Crystallographic curiosities: polymorphism and structures with Z′ > 1

Polymorphs often have different values of Z′, the number of independent molecules in the asymmetric unit of the crystal structure. Structures with Z′ > 1 are a small minority, particularly so for Z′ > 2, and many are associated with packing problems, disorder and weak intermolecular interactions. These phenomena are fascinating and have important practical implications.     

A phase transition from monoclinic C2 with Z′ = 1 to triclinic P1 with Z′ = 4 for the quasiracemate l‐2‐aminobutyric acid–d‐methionine (1/1)

Racemates of hydrophobic amino acids with linear side chains are known to undergo a unique series of solid‐state phase transitions that involve sliding of molecular bilayers upon heating or cooling. Recently, this behaviour was shown to extend also to quasiracemates of two different amino acids with opposite handedness [Görbitz & Karen (2015). J. Phys. Chem. B, 119 , 4975–4984]. Previous investigations are here extended to an l ‐2‐aminobutyric acid–d ‐methionine (1/1) co‐crystal, C₄H₉NO₂·C₅H₁₁NO₂S. The significant difference in size between the –CH₂CH₃ and –CH₂CH₂SCH₃ side chains leads to extensive disorder at room temperature, which is essentially resolved after a phase transition at 229 K to an unprecedented triclinic form where all four d ‐methionine molecules in the asymmetric unit have different side‐chain conformations and all three side‐chain rotamers are used for the four partner l ‐2‐aminobutyric acid molecules.     

A simple graphical approach to predict local residue conformation using NMR chemical shifts and density functional theory

The dependency of amino acid chemical shifts on φ and ψ torsion angle is, independently, studied using a five‐residue fragment of ubiquitin and ONIOM(DFT:HF) approach. The variation of absolute deviation of ¹³C^α chemical shifts relative to φ dihedral angle is specifically dependent on secondary structure of protein not on amino acid type and fragment sequence. This dependency is observed neither on any of ¹³C^β, and ¹H^α chemical shifts nor on the variation of absolute deviation of ¹³C^α chemical shifts relative to ψ dihedral angle. The ¹³C^α absolute deviation chemical shifts (ADCC) plots are found as a suitable and simple tool to predict secondary structure of protein with no requirement of highly accurate calculations, priori knowledge of protein structure and structural refinement. Comparison of Full‐DFT and ONIOM(DFT:HF) approaches illustrates that the trend of ¹³C^α ADCC plots are independent of computational method but not of basis set valence shell type. © 2016 Wiley Periodicals, Inc.     

A diagonal measure and a local distance matrix to display relations between objects and variables

Proper permutation of data matrix rows and columns may result in plots showing striking information on the objects and variables under investigation. To control the permutation first, a diagonal matrix measure D was defined expressing the size relations of the matrix elements. D is essentially the absolute norm of a matrix where the matrix elements are weighted by their distance to the matrix diagonal. Changing the order of rows and columns increases or decreases D. Monte Carlo technique was used to achieve maximum D in the case of the object distance matrix or even minimal D in the case of the variable correlation matrix to get similar objects or variables close together. Secondly, a local distance matrix was defined, where an element reflects the distances of neighboring objects in a limited subspace of the variables. Due to the maximization of D in the local distance matrix by row and column changes of the original data matrix, the similar objects were arranged close to each other and simultaneously the variables responsible for their similarity were collected close to the diagonal part defined by these objects. This combination of the diagonal measure and the local distance matrix seems to be an efficient tool in the exploration of hidden similarities of a data matrix. Copyright © 2009 John Wiley & Sons, Ltd.     

A simple alternative to the pseudo‐π method

In this work, we introduce an approximate method for the multicenter index calculation that is very simple in implementation and has the same computational cost as the pseudo‐π approach. In contrast to the latter, however, the newly proposed method does not require additional single‐point calculations and is capable of quantifying multicenter electron sharing in aromatic rings containing heteroatoms and transition metals.     

