibitor and DHPS confirmed its stability at pABA catalytic site. Outcomes of the present work provide deeper insight in designing novel drug candidates for pathogenic Escherichia coli strains.     

New insights into the reaction of zinc alkyls with dioxygen

Studies on the reaction of zinc alkyls with O2 are reported which demonstrate that the selective oxygenation of organozinc compound is viable. The reaction of [EtZn(azol)]n (azol = deprotonated 1-aziridineethanol) with an excess of dry O2 in toluene affords the zinc ethylperoxide [EtOOZn(azol)]2[EtZn(azol)]2, while the analogous reaction between Me2Zn and O2 results in the isolation of the Me6Zn7(OMe)8 cluster in high yield.     

New insights into applicability of electron-counting rules in transition metal encapsulating Ge cage clusters

The relative stability of Sc, Ti, and V encapsulating Ge(n) clusters in the size range n = 14-20 has been studied through first-principles electronic structure calculations based on density functional theory. Variations of the embedding energy, gap between the highest occupied and the lowest occupied molecular orbitals, ionization potential, vertical detachment energy, and electron affinity with cluster size have been calculated to identify clusters with enhanced stability. The enhanced stability of some clusters can be very well explained as due to the formation of a filled shell free-electron gas inside the Ge cages. For the first time, direct evidence of the formation of a free-electron gas is also presented. In some other clusters, enhanced stability is found to originate from geometric effects. Some clusters that may be expected to have enhanced stability from simple electron counting rules do not show that. These results provide new insights into the long-standing question of whether electron counting rules can explain the relative stability of transition metal encapsulated semiconductor clusters and show that these clusters are too complex for such simple generalizations.     

New insights into the stereoselectivity of the aryl zinc addition to aldehydes

The addition of Ph(2)Zn to aldehydes has been investigated by DFT calculations. The experimentally observed increase in enantioselectivity upon addition of Et(2)Zn to the reaction mixture is rationalized from calculations of all isomeric transition states. Spectator ethyl groups in the transition state do not lower the intrinsic activation barrier, but instead increase it. In the presence of a bulky ligand, the inherently preferred all-phenyl transition state is selectively disfavored. The paths with less sterically demanding spectator ethyl groups will experience a more drastic ligand acceleration, and thus the influence of the ligand would be expected to be stronger in the presence of Et(2)Zn, in agreement with experimental observations.     

New insights into the reaction mechanisms of phenylium ions with benzene

The chemistry of phenylium (benzen-1-ylium) cations with benzene is investigated by using a guided ion beam tandem mass spectrometer. The main ionic products from the reaction of C6H5+ with C6H6 are observed at m/z 155 (covalent adduct C12H11+), 154 (C12H10+), 153 (C12H9+), 129 (C10H9+), and 115 (C9H7+). We propose a mechanism according to which channels at m/z 154-115 are formed by elimination of stable neutral molecules (such as H2, C2H2, C3H4) from the collision complex C12H11+, for which the most plausible structure is protonated biphenyl. The proposed mechanism is demonstrated by using partial isotopical labeling of reagents to look for possible H/D atom scrambling. Almost the same ions are produced when benzene is chemically ionized at atmospheric pressure in an APCI source from which oxygen is excluded. Because an ion trap analyzer is coupled to this source, tandem MS experiments can be performed, allowing structural details to be established. Moreover, the use of partially deuterated reagents has allowed the detection of minor reactive channels resulting from charge exchange and H-/D- hydride-transfer processes. Theoretical calculations show that the most stable structure for ions at m/z 129 C10H9+ is that of protonated naphthalene, resulting from the loss of an acetylene molecule by the condensation product, with a reaction exothermicity of 1.27 eV. We have found a possible barrierless pathway for such a channel that might be viable for the synthesis of naphthalene, the smallest PAH, even at low collision energies and therefore would be of particular astrochemical relevance.     

