Probing the functional requirements of the l-haba side-chain of amikacin—synthesis, 16S A-site rRNA binding, and antibacterial activity

The l-amino group in amikacin was acylated with a variety of 2-hydroxy aminocarboxylic acids to probe the effect of acylation on ribosomal binding and antibacterial activity. The N-hydroxy urea analogue of amikacin (8a) in which the 2-S-hydroxyl-bearing carbon was replaced by an N-OH group was equally active against S. aureus and E. coli in vitro. The analogous tobramycin variant 9 was more active than amikacin.     

Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2

The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield). The catalyst was found to be equally active with a loading of 0.1 mol %. Preliminary mechanistic investigations show that an iron-catalyzed hydrometalation is followed by transmetalation and reaction with the electrophile (CO(2)).     

Deletion of the oxetane ring in docetaxel analogues: synthesis and biological evaluation

Two new docetaxel analogues have been prepared starting from 10-deacetylbaccatin III. Both derivatives lack the oxetane D-ring but possess the 4alpha-acetoxy group, which is important for biological activity. The influence of a more or less constrained C-ring was evaluated by adding, or not adding, a double bond in this ring. Both compounds were found to be equally less active than docetaxel in biological assays. [reaction: see text]     

Active layer of fuel cell electrode with polymer electrolyte: Modeling of support grains, calculation of overall cathode characteristics

The active layer of the cathode of a fuel cell with polymer electrolyte (Nafion) is considered. The optimum carbon support structure is constructed using computer simulation: its carbon “skeleton” possesses the maximum outer surface area and provides electronic conductivity of the grains, support cubes, along the three coordinate axes. Nafion is absent in the support grain, so that the grain is capable of participating only in the transport of oxygen molecules, it possesses no proton conductivity. An estimate of all parameters of an optimum support grain is provided; in particular, the value of the effective Knudsen diffusion coefficient of oxygen is established. After this, effective proton conductivity and effective Knudsen diffusion coefficient are calculated already on the whole active layer scale, according to the model of equally sized cube grains of three types. In conclusion, the overall current in the active layer of a cathode with a polymer electrolyte was calculated for the percolation cluster consisting only of Nafion grains and the Knudsen diffusion of oxygen created only by a combined gas percolation cluster consisting of void grains and all support grains. The overall current value for t = 80°C and pressure of p* = 101 kPa proved to be low, hundreds of mA/cm². The current value can apparently be increased to several A/cm² if the support grains are developed that would simultaneously possess both proton conductivity and ability to sustain oxygen diffusion.     

DNA STRAND BREAKS IN MAMMALIAN CELLS EXPOSED TO LIGHT IN THE PRESENCE OF RIBOFLAVIN AND TRYPTOPHAN

Abstract— When mammalian cells were exposed to visible-fluorescent light or near-UV light in the medium containing riboflavin and L-tryptophan, single-strand breaks appeared in their DNA. This did not occur if either riboflavin or tryptophan was omitted from the medium. The same effect was observed when cells were added to the pre-irradiated medium, indicating that a stable photoproduct was responsible. The induced DNA lesions were shown to be equally repairable in both excision proficient and defective (xeroderma pigmentosum) human cell lines. The active photoproduct formed was shown to be hydrogen peroxide. The possible relationship between these results and the near-UV induced killing of mammalian cells is discussed.     

Catalysis of cure reaction of ɛ-caprolactam-blocked polyisocyanate with diol using non-tin catalysts

Absract

Catalysis of cure reaction of ?-caprolactam-blocked polyisocyanate with 1,4-butane diol in the presence of DABCO - a tertiary amine, tin(II) 2-ethylhexanoate and non-tin organometallics like bismuth neodecanoate, calcium(II) 2-ethylhexanoate and zinc(II) 2-ethylhexanoate was investigated. The activity of these catalysts was studied by the determination of cure-time (gel-time) and analysis of absolute molecular weight of cured polymers. Cure-time results indicated that all the non-tin organometallics act as catalysts; they were more active than DABCO and except bismuth neodecanoate, other two non-tin compounds were also found to be equally active or more active than tin(II) 2-ethylhexanoate. Within the three organometallics studied, zinc (II) 2-ethylhexanoate showed highest catalytic activity, it reduced the cure-time more than 50% compared to the uncatalysed reaction. In the case of bismuth neodecanoate catalysed reaction, it was found that the viscosity was build-up to a certain limit and then decreased; this catalyst assisted chain degradation was confirmed by the analysis of molecular weight of polymers as a function of time. Catalytically active new species was formed when mixing the solution of DABCO to the solution of zinc (II) 2-ethylhexanoate and this formation was confirmed using FT-IR and UV-visible spectroscopy, but this species not showed synergism.     

