The caged state of some small molecules in the C_(60) cage

The potential energy curves of some small molecules, H2, N2, O2, F2, HF, CO and NO, in the caged state within C60 cage and in the free state have been calculated by the quantum-chemical method AM1. In this study, the focus is on the cage effect of C60, and the concept of caged state is put forward. The results show that the bond lengths in the caged states are not much different from those in their corresponding free states, but the bond intensities in the caged states are much greater than those in their corresponding free states.     

Application of at-line two-dimensional liquid chromatography–mass spectrometry for identification of small hydrophilic angiotensin I-inhibiting peptides in milk hydrolysates

A two-dimensional chromatographic method with mass spectrometric detection has been developed for identification of small, hydrophilic angiotensin I-inhibiting peptides in enzymatically hydrolysed milk proteins. The method involves the further separation of the poorly retained hydrophilic fraction from a standard C₁₈ reversed-phase column on a hydrophilic interaction liquid chromatography (HILIC) column. The latter column is specifically designed for the separation of hydrophilic compounds. Narrow fractions collected from the HILIC column were analysed for their angiotensin I-converting enzyme (ACE) inhibiting potential in an at-line assay. Fractions showing significant inhibition of ACE were analysed by LC–MS for structure elucidation. With this method the main peptides responsible for ACE-inhibition in the hydrophilic part of a milk hydrolysate could be determined. The ACE-inhibiting peptides RP, AP, VK, EK, and EW explained more than 85% of ACE-inhibition by the hydrophilic fraction.     

Development of small molecules designed to modulate protein–protein interactions

Summary Protein–protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein–protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the “privileged-structure hypothesis” [Che, Ph.D. Thesis, Washington University, 2003] – that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists – to address the challenges inherent in the discovery of small-molecule inhibitors of protein–protein interactions.This paper is adapted from a presentation at the 230th National Meeting of the American Chemical Society, Washington DC, August 28 – September 1, 2005, Abstract COMP-136.     

Determination of comprehensive in silico determinants as a strategy for identification of novel PI3Kα inhibitors

Structural Chemistry - The PI3KCA gene functions by activating cascade signaling pathways leading to cell proliferation, survival, and growth. Being one of the frequently aberrant kinase in various...     

Improved silica xerogel film processing for MALDI-TOF–MS quantitative analysis of peptides and small molecules

In this work, sol–gel derived silica films were prepared for direct desorption/ionization of organic compounds in MALDI-TOF–MS analysis with the aim of improving method precision and of reducing interfering signals at low m/z values. Two commonly used MALDI matrices, 2,5-dihydroxybenzoic acid (DHB) and α-cyano-4-hydroxycinnamic acid (CHCA), were incorporated into the sol–gel network in order to absorb laser energy and to induce analyte desorption/ionization with low or absent background signals in the mass spectra. To achieve a reproducible xerogel film formation, experimental parameters for its deposition were optimized. The gel matrices were characterized by Fourier Transform Infrared (FT-IR) spectroscopy, X-ray Diffraction (XRD), and Scanning Electron Microscopy (SEM) analysis. The results proved the embedding of the matrix molecules in a disperse form into the homogeneous sol–gel material. The sol–gel matrix was then tested for the qualitative and quantitative analysis of two reference peptides, such as Bradykinin and P₁₄R. In addition, spectral quality and method performance were assessed for quantitation of melamine, a low-molecular weight compound of food safety concern. In all cases, high quality spectra and excellent mass accuracy (between 3.5 and 13 ppm) were observed. Furthermore, the experimental results evidenced a significant improvement of the measurement repeatability on spot and between spots (relative standard deviation <10%), with respect to the traditional dried-droplet sample deposition method. Good sensitivity and linearity in the concentration range explored were obtained for peptides and melamine, demonstrating the suitability of the sol–gel-based matrix to be used for quantitative analysis.     

The design and characterisation of sol–gel coatings for the controlled-release of active molecules

The controlled release of active agents from a matrix has become increasingly important for oral, transdermal or implantable therapeutic systems, due to the advantages of safety, efficacy and patient convenience. Controlled-release hybrid (organic–inorganic) sol–gel coating synthesis has been performed to create a sol with an active molecule included (procaine). Synthesis procedures included acid-catalysed hydrolysis, sol preparation, the addition of a procaine solution to the sol, and the subsequent gelation and drying. The alkoxide precursors used were triethoxyvinylsilane and tetraethyl-orthosilicate (TEOS) in molar ratios of 1:0, 9:1, 8:2 and 7:3. After the determination of the optimal synthesis parameters, the material was physicochemically characterised by silicon-29 nuclear magnetic resonance (²⁹Si-NMR) and Fourier transform infrared spectroscopy, contact angle analysis and electrochemical impedance spectroscopy tests. Finally, the materials were assayed in vitro for their ability to degrade by hydrolysis and to release procaine in a controlled manner. The sustained release of procaine over a 3-day period was demonstrated. A close correlation between release and degradation rates suggests that film degradation is the main mechanism underlying the control of release. Electrochemical analysis reveals the formation of pores and water uptake during the degradation. The quantity of TEOS is one of the principal parameters used to determine the kinetics of degradation and procaine release.     

