Application of hydroxyproline derivatives in enantioselective α-amination reactions in organic and aqueous environments: a structure-activity relationship study

We examined the activity of a series of L-hydroxyproline derivatives in enantioselective α-amination reaction between diethyl azodicarboxylate and propanal both in organic and aqueous media. In organic media most of the catalysts showed high activity and enantioselectivities comparable to that accessible with L-proline that is among the best catalysts in the reaction. The catalysts showed good activity under aqueous conditions as well; however, only low enantioselectivities were obtained in this case, primarily due to the racemisation of the product under the reaction conditions. Thus, the attempted achiral acid/base additive-driven stereocontrol was not feasible on a practical level.     

Mechanism of homogeneously and heterogeneously catalysed Meerwein-Ponndorf-Verley-Oppenauer reactions for the racemisation of secondary alcohols

The mechanism of hydrogen transfer from alcohols to ketones, catalysed by lanthanide(III) isopropoxides or zeolite Beta has been studied. For the lanthanide catalysed reactions, (S)-1-phenyl-(1-(2)H(1))ethanol and acetophenone were used as case studies to determine the reaction pathway for the hydrogen transfer. Upon complete racemisation all deuterium was present at the 1-position, indicating that the reaction exclusively takes place via a carbon-to-carbon hydrogen transfer. Zeolite Beta with different Si/Al ratios was applied in the racemisation of (S)-1-phenylethanol. In this case the racemisation does not proceed via an oxidation/reduction pathway but via elimination of the hydroxy group and its re-addition. This mechanism, however, is not characteristic for all racemisation reactions with zeolite Beta. When 4-tert-butyl cyclohexanone is reduced with this catalyst, a classical MPV reaction takes place exclusively. This demonstrates that zeolite Beta has a substrate dependent reaction pathway.     

Synthesis and stability of small molecule probes for Pseudomonas aeruginosa quorum sensing modulation

The human pathogen Pseudomonas aeruginosa uses N-butyryl-L-homoserine lactone (BHL) and N-(3-oxododecanyl)-L-homoserine lactone (OdDHL) as small molecule intercellular signals in a phenomenon known as quorum sensing (QS). QS modulators are effective at attenuating P. aeruginosa virulence; therefore, they are a potential new class of antibacterial agent. The lactone in BHL and OdDHL is hydrolysed under physiological conditions. The hydrolysis proceeds at a rate faster than racemisation of the alpha-chiral centre. Non-hydrolysable, non-racemic analogues (small molecule probes) were designed and synthesised, replacing the lactone with a ketone. OdDHL analogues were found to be relatively unstable to decomposition unless they were difluorinated between the beta-keto amide. Stability studies on a non-hydrolysable, cyclohexanone analogue indicated that racemisation of the alpha-chiral centre was relatively slow. This analogue was assayed to show that the L-isomer is likely to be responsible for the QS autoinducing activity in P. aeruginosa and Serratia strain ATCC39006.     

Spectrophotometric determination of α-hydroxytropolone pKa values: A structure-acidity relationship study

α-Hydroxytropolones (αHTs) have a wealth of biological activity owing to their ability to serve as metal-binding fragments for many therapeutically valuable dinuclear metalloenzymes. They also have the potential to exist in as many as 4 protonation states under aqueous acidic or basic conditions. The following details how UV absorption can be used to generate pK_a values on a series of αHTs. The studies also provide some knowledge into how the acidity and basicity change with some different functional groups. These studies thus provide new strategies and knowledge that could be valuable in leveraging αHTs as metal-binding fragments in drug-development pursuits.     

Initial state and transition state contributions to solvent effects on rate constants for racemisation and dissociation of the [Fe(phen)3]2+ cation in DMSO-water mixtures

Summary Rate constants for racemisation and dissociation of the tris(1,10-phenanthroline)iron(II) cation, and solubilities of its picrate, are reported for dimethyl sulphoxide-water mixtures (0 to 40% by vol DMSO) at 298.2 K. The observed solvent effects on reactivity are analysed in terms of initial state and transition state contributions, and the pattern established compared with patterns for methanol- and acetone-water mixtures. In all cases the hydrophobic periphery of the ligand is dominant. Rate constants are also reported for racemisation and dissociation of the analogous complex [Fe(sb)₃]²⁺, where sb = the Schiff base from 2-benzoylpyridine andp-toluidine, in aqueous methanol.     