Synthesis of chiral 2-(4-phenoxyphenylsulfonylmethyl)thiiranes as selective gelatinase inhibitors

[reactions: see text] Compound 1, 2-(4-phenoxyphenylsulfonylmethyl)thiirane, is a selective inhibitor of gelatinases, which is showing high promise in studies of animal models for cancer metastasis and stroke. The (R)-1 and (S)-1 enantiomers of compound 1 were each synthesized in this study and were shown to be equally active in inhibition of gelatinases.     

Application of an efficient multireference approach to free-base porphin and metalloporphyrins: ground, excited, and positive ion states

The improved virtual orbital-complete active space configuration interaction (IVO-CASCI) method is applied to determine the geometries of the ground state of free-base porphin and its metal derivatives, magnesium and zinc porphyrins. The vertical excitation energies and ionization potentials are computed at these optimized geometries using an IVO-based version of multireference Mo?ller-Plesset (IVO-MRMP) perturbation theory. The geometries and excitation energies obtained from the IVO-CASCI and IVO-MRMP methods agree well with experiment and with other correlated many-body methods. We also provide the ground state vibrational frequencies for free-base porphin and Mg-porphyrin. All frequencies are real in contrast to self-consistent field treatments which yield an imaginary frequency. Ground state normal mode frequencies (scaled) of free-base porphin and magnesium porphyrin from IVO-CASCI and complete active space self-consistent field methods are quite similar and are consistent with Becke-Slater-Hartree-Fock exchange and Lee-Yang-Parr correlation density functional theory calculations and with experiment. In addition, geometries are determined for low-lying excited state triplets and for positive ion states of the molecules. To our knowledge, no prior experimental and theoretical data are available for these excited state geometries of magnesium and zinc porphyrins. Given that the IVO-CASCI and IVO-MRMP computed geometries and excitation energies agree favorably with experiment and with available theoretical data, our predicted excited state geometries should be equally accurate.     

Configuration and E/Z interconversion mechanism of O(S)-allyl-S(O)-methyl-N-(acridin-9-yl) iminothiocarbonate

The configuration and dynamic behavior of O-allyl-S-methyl-N-(acridin-9-yl)iminothiocarbonate (1) and its S-allyl-O-methyl regioisomer (2) were studied using quantum chemical calculations and by applying a novel graphical method to scatter maps obtained from MD simulations for evaluation of an NOE-weighted internuclear distance (r(NOE)). Energy calculations indicated that the Z configuration was predominant for each compound and, further, this was supported both by the calculated chemical shifts and the r(NOE). Both N-inversion- and rotation-type transition-state structures were also calculated for the E/Z isomerization process, the results indicating that the preferred interconversion mechanism for 1 is N-inversion, but contrastingly, interconversion via rotation is equally as probable as N-inversion for 2. This supports the notion that one or the other or both pathways can be active and each system needs to be assessed on a case-by-case basis.     

Infrared studies of the ferroelectric transition in ammonium sulphate

The pressure and temperature dependence of the symmetric stretching vibration band, ν1, of the the sulphate ion in ammonium sulphate (rendered weakly infrared active by the crystal field) was investigated. The sudden increase in intensity at the transition temperature has been found to be accompanied by an equally sharp shift in frequency. A pressure-temperature phase diagram for the ferroelectric phase transition of ammonium sulphate has been obtained. The contributions to the transition mechanism made by the order-disorder change for the NH⁺₄ orientations, the strengthening of the hydrogen bond and the distortion of the SO⁼₄ ions are discussed.     