New insights into the interaction of hydrogen atoms with boron-substituted carbon

Boron substitution in carbon materials has been comprehensively investigated using the density functional theory method. It was found that there is a correlation between the stability of the graphene sheet, the distribution of pi electrons, the electrostatic potential, and the capability for hydrogen-atom adsorption. Boron substitution destabilizes the graphene structure, increases the density of the electron wave around the substitutional boron atoms, and lowers the electrostatic potential, thus improving the hydrogen adsorption energy on carbon. However, this improvement is only ca. 10-20% instead of a factor of 4 or 5. Our calculations also show that two substitutional boron atoms provide consistent and reliable results, but one substitutional boron results in contradictory conclusions. This is a warning to other computational chemists who work on boron substitution that the conclusion from one substitutional boron might not be reliable.     

New insights into the anti-hepatoma mechanism of Alisol G-metal ions complexes based on c-myc DNA

This study investigated the anti-hepatoma molecular mechanism of Alisol G, which is an effective component of the Chinese medicine Alisma orientalis, in the presence of metal ions Cu²⁺ and Fe³⁺ based on c-myc DNA. Here, a combination of Alisol G and metal ions (Cu²⁺, Fe³⁺) to augment anti-hepatoma efficiencies of Alisol G has been identified by methyl thiazolyl tetrazolium (MTT) assay. Network pharmacology revealed that c-myc DNA was the potential target of Alisol G with respect to its anti-hepatoma effects. By performing multi-spectroscopic analyses, we showed that the interaction of Alisol G with c-myc DNA was a process of static quenching. The binding constants and thermodynamic constants indicated that a 1:1 complex was formed between Alisol G and c-myc DNA. Moreover, metal ions strengthened the interaction between Alisol G and c-myc DNA. Molecular docking and molecular dynamics simulation further unveiled that the higher binding affinity between Alisol G-Fe³⁺ complex and c-myc DNA as compared to Alisol G-Cu²⁺ complex. This probably resulted from the polarization of metal ions and the structural flexion of Alisol G. The C22-O31-H76 and C18-O32-H77 of Alisol G were key groups in the interaction with c-myc DNA. Addition of metal ion, had greatly changed the c-myc DNA-binding domain of Alisol G while didn’t affect the kinetic stability of the interaction, thus facilitating the insertion of Alisol G into c-myc DNA A-T base pair. Importantly, the DG113 of c-myc DNA was important for its binding to metal ions. Together, our findings suggested that Alisol G in combination with metal ions may be an efficient and promising option for the treatment of liver cancer.     

New insights into the solubilization of Bodipy dyes

Several Bodipy dyes were synthesized with various substituents designed to improve the water solubility. Among the different synthetic strategies protection of sulfonate groups by pyrrole of indopyrrole appears efficient but the deprotection step does not offer viable routes. Conversion of the bromopyrene or iodo Bodipy compounds to sulfobetaine derivatives is feasible either by cross-coupling directly the ethynylsulfobetaine or by first cross-coupling 1-(N,N-dimethylamino)-prop-2-yne followed by quaternization of the dimethylamino residue with 1,3-propanesultone. Some of these dyes (Bodipy’s and pyrene) are reasonably soluble in water and remain highly fluorescent in polar solvents and water.     

New insights into the structure of polyelectrolyte complexes

The formation of polyelectrolyte complexes (PECs) from oppositely charged linear polyelectrolytes (PELs) was studied using static light scattering at various salt concentrations. The PELs used were poly(allylamine hydro chloride) (PAH) and the two polyanions poly(acrylic acid) (PAA) and poly(methacrylic acid) (PMAA). Physical characteristics such as the radii of gyration, molecular weights, and water contents of the PECs were determined at various molar mixing ratios. Despite relatively small differences in chemical structure between PAA and PMAA, fairly large differences were detected in these physical characteristics. Generally, PECs comprising PMAA were larger and contained more water. Moreover, by using cryogenic transmission electron microscopy, transmission microscopy and atomic force microscopy, shape and structure of the prepared PECs were investigated both in solution and after drying. The PECs were found to be spherical in solution and the shape was retained after freeze-drying. PECs adsorbed on silica surfaces and dried in air at room-temperature still showed a three-dimensional structure. However, the relatively low aspect ratios indicated that the PECs collapsed significantly due to interactions with the silica during adsorption and drying. At intermediate ionic strengths (1-10 mM), stagnation point adsorption reflectometry (SPAR) showed that the adsorption of low charged cationic PAH-PAA PECs on silica surfaces increased if the pH value was increased from pH 5.5 to 7.5.     