The nature of the P–P bond in carbene-stabilized diphosphorus complex

The nature of the P–P bond in the recently synthesized N-heterocyclic carbene-stabilized diphosphorus complex has been investigated by the built-in fragment-oriented approach using DFT calculations. The result leads us to investigate the stabilization of diphosphorus. It is concluded that a weakening factor, which can be engendered through such methods as orbital mixing, antibonding interaction, or ligand–receptor interactions, is the key to stabilize the highly reactive diphosphorus molecule.     

The intricacies of the stacking interaction in a pyrrole–pyrrole system

Extensive calculations of potential energy surfaces for parallel-displaced configurations of pyrrole–pyrrole systems have been carried out by the use of a dispersion-corrected density functional. System geometries associated with the energy minima have been found. The minimum interaction energy has been calculated as ?5.38 kcal/mol. However, bonding boundaries appeared to be relatively broad, and stacking interactions can be binding even for ring centroid distances larger than 6 Å. Though the contribution of the correlation energy to intermolecular interaction in pyrrole dimers appeared to be relatively small (around 1.6 smaller than it is in a benzene–benzene system), this system’s minimum interaction energy is lower than those calculated for benzene–benzene, benzene–pyridine and even pyridine–pyridine configurations. The calculation of the charges and energy decomposition analysis revealed that the specific charge distribution in a pyrrole molecule and its relatively high polarization are the significant source of the intermolecular interaction in pyrrole dimer systems.     

How are small ions involved in the compaction of DNA molecules?

DNA is a genetic material found in all life on Earth. DNA is composed of four types of nucleotide subunits, and forms a double-helical one-dimensional polyelectrolyte chain. If we focus on the microscopic molecular structure, DNA is a rigid rod-like molecule. On the other hand, with coarse graining, a long-chain DNA exhibits fluctuating behavior over the whole molecule due to thermal fluctuation. Owe to its semiflexible nature, individual giant DNA molecule undergoes a large discrete transition in the higher-order structure. In this folding transition into a compact state, small ions in the solution have a critical effect, since DNA is highly charged. In the present article, we interpret the characteristic features of DNA compaction while paying special attention to the role of small ions, in relation to a variety of single-chain morphologies generated as a result of compaction.     

Effect-directed analysis: a promising tool for the identification of organic toxicants in complex mixtures?

Wastewater effluents, groundwater, surface water, sediments, soils and air particulate matter are often contaminated by a multitude of chemicals. Since often no a priori knowledge of relevant toxicants exists, chemical analysis alone is not an appropriate tool for hazard assessment. Instead, a linkage of effect data and hazardous compounds is required. For that purpose, effect-directed analysis (EDA) was developed, which is based on a combination of biotesting, fractionation procedures and chemical analytical methods. Since a controversial discussion about the prospects of success in relation to the expense exists, the current methodological state of EDA for organic toxicants in complex mixtures and important results are reviewed in this paper with the aim of establishing criteria for the successful use of this promising tool. While EDA is a powerful tool to identify specifically acting individual toxicants close to the source of emission, it is inappropriate for screening purposes and often may fail in remote areas where the concentrations of specific toxicants are too low relative to the nonspecific toxicity of the whole mixture of natural and anthropogenic compounds. The biological tools have to be carefully selected with respect to their ability to detect specific effects and their significance in hazard assessment. Sophisticated chemical tools are required to identify individual toxicants in mixtures of thousands of compounds, which are typical for contaminated environments.     

Size does matter! Label-free detection of small molecule–protein interaction

This review is focused on methods for detecting small molecules and, in particular, the characterisation of their interaction with natural proteins (e.g. receptors, ion channels). Because there are intrinsic advantages to using label-free methods over labelled methods (e.g. fluorescence, radioactivity), this review only covers label-free techniques. We briefly discuss available techniques and their advantages and disadvantages, especially as related to investigating the interaction between small molecules and proteins. The reviewed techniques include well-known and widely used standard analytical methods (e.g. HPLC-MS, NMR, calorimetry, and X-ray diffraction), newer and more specialised analytical methods (e.g. biosensors), biological systems (e.g. cell lines and animal models), and in-silico approaches.     