Sorption of europium by malt spent rootlets, a low cost biosorbent: effect of pH, kinetics and equilibrium studies

The uptake of lanthanide elements by naturally abundant materials, is a matter of great economic and environmental interest. This study is an exploration of the potential utilization of malt spent rootlets (MSR), which are by-products of malting process, for a cost effective pre-concentration of Eu(III). The effect of solution pH, contact time and initial concentration under constant ionic strength and temperature were studied. Kinetic data were applied to pseudo-first, second order and Elovich equations, as well as intra-particle diffusion model. Pseudo-second order and Elovich equation seem to fit our data equally well, whereas diffusion contributes to the whole process. Equilibrium data were evaluated using Langmuir, Freundlich and Dubinin-Radushkevich equations. According to Langmuir model, which fits the data better, europium maximum capacities for MSR and active carbon were found 156 and 86 mg/g respectively, indicating that MSR is a promising biosorbent.     

Ring functions,as polarization functions,forab initio calculations on small rings: Dioxirane

The exponents and relative positions have been optimized for bond functions to be used as polarization functions in the theoretical treatment of small cycles. The transferability of the conventional bond functions to this type of “compact” systems is analyzed for the particular case of dioxirane and it is shown that they can be replaced by a single function located inside the ring (ring function) which describes equally well the polarization effects on the equilibrium geometry, charge distribution and dipole moment. These conclusions are corroborated by the characteristics exhibited by the corresponding localized molecular orbitals.     

Optically active seleninate esters: isolation, absolute configuration, racemization mechanism, and transformation into chiral selenoxide

Optically active seleninate esters were obtained for the first time by chromatographic resolution on an optically active column. The absolute configurations of the optically active seleninate esters were determined by comparing their chiroptical properties with those of two analogous sulfinate esters, the absolute configuration of one of which is known and that of the other was determined by X-ray crystallographic analysis. The optically active seleninate esters were found to racemize in solution. Kinetic studies of the racemization, the oxygen exchange reaction with H(2)(18)O, and theoretical studies clarified that the racemization of the optically active seleninate esters in solution proceeded via an achiral hypervalent selenurane intermediate that was formed by the reaction with water. The reaction of the optically active seleninate ester and the sulfinate ester having bulky substituents with Grignard reagents was found to proceed with the retention of stereochemistry to give an optically active selenoxide and sulfoxides, respectively.     

Improving metal ion specificity during in vitro selection of catalytic DNA

Metal ions play important roles in both the structure and function of catalytic DNA and RNA. While most natural catalytic RNA molecules (ribozymes) are active in solutions containing Mg(2+), in vitro selection makes it possible to search for new catalytic DNA/RNA that are specific for other metal ions. However, previous studies have indicated that the in vitro selection protocols often resulted in catalytic DNA/RNA that were equally active or sometimes even more active with metal ions other than the metal ion of choice. To improve the metal ion specificity during the in vitro selection process, we implemented a negative selection strategy where the nucleic acid pool was subjected to a solution containing competing metal ions. As a result, those nucleic acids that were active with those metal ions are discarded. To demonstrate the effectiveness of the negative selection strategy, we carried out two parallel in vitro selections of Co(2+)-dependent catalytic DNA. When no negative selection was used in the selection process, the resulting catalytic DNA molecules were more active in solutions of Zn(2+) and Pb(2+) than in Co(2+). On the other hand, when the negative selection steps were inserted between the normal positive selection steps, the resulting catalytic DNA molecules were much more active with Co(2+) than in other metal ions including Zn(2+) and Pb(2+). These results suggest strongly that in vitro selection can be used to obtain highly active and specific transition metal ion-dependent catalytic DNA/RNA, which hold great promise as versatile and efficient endonucleases as well as sensitive and selective metal ion sensors.     