Photoreaction of New Psoralen Analogs with DNA: Sequence and Mutation Specificity in the Escherichia coli lacZ Gene

New thio- and seleno-analogs of psoralen were synthesized and analyzed for their photoreactivity toward DNA. Using oligonucleotides of denned sequence, we first showed that these derivatives predominantly generated interstrand crosslinks at 5′-TpA sites. We also observed a surprisingly high reactivity of 7H-thiopyrano[3,2-f][l]benzofuran-7-one (PSO[0-S]) with the BamHl and PstI oligomers, giving rise to the formation of crosslinks at 5′-ApT sites and of the thymidine-psoralen-cytosine type. Next, the sequence specificity in the photochemical binding of all the compounds was investigated in two DNA fragments encompassing the lacZ gene of Escherichia coli, using the T₄ DNA polymerase sequencing methodology. Resulting maps demonstrated that thio-and seleno-analogs of psoralen preferentially photoreact-ed with thymine and cytosine residues. The AT-rich sequences proved to be particularly reactive sites as did adjacent thymines, especially at C-surrounding residues. Likewise, photoaddition at cytosines in CA/AC context was observed. It was highly significant that all of the derivatives exhibited similar sequence specificities with only minor differences. However, PSO(O-S) differed from the other heteropsoralens. Photoadducts occurred with a higher frequency at AC and CA dinucleotides, and new sites were detected. A comparison with 8-methoxypsor-alen photobinding is also reported. Finally, the mutagenic consequences of photoadducts induced in M13mp19 DNA by PSO(O-S) were determined in a forward system that detects all classes of mutagenic events. The high phototoxicity exhibited by PSO(O-S) could be attributed to crosslinks, and the comparison of the observed mutational specificity with the photoadduct distribution within the same gene showed that mutations were targeted at potential monoadduct sites where photolesions were detected in our footprinting experiments     

New insights into the visible-light-induced DNA cleavage activity of dipyridoquinoxaline complexes of bivalent 3d-metal ions

Dipyridoquinoxaline (dpq) complexes of bivalent 3d-metal ions, viz., [FeII(dpq)3](PF6)2 (1), [CoII(dpq)3](ClO4)2 (2), [NiII(dpq)3](ClO4)2 (3), [CuII(dpq)2(H2O)](ClO4)2 (4), [ZnII(dpq)3](ClO4)2 (5), and [ZnII(dpq)2(DMF)2](ClO4)2 (5a) (DMF = N,N-dimethylformamide), are prepared and their photoinduced DNA cleavage activity studied. Structural characterization for the complexes 1 and 5a is done by single-crystal X-ray crystallography. All the complexes show efficient binding propensity to calf thymus DNA with a binding constant (K) value of approximately 10(5) M(-1). Complexes 1, 2, and 4 show metal-based cyclic voltammetric responses at 1.2, 0.4, and 0.09 V (vs SCE) in DMF 0.1 M [Bun4N](ClO4) assignable to the respective FeIII/FeII, CoIII/CoII, and CuII/CuI couples. The NiII and ZnII complexes do not show any metal-based redox process. The dpq-based reductions are observed in the potential range of -1.0 to -1.7 V vs SCE. DNA melting and viscosity data indicate the groove-binding nature of the complexes. Control experiments using distamycin-A suggest a minor groove-binding propensity of the complexes. The complexes exhibit photoinduced cleavage of supercoiled pUC19 DNA in UV light of 365 nm. The diamagnetic d6-FeII and d10-ZnII complexes are cleavage-inactive on irradiation with visible light. The paramagnetic d7-CoII and d9-CuII complexes exhibit efficient DNA cleavage activity on photoirradiation at their respective d-d band. The paramagnetic d8-NiII complex displays only minor DNA cleavage activity on irradiation at its d-d band. The DNA cleavage reactions at visible light under aerobic conditions involve the formation of hydroxyl radical. The CoII complex shows photocleavage of DNA under an argon atmosphere. Theoretical calculations on the complexes suggest a photoredox pathway in preference to a type-2 process forming singlet oxygen for the visible-light-induced DNA cleavage activity of the 3d-metal complexes. The theoretical data also predict that the photoredox pathway is favorable for the 3d7-CoII and 3d9-CuII complexes to exhibit DNA cleavage activity, while the analogous 3d6-FeII and 3d8-NiII complexes are energetically unfavorable for the exhibition of such activity under visible light. The CoII and CuII complexes are better suited for designing and developing new metal-based PDT agents than their cleavage-inactive FeII, NiII, and ZnII analogues.     