A simple and high‐resolution HPLC‐PDA method for simultaneous quantification of local anesthetics in in vitro buccal permeation enhancement studies

A simple, isocratic, high‐resolution and prompt HPLC‐PDA method was developed and validated for the simultaneous quantification of prilocaine (PCL) and lidocaine (LCL) hydrochlorides in in vitro buccal iontophoresis‐driven permeation studies. A reversed‐phase C₁₈ column (250 mm x 4.6 mm, 3μm, 110Å) was used for the chromatographic separation. The mobile phase contained acetonitrile: 0.1M sodium phosphate buffer, pH 7.0 (1:1, v/v), plus 0.05% (v/v) diethylamine. The isocratic flow rate was set at 1 mL/min and the detection wavelength was 203 nm. PCL and LCL eluted in 8.9 min and 13 min, respectively, and the system suitability parameters varied within an acceptable range. The method was selective, sensitive, precise, accurate and robust, producing a linear plot at the concentration range of 0.25 to 10 µg/mL. The application of this method was demonstrated by a significant enhancement of the permeation of PCL and LCL with the application of iontophoresis (1 mA/cm² per 1 h) through isolated porcine esophageal epithelium. The amount of the drug retained in the epithelium also increased with the application of an electrical current. Copyright © 2015 John Wiley & Sons, Ltd.     

A simple representation of energy matrix elements in terms of symmetry‐invariant bases

When a system under consideration has some symmetry, usually its Hamiltonian space can be parallel partitioned into a set of subspaces, which is invariant under symmetry operations. The bases that span these invariant subspaces are also invariant under the symmetry operations, and they are the symmetry‐invariant bases. A standard methodology is available to construct a series of generator functions (GFs) and corresponding symmetry‐adapted basis (SAB) functions from these symmetry‐invariant bases. Elements of the factorized Hamiltonian and overlap matrix can be expressed in terms of these SAB functions, and their simple representations can be deduced in terms of GFs. The application of this method to the Heisenberg spin Hamiltonian is demonstrated. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Ion-pair adsorption film colorimetry — A new simple method for ppb level of aluminum ion in water sample

A new, highly sensitive and simple colorimetric method for trace aluminum(III) with 2,2-dihydroxyazobenzene, H₂L, is described, based on the ion-pair adsorption of the anionic Al chelate, [A1L₂ ^–, with crystal violet cation, CV⁺, on the surface of Polyvinylchloride film plasticized with dioctylphthalate. The blue violet species, CV⁺[A1L₂]^–, is enriched onto the transparent film, leading to a remarkable enhancement of the sensitivity, and the detection limits are 3 ng/ml by spectrophotometry and 5 ng/ml by visual colorimetry, respectively. Using spectrophotometer, a linear calibration curve is obtained over the concentration range of 0 to 50 ng/ml of Al. Further, the color system, consisting of red ([A1L₂]^–), yellow (H₂L), and blue violet (CV⁺), gave clear color changes suitable for visual determination of aluminum with an applicable range of 0 to above 3000 ng/ml. The four different color zones are khaki for 0–5 ng/ml, reddish-brown for 5–200 ng/ml, blue violet for 200 ng/ml-3g/ml, and colorless for more than 3g/ml. The proposed method has been successfully applied for the determination of aluminum in tap waters.     

A simple and rapid HPLC‐UV method for the determination of retigabine in human plasma

A simple and rapid high‐performance liquid chromatographic method with ultraviolet detection was developed for the quantitative determination of retigabine, known also as ezogabine, in human plasma. The assay uses a simple solid‐phase extraction for sample preparation and direct injection of the extract into the chromatograph. Flupirtine is used as an internal standard. Chromatographic separation is achieved on a C₁₈ Chromolith column (Chromolith Performance, 100 × 4.6 mm i.d.), using as mobile phase water/acetonitrile/methanol (72:18:10 v/v/v) mixed with 0.1% of 85% phosphoric acid. Isocratic elution is conducted at a flow rate of 1.5 mL min⁻¹. The total duration of a chromatographic run is 7 min. Calibration curves are linear over the 25–2000 ng mL⁻¹ concentration range, with a limit of quantitation of 25 ng mL⁻¹. Other performance characteristics include high precision (intra‐ and inter‐day coefficients of variation ≤12.6%) and high accuracy (99.7%–108.7%). The method is suitable for the investigation of concentration–response relationships in patients receiving therapeutic doses of retigabine.     