Sorption of aqueous carbonic, acetic, and oxalic acids onto alpha-alumina

The presence of organic complexing agents can modify the behavior of a surface. This study aims to better understand the impact of carboxylic acids (acetic, oxalic, and carbonic acids) issued from cellulose degradation and equally naturally present in soils. First, evidence of two different kinds of sites for chloride adsorption onto alpha-alumina and another for sodium sorption was provided. Consequently, no competition between these cation and anion sorptions occurs on alpha-alumina. The associated exchange capacities and ionic exchange constants were measured. Second, the adsorption behavior of the carboxylic acids was studied as a function of aqueous -log[H(+)] and 0.01 to 0.1 M ionic strength (NaCl), and modeled by using mass action law for ideal biphasic systems. The carboxylic acids were found to be adsorbed on the same sites as chloride ions. The competition between organic ligands and chloride ions was satisfactorily accounted for by the model assuming the deprotonated form of the ligands was sorbed on alpha-alumina. The model also allowed us to interpret the adsorption of all species under various conditions without any extra fitting parameters.     

Facile solid-phase synthesis of cyclic decapeptide antibiotic streptocidins A-D

Total synthesis of decapeptide antibiotics streptocidins A-D from Streptomyces sp. Tü 6071 was accomplished for the first time by solid-phase peptide synthesis followed by traceless cyclization of the activated linear precursors, without protection of nucleophilic side chain. Synthetic products were equally active as the natural products isolated from the bacterial source and found to possess similar bacterial selectivity as other members in the amphipathic antimicrobial cyclic decapeptide family.     

Ring-modified analogues and molecular dynamics studies to probe the requirements for fungicidal activities of malayamycin A and its N-nucleoside variants

The importance of functional group orientations and the integrity of the bicyclic perhydrofuran core of malayamycin A and two equally active N-nucleoside analogues as fungicides were investigated. Two analogues 10 and 11, representing a THP-truncated and a bicyclic aza-variant, were synthesized and found to be inactive. Molecular dynamics studies on malayamycin A and analogues were performed to highlight the importance of properly orientating the urea and methyl ether groups.     

The quenched instationary polymerization system, 1. Derivation of the radical and polymer chain length distributions for the case of δ‐pulse like initiation

A new instationary polymerization system is presented including, as an essential element, the complete deactivation of all active radicals by reaction with an inhibitor at a certain time after chain initiation. The complete kinetic scheme, the set of differential equations, as well as the analytical solutions are presented. A proof is presented that the reaction with the inhibitor during the quench period dominates any other possible reaction such as propagation and bimolecular termination. As a result, the radical spectrum present at the beginning of the quench period is converted (almost) completely unchanged and instantaneously into a polymer chain length distribution. The quenched radical spectrum appears as a single additional peak in the experimentally observable total chain length distribution. In the case of δ‐pulse initiation the analytical solutions of the differential equations reduce to a simple poisson distribution for the radical concentrations as a function of time. Theoretical expressions for the maximum and the points of inflections (low and high molecular weight side) were derived and their applicability for the direct determination of k_p was tested. All of them turned out to be equally well suited for this purpose.     

Virtual Screening and Structure Generation Applied to Drug Design

The methods of computer-aided drug design can be divided into two categories according to whether or not the structures of receptors are known1, corresponding to two principal strategies: (1) searching the bio-active ligands against virtual combinatorial libraries and calculating the affinity energy between ligand and receptor by docking ; (2) QSAR and 3D-structure data-mining. 3D-QSAR method is now applied widely to drug discovery, but this method is generally limited to refine the structu…     

Adapting the DeepSARM approach for dual-target ligand design

The structure–activity relationship (SAR) matrix (SARM) methodology and data structure was originally developed to extract structurally related compound series from data sets of any composition, organize these series in matrices reminiscent of R-group tables, and visualize SAR patterns. The SARM approach combines the identification of structural relationships between series of active compounds with analog design, which is facilitated by systematically exploring combinations of core structures and substituents that have not been synthesized. The SARM methodology was extended through the introduction of DeepSARM, which added deep learning and generative modeling to target-based analog design by taking compound information from related targets into account to further increase structural novelty. Herein, we present the foundations of the SARM methodology and discuss how DeepSARM modeling can be adapted for the design of compounds with dual-target activity. Generating dual-target compounds represents an equally attractive and challenging task for polypharmacology-oriented drug discovery. The DeepSARM-based approach is illustrated using a computational proof-of-concept application focusing on the design of candidate inhibitors for two prominent anti-cancer targets.