Organic-coated silver nanoparticles in biological and environmental conditions: Fate,stability and toxicity

This review paper presents the overview of processes involved in transformation of organic-coated silver nanoparticles (AgNPs) in biological systems and in the aquatic environment. The coating on AgNPs greatly influences the fate, stability, and toxicity of AgNPs in aqueous solutions, biological systems, and the environment. Several organic-coated AgNP systems are discussed to understand their stability and toxicity in biological media and natural water. Examples are presented to demonstrate how a transformation of organic-coated AgNPs in an aqueous solution is affected by the type of coating, pH, kind of electrolyte (mono- or divalent), ionic strength, organic ligands (inorganic and organic), organic matter (fulvic and humic acids), redox conditions (oxic and anoxic), and light. Results of cytotoxicity, genotoxicity, and ecotoxicity of coated AgNPs to food chain members (plants, bacteria, and aquatic and terrestrial organisms) are reviewed. Key factors contributing to toxicity are the size, shape, surface coating, surface charge, and conditions of silver ion release. AgNPs may directly damage the cell membranes, disrupt ATP production and DNA replication, alternate gene expressions, release toxic Ag⁺ ion, and produce reactive oxygen species to oxidize biological components of the cell. A progress made on understanding the mechanism of organic-coated AgNP toxicity using different analytical techniques is presented.     

Synthesis and inclusion properties of pillar[n]arenes

A detailed study of the reaction conditions revealed that a quantitative cyclocondensation of 1,4-dialkoxy-2,5-bis(alkoxymethyl)-benzenes to pillar[n]arenes can be achieved by catalysis of p-toluenesulfonic acid in CH₂Cl₂. Major product of this new reaction is in each case a cyclopentamer (n = 5), but small amounts of the pillar[n]arenes with n = 6, 7 and 10 can be obtained as well. Different alkoxy groups in 1- and 4-position lead to regioisomers. All cyclooligomers exist in pillar structures as pair of enantiomers, which show a racemisation at room temperature, which is fast in terms of the NMR time scale. The racemisation process occurs by rotation of the 1,4-phenylene segments in the macrocyclic rings. Pillar[n]arenes exhibit novel host–guest behavior.     

Computational study of the Zr4+ tetranuclear polymer, [Zr4(OH)8(H2O)16]8+

The Zr(4+) tetramer, [Zr(4)(OH)(8)(H(2)O)(16)](8+), is thought to be the major component of the Zr(4+) polymer system in aqueous solution, present as a dominant ionic cluster species compared to other Zr(4+) clusters under various experimental conditions. Despite widespread applications of zirconium, the structure and dynamics of the tetramer in aqueous solution are not well understood. We conducted a combination of ab initio molecular dynamics and quantum mechanical studies in the gas phase and aqueous solution and related our results to the available experimental data to provide atom-level information on the behavior of this species in aqueous solution. Our simulations indicate that the tetramer structure is stable on the picosecond time scale in an aqueous environment and that it is of a planar form, comprising eight-coordinated Zr(4+) ions with an antiprism/irregular dodecahedron ligand arrangement. In combination with our studies of Zr(4+) dimer and trimer clusters, our results provide detailed geometrical information on structural motifs for building zirconium polymers and suggest a possible polymerization path.     