New insights into the conversion of electropherograms to the effective electrophoretic mobility scale

CE–MS is increasingly gaining momentum as an analytical tool in metabolomics, due to its ability to obtain information about the most polar elements in biological samples. This has been helped by improvements of robustness in peak identification by means of mobility-scale representations of the electropherograms (mobilograms). As a necessary step toward facilitating the use of CE–MS for untargeted metabolomics data, the authors previously developed and introduced ROMANCE, a software automating mobilogram generation for large untargeted datasets through a simple and self-contained user interface. Herein, we introduce a new version of ROMANCE including new features such as compatibility with other types of data (targeted MS data and 2D UV-Vis absorption-like electropherograms), and the much needed additional flexibility in the transformation parameters (including field ramping and the use of secondary markers), more measurement conditions (depending on detection and integration modes), and most importantly tackling the issue of quantitative peak conversion. First, we present a review of the current theoretical framework with regard to peak characterization, and we develop new formulas for multiple marker peak area corrections, for anticipating peak position precision, and for assessing peak shape distortion. Then, the new version of the software is presented and validated experimentally. We contrast the multiple marker mobility transformations with previous results, finding increased peak position precision, and finally we showcase an application to actual untargeted metabolomics data.     

New insights into the mechanism of flow-electrode capacitive deionization

We report on Faradaic reactions producing H⁺ (anode) and OH^– (cathode) in flow-electrode capacitive deionization (FCDI) operated at 1.2 V. These reactions underline an additional electrodialytical desalination mechanism within capacitive deionization, which proceeds in parallel to the known electrosorption mechanism. Examination of flow-electrodes (100 ml each, 5% (wt) activated carbon) during FCDI (121 cm² effective membrane area) of 150 ml, 4 g/l NaCl solution revealed that significant amounts of Na⁺ and Cl⁻ ions (up to 50% and 30% of Cl⁻ and Na⁺, respectively) were not adsorbed in the activated carbon particles but were rather dissolved in the aqueous phase of the flow-electrodes. Production of acid (resulting in pH ≈ 1.5) and base (pH ≈ 12.5) in the flow-anode and -cathode solutions was observed during the operation. Reverse pH behaviors were obtained during the regeneration of the flow-electrodes by potential reversal. pH neutralization of the flow-electrode solutions resulted in a sharp increase in both the desalination rate and the electric current of the FCDI cell. Reacting NaOH and HCl in a short-circuited FCDI cell resulted in NaCl production in the water compartment and pH neutralization of both flow-electrodes.Apparently reversible Faradaic reactions that occur on the flow electrodes in the FCDI can be dependent on the properties of the carbon material, electrolyte composition and applied operational parameters (e.g. cell potential) and need to be studied in further detailed investigations.     