A novel FRET approach for in situ investigation of cellulase–cellulose interaction

A novel real-time in situ detection method for the investigation of cellulase–cellulose interactions based on fluorescence resonance energy transfer (FRET) has been developed. FRET has been widely used in biological and biophysical fields for studies related to proteins, nucleic acids, and small biological molecules. Here, we report the efficient labeling of carboxymethyl cellulose (CMC) with donor dye 5-(aminomethyl)fluorescein and its use as a donor in a FRET assay together with an Alexa Fluor 594 (AF594, acceptor)–cellulase conjugate as acceptor. This methodology was successfully employed to investigate the temperature dependency of cellulase binding to cellulose at a molecular level by monitoring the fluorescence emission change of donor (or acceptor) in a homogeneous liquid environment. It also provides a sound base for ongoing cellulase–cellulose study using cellulosic fiber.     

Carbon-carbon bond-forming reactions of α-thioaryl carbonyl compounds for the synthesis of complex heterocyclic molecules

Strategies for the formation of carbon-carbon bonds from the α-thioaryl carbonyl products of substituted lactams are described. Although direct functionalization is possible, a two step process of oxidation and magnesium-sulfoxide exchange has proven optimal. The oxidation step results in the formation of two diastereomers that exhibit markedly different levels of stability toward elimination, which is rationalized on the basis of quantum mechanical calculations and X-ray crystallography. Treatment of the sulfoxide with i-PrMgCl results in the formation of a magnesium enolate that will undergo an intramolecular Michael addition reaction to form two new stereogenic centers. The relationship between the substitution patterns of the sulfoxide substrate and the efficiency of the magnesium exchange reaction are also described.     

A study of interaction of two ethylene molecules by the semiempirical complete configuration interaction method in π-electron approximation

The semiempirical complete configuration interaction method in -electron approximation has been used to calculate the energies of states of a system composed of two interacting ethylene molecules and having the D _2h symmetry. Oscillator strengths for the allowed transitions have been also calculated. If conjugation effects between the ethylene molecules are disregarded the hypochromism found by Nesbet is not obtained in this higher approximation. Consideration of conjugation effects results in hypochromism of the longest-wavelength allowed transition. The bathochromic shift of this band occurs at smaller distances between the two ethylene molecules than the hypochromic effect. Some general features of transannular interaction and the rôle of conjugation effects in the hypochromism of helical polynucleotides are discussed. The qualitative similarity of the cyclobutadiene energy spectra calculated by the semiempirical and by the theoretical methods of complete configuration interaction is pointed out.

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Zusammenfassung Mittels der halbempirischen Methode der vollständigen Konfigurationswechselwirkung wurden die Eigenwerte der Energie eines Systems von gp-Elektronen, bestehend aus zwei äthylenmolekülen mit der Symmetrie D _2h , sowie die Oszillatorstärke erlaubter Übergänge berechnet. Bei Vernachlässigung der Konjugationseffekte tritt der hypochrome Effekt Nesbets in dieser höheren Näherung nicht auf. Berücksichtigung von Konjugationseffekten ergibt eine Intensitätsschwächung der Bande des langwelligsten erlaubten Überganges. Bei dieser Bande überwiegt bei kleinem Abstand der Äthylenmoleküle der bathochrome Effekt. Einige allgemeine Aspekte transannularer Wechselwirkung und die Rolle von Konjugationseffekten im Hypochromismus spiraliger Polynukleotide werden erörtert. Die qualitative Ähnlichkeit von Cyclobutadienspektren, die einerseits nach der halbempirischen, andererseits nach der theoretischen Methode der vollständigen Konfigurationswechselwirkung berechnet wurden, wird aufgezeigt.

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Résumé A l'aide de la méthode semiempirique de l'interaction de configuration complète, les valeurs propres de l'énergie d'un système d'électrons gp, consistant en deux molécules d'éthylène et ayant la symétrie D _2h , et les forces oscillatrices des transitions permises ont été calculées. Si l'on néglige les effets de conjugaison, l'effet hypochrome de Nesbet n'apparaît pas dans cette approximation élevée. Si l'on tient compte des effets de conjugaison, il en résulte une diminution de l'intensité de la transition permise de plus grande longueur d'onde. Dans le cas de cette bande, l'effet bathochrome l'emporte, quand la distance entre les molécules d'éthylène est petite. Quelques aspects communs des interactions transannulaires et le rôle des effets de conjugaison dans l'hypochromisme des polynucléotides en hélice sont discutés. On montre la ressemblance qualitative entre les spectres du cyclobutadiène, calculés et par la méthode semiempirique et par la méthode théorique de l'interaction de configuration complète.