Water-catalyzed racemisation of lactide

The reactions of lactide racemisation, hydrolysis, or alcoholysis in the presence of water or anhydrous alcohol have been investigated separately. A small amount of water leads to lactide racemisation, hydrolysis, or both. Water acts as a catalyst for the racemisation of lactide. The racemisation mechanism has been studied by substituting D₂O instead of H₂O and measuring the substituent by gas chromatography-mass spectrometry (GC-MS). The experimental results show that the hydrogen atom on a chiral carbon of lactide is substituted by a ²H atom of D₂O. The reaction of lactide with water is in good agreement with the mechanism of addition-elimination. The addition of water to the carbonyl group produces an intermediate with a pair of hydroxyls connected to a carbon atom. If a hydroxyl hydrogen atom is transferred to the ester bond (CO-O), the hydrolysis of lactide generally occurs. Any of these hydroxyls could also be dehydrated with the close methine, thus producing an enolate, and the transfer of hydrogen from the enolic hydroxyl group results in lactide racemisation. The conversion of d- or l-lactide into meso-lactide is a reversible and endothermic reaction when catalyzed by water. When lactide reacts with alcohol, its alcoholysis occurs more readily than its racemisation.     

Time-resolved biomarker discovery in 1H-NMR data using generalized fuzzy Hough transform alignment and parallel factor analysis

This work addresses the subject of time-series analysis of comprehensive ¹H-NMR data of biological origin. One of the problems with toxicological and efficacy studies is the confounding of correlation between the administered drug, its metabolites and the systemic changes in molecular dynamics, i.e., the flux of drug-related molecules correlates with the molecules of system regulation. This correlation poses a problem for biomarker mining since this confounding must be untangled in order to separate true biomarker molecules from dose-related molecules. One way of achieving this goal is to perform pharmacokinetic analysis. The difference in pharmacokinetic time profiles of different molecules can aid in the elucidation of the origin of the dynamics, this can even be achieved regardless of whether the identity of the molecule is known or not. This mode of analysis is the basis for metabonomic studies of toxicology and efficacy. One major problem concerning the analysis of ¹H-NMR data generated from metabonomic studies is that of the peak positional variation and of peak overlap. These phenomena induce variance in the data, obscuring the true information content and are hence unwanted but hard to avoid. Here, we show that by using the generalized fuzzy Hough transform spectral alignment, variable selection, and parallel factor analysis, we can solve both the alignment and the confounding problem stated above. Using the outlined method, several different temporal concentration profiles can be resolved and the majority of the studied molecules and their respective fluxes can be attributed to these resolved kinetic profiles. The resolved time profiles hereby simplifies finding true biomarkers and bio-patterns for early detection of biological conditions as well as providing more detailed information about the studied biological system. The presented method represents a significant step forward in time-series analysis of biological ¹H-NMR data as it provides almost full automation of the whole data analysis process and is able to analyze over 800 unique features per sample. The method is demonstrated using a ¹H-NMR rat urine dataset from a toxicology study and is compared with a classical approach: COW alignment followed by bucketing.     

Comparison of the absorption, emission, and resonance Raman spectra of 7-hydroxyquinoline and 8-bromo-7-hydroxyquinoline caged acetate

To better understand the deprotection reaction of the new promising phototrigger compound BHQ-OAc (8-bromo-7-hydroxyquinoline acetate), we present a detailed comparison of the UV-vis absorption, resonance Raman, and fluorescence spectra of BHQ-OAc with its parent compound 7-hydroxyquinoline in different solvents. The steady-state absorption and resonance Raman spectra provide fundamental information about the structure, properties, and population distribution of the different prototropic forms present under the different solvent conditions examined. The species present in the excited states that emit strongly were detected by fluorescence spectra. It is shown that the ground-state tautomerization process of BHQ-OAc is disfavored compared with that of 7-HQ in aqueous solutions. The observation of the tautomeric form of BHQ-OAc in neutral aqueous solutions demonstrates the occurrence of the excited-state proton-transfer process, which would be a competing process for the deprotection reaction of BHQ-OAc in aqueous solutions.     