New insights into the conformational properties of α-C-glucosides

A series of alkyl α-d-C-glucopyranosides were synthesized and their conformational properties analyzed by CD and NMR spectroscopy. The conformational analysis revealed that the hydroxymethyl group populations (torsion angle ω, O1–C1–C2–O2) and those around the C-glucopyranosidic bond (torsion angle Φ; O2–C6–C7–C8) depend on the structural nature of the C-aglycon. The gt and the exo–syn populations increased as the C-aglycon became more substituted. Linear correlations between these rotational populations and proton chemical shifts versus the Taft’s steric parameters revealed the significant role of the C-aglycon in the overall conformation of C-glucosides. The stereoelectronic exo-deoxoanomeric effect, affecting the rotation of the hydroxymethyl group, becomes more important as the steric hindrance of motion increases. A pseudo-anomer rotational comparison study was also performed.     

New insights into the mechanism of palladium-catalyzed allylic amination

A comparative investigation into palladium-catalyzed allylic amination of unsubstituted aziridines and secondary amines has been carried out. The use of NH aziridines as nucleophiles favors formation of valuable branched products in the case of aliphatic allyl acetates. The regioselectivity of this reaction is opposite to that observed when other amines are used as nucleophiles. Our study provides evidence for the palladium-catalyzed isomerization of the branched (kinetic) product formed with common secondary amines into the thermodynamic (linear) product. In contrast, the branched allyl products obtained from unsubstituted aziridines do not undergo the isomerization process. Crossover experiments indicate that the isomerization of branched allylamines is bimolecular and is catalyzed by Pd(0). The reaction has significant solvent effect, giving the highest branched-to-linear ratios in THF. This finding can be explained by invoking the intermediacy of sigma-complexes, which is consistent with NMR data. The apparent stability of branched allyl aziridines towards palladium-catalyzed isomerization is attributed to a combination of factors that stem from a higher degree of s-character of the aziridine nitrogen compared to other amines. The reaction allows for regio- and enantioselective incorporation of aziridine rings into appropriately functionalized building blocks. The resulting methodology addresses an important issue of forming quaternary carbon centers next to nitrogen. The new insights into the mechanism of palladium-catalyzed allylic amination obtained in this study should facilitate synthesis of complex heterocycles, design of new ligands to control branched-to-linear ratio, as well as absolute stereochemistry of allylamines.     

Interference by complex structures of target DNA with specific PCR amplification

It has been considered that target DNA is a forgiving component for PCR amplification. Herein we present evidence to demonstrate that secondary structure located at the end of a template may interfere with the specificity of amplification. Experiments indicate that nonspecific amplification results from a long stretch of stem and loop structures at the 3′ end of prochymosin cDNA. Based on the sequence of mRNA coding for prochymosin, it is argued that the sequence responsible for the formation of the complex structure described here is most likely generated during synthesis of the second cDNA strand.     

Screen-printed electrochemical hybridization biosensor for the detection of DNA sequences from the Escherichia coli pathogen

An electrochemical biosensor for the specific detection of short DNA sequences from the E. coli pathogen is described. This hybridization device relies on the immobilization of a 25-mer oligonucleotide probe, from the E. coli lacZ gene, onto a screen-printed carbon electrode. Chronopotentiometric detection of the Co(bpy)₃⁺³ indicator is used for monitoring the hybridization event. Numerous variables of the assay protocol, including those of the probe immobilization step, the hybridization event, and the indicator association/detection, are characterized and optimized. Hybridization times of 2- and 30-min are sufficient for detecting 300- and 50 ng/mL, respectively, of the E. coli DNA target. Applicability to analysis of untreated environmental water samples is illustrated. Such single-use electrochemical sensors hold great promise for decentralized environmental and food testing for the E. coli pathogen.     

New insights into NIS-promoted aminocyclization. Synthesis of decahydroquinolines from 2-allylcyclohexylamines

Bishomoallylic secondary amines embodying the 2-allyl-N-benzylcyclohexylamine unit react with NIS to undergo cyclization through 6-endo processes in either the cis or trans series. Nevertheless, when the resulting cis-3-iododecahydroquinolines are treated with Al2O3, the exo derivatives evolve into octahydroindoles and the endo derivatives keep the same backbone, the configuration being retained in the generated alcohols.