Stereoselective hydrolysis of sec-mono-alkyl sulfate esters with retention of configuration

An optimised method for the stereoselective hydrolysis of sec-alkylsulfate monoesters with absolute retention of configuration was developed. Under optimised conditions, clean hydrolysis of (R)-2-octyl sulfate was achieved in aqueous t-butyl methyl ether (3:97) using 0.6 equiv of p-toluenesulfonic acid as catalyst and 0.33 equiv of dioxane as mediator to give (R)-2-octanol as the sole product in the absence of side reactions, such as racemisation or elimination.     

pH Induced Partitioning and Interactions of Ciprofloxacin Hydrochloride with Anionic Surfactant Sodium Dodecyl Sulfate Using Ultraviolet and Fourier Transformed Infrared Spectroscopy Study

Ultraviolet (UV) and Fourier transformed infrared (FTIR) spectra of ciprofloxacin hydrochloride (Cpf) were studied under different pH conditions. The effect of aqueous, strong acidic, (pH 0.5–1.0) and a basic (pH 9.2) conditions on spectral behavior of Cpf was investigated in aqueous as well as in micellar environment of sodium dodecyl sulfate (SDS). Cpf shows partitioning from aqueous to micellar phase in a strong acidic as well as in a basic environment. Cpf shows no partitioning or binding to micelle in aqueous phase. Conductivity studies show that critical micelle concentration of SDS is increased with increasing concentration of Cpf. Different sites are responsible for binding under different pH conditions.     

An unusual intramolecular hetero-Diels-Alder cycloaddition

A new reaction of erythronolides, an intramolecular hetero-Diels-Alder, has been discovered. Heated aqueous alcoholic solutions of ABT-773 (1) and its cis isomer (3) convert slowly to cycloadducts 2 and 4, respectively. Optimal reaction conditions, mechanistic studies supported by molecular modeling, and biological activity data are reported. Single-crystal X-ray structures for both adducts 2 and 4 have been obtained.     

Production and purification of tartrate dehydrogenase

Tartrate dehydrogenase (TDH) is a stereospecific intracellular enzyme produced byPseudomonas putida. Several methods for separation of nucleic acids from the proteins in cell homogenate were compared in this study. These methods included precipitation (using streptomycin sulfate, manganous sulfate, and protamine sulfate) and aqueous two-phase extraction. Under optimal conditions of separation, a single-step aqueous two-phase extraction followed by back-extraction of the enzyme from enzyme-rich PEG-phase resulted in77% recovery of enzyme. This compared favorably with 50% enzyme recovery using protamine sulfate treatment. Furthermore, the remaining enzyme activity was accounted in the nucleic acid-rich dextran phase and the spent-PEG phase, suggesting that a multistep extraction process would increase enzyme recovery even more. Under the conditions of aqueous two-phase extraction, the selectivity of proteins over nucleic acids was 30, indicating a high degree of separation of proteins and nucleic acids in this process. The experimental data and their implications are presented.

     

Immobilisation of Chirasil-Val on glass capillaries

Summary Immobilisation methods of the chiral silicone stationary phase Chirasil-L-Val have been studied. In addition to the standard techniques of radical-induced immobilisation with dicumyl peroxide and azo tert-butane, immobilisation was solely achieved by thermal treatment: conditioning at low flow-rates or under stop-flow conditions led to unexpectedly high immobilisation despite mild temperatures. The presence of water vapor in the carrier gas accelerated the immobilisation process. While up to 75% immobilisation was attainable with both ATB and thermal methods, immobilisation with DCUP did not exceed 50%, despite relatively high DCUP concentrations.Whilst all immobilisation methods were accompanied by varying degrees of racemisation at the chiral centre, it was possible to establish conditions that yielded a high immobilisation (in excess of 70%) with a negligible loss in enantiomeric selctivity. The immobilisation reactions also slightly affected the polarity of the stationary phase, reflected in a shift of the Kovats-Indices of amino acid derivatives and in the accompanying Squalane-Effect. With respect to immobilisation, racemisation and polarity shift, thermal immobilisation with water-saturated carrier gas proved to be the optimum method.     

The Chemistry of 4-Substituted Oxazaphosphorinanes (OAP) (Tools for Cancer Research and Therapy)

Abstract

Novel chemical approaches resulted in 4-substituted OAP derivatives, linked by a sulfur, orygen or nitrogen atom to C-4. The cis- and trans-epimers were stereoselectively synthesized from the key intermediate 4-hydroxycyclophosphamide. An alternative route will be presented. The stereochemistry of 4-substituted OAP are confirmed by single crystal X-ray analysis and by NMR-spectra for more than 50 compounds. The connectivities of the nuclei observed in the homonuclear and heteronuclear COSY plots are summarized with data. In aqueous solution 4-substituted OAP are hydrolyzed with a half-life at physiological conditions of a few minutes for S-derivatives and of about 20 hours for the more stable N-derivatives. The pH-dependance of the hydrolysis rates including epimerisation and transthioacetalisation are submitted. Pharmacokinetical and biological activity data are presented.     

Nucleophile-assisted racemisations of halosilanes — kinetic studies

Kinetic studies have been carried out on the nucleophile-induced racemisation of PhMeCHSiMe₂X, 2, X = triflate, Br or Cl. Thirteen nucleophiles were studied. The results are interpreted in terms of two competing mechanisms for racemisation: (a) nucleophile attack on a silane-nucleophile complex formed by displacement of the halide by the nucleophile, and (b) halide-halosilane exchange, with inversion of configuration. Solvent effects were examined, and kinetic orders in the nucleophile and in one case for the halosilane were determined. The order in added nucleophile varied between one and two, with strong nucleophiles in polar media. Anomalously high orders in nucleophile were observed in non-polar media and are ascribed to aggregation of the nucleophile. A kinetic analysis of the competing mechanisms was attempted, and was consistent with the experimental findings. In this particular series of reactions involving compounds with good leaving groups and relatively powerful nucleophiles there was no evidence for intermediates involving extracoordinate silicon.     

Chemical and biological sensors based on organic thin-film transistors

The application of organic thin-film transistors (OTFTs) to chemical and biological sensing is reviewed. This review covers transistors that are based on the modulation of current through thin organic semiconducting films, and includes both field-effect and electrochemical transistors. The advantages of using OTFTs as sensors (including high sensitivity and selectivity) are described, and results are presented for sensing analytes in both gaseous and aqueous environments. The primary emphasis is on the major developments in the field of OTFT sensing over the last 5–10 years, but some earlier work is discussed briefly to provide a foundation.     

Approaches to the description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors

The influence of a xenobiotic compound on an organism is usually summarized by the expression biological activity. If a controlled, therapeutically relevant, and regulatory action is observed the compound has potential as a drug, otherwise its toxicity on the biological system is of interest. However, what do we understand by the biological activity? In principle, the overall effect on an organism has to be considered. However, because of the complexity of the interrelated processes involved, as a simplification primarily the "main action" on the organism is taken into consideration. On the molecular level, biological activity corresponds to the binding of a (low-molecular weight) compound to a macromolecular receptor, usually a protein. Enzymatic reactions or signal-transduction cascades are thereby influenced with respect to their function for the organism. We regard this binding as a process under equilibrium conditions; thus, binding can be described as an association or dissociation process. Accordingly, biological activity is expressed as the affinity of both partners for each other, as a thermodynamic equilibrium quantity. How well do we understand these terms and how well are they theoretically predictable today? The holy grail of rational drug design is the prediction of the biological activity of a compound. The processes involving ligand binding are extremely complicated, both ligand and protein are flexible molecules, and the energy inventory between the bound and unbound states must be considered in aqueous solution. How sophisticated and reliable are our experimental approaches to obtaining the necessary insight? The present review summarizes our current understanding of the binding affinity of a small-molecule ligand to a protein. Both theoretical and empirical approaches for predicting binding affinity, starting from the three-dimensional structure of a protein-ligand complex, will be described and compared. Experimental methods, primarily microcalorimetry, will be discussed. As a perspective, our own knowledge-based approach towards affinity prediction and experimental data on factorizing binding contributions to protein-ligand binding will be presented.