A membrane-protected micro-solid-phase extraction method based on molecular imprinting and its application to the determination of local anesthetics in cosmetics

As local anesthetics that are illegally added to cosmetics are harmful to consumer health, it is necessary to establish an efficient method for detecting these substances. Herein, a molecularly imprinted polymer (bupivacaine) was prepared by bulk polymerization and packed into a hollow fiber for use as an extraction phase to fabricate a membrane-protected micro-solid-phase extraction device. The optimal values of the influencing parameters for the microextraction process were as follows: a sample solution pH of 9.0, a loading and washing time of 2 h, and an elution time of 32 min. A gas chromatography-mass spectrometry method was established for the determination of local anesthetics and coupled with the microextraction method to successfully detect local anesthetics in cosmetic samples. The calibration curve for the proposed method was linear in the range of 0.4–50 mg/L and showed a good correlation coefficient (r²). The limits of detection for local anesthetics were in the range of 0.01–0.71 mg/L. The molecularly imprinted polymer exhibited good imprinting and selectivity, the micro-solid-phase extraction device was simple and inexpensive and fabrication was reproducible. The combination of molecular imprinting technology, membrane separation, and micro-solid-phase extraction methods used in this study can potentially be applied to pretreat local anesthetics in cosmetic samples.     

A simple method for the anionic polymerization of α-carbonyl acids in water

Anionic polymerization of α-carbonyl acids such as ketomalonic acid, glyoxylic acid, and pyruvic acid, via carbonyl group to form the corresponding polyether in basic aqueous media, was presented. Cogeneration of carbonyl form of monomer and the carbanion of tartronic acid disodium salt was essential for the anionic polymerization. © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 189–193, 1998     

A new strategy to improve the predictive ability of the local lazy regression and its application to the QSAR study of melanin‐concentrating hormone receptor 1 antagonists

In the quantitative structure‐activity relationship (QSAR) study, local lazy regression (LLR) can predict the activity of a query molecule by using the information of its local neighborhood without need to produce QSAR models a priori. When a prediction is required for a query compound, a set of local models including different number of nearest neighbors are identified. The leave‐one‐out cross‐validation (LOO‐CV) procedure is usually used to assess the prediction ability of each model, and the model giving the lowest LOO‐CV error or highest LOO‐CV correlation coefficient is chosen as the best model. However, it has been proved that the good statistical value from LOO cross‐validation appears to be the necessary, but not the sufficient condition for the model to have a high predictive power. In this work, a new strategy is proposed to improve the predictive ability of LLR models and to access the accuracy of a query prediction. The bandwidth of k neighbor value for LLR is optimized by considering the predictive ability of local models using an external validation set. This approach was applied to the QSAR study of a series of thienopyrimidinone antagonists of melanin‐concentrating hormone receptor 1. The obtained results from the new strategy shows evident improvement compared with the commonly used LOO‐CV LLR methods and the traditional global linear model. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

A simple and efficient method to prepare thioesters in aqueous solutions

A simple method is described for the efficient synthesis of biologically-active thioesters in aqueous solutions. The method utilizes imidazole as a catalyst and easily synthesized acyl or aminoacyl adenylates to synthesize a variety of thioesters, from small molecules to macromolecules. Yields in excess of 90% can be achieved in less than 10 min at room temperature. Specifically, functional derivatization of RNA with biotin via thioester linkage is demonstrated.     

Long‐range corrected density functionals combined with local response dispersion: A promising method for weak interactions

Density functional theory, in general, is considered to underestimate the weak van der Waals type of intermolecular interactions. We optimized parameters of the local response dispersion (LRD) method applied to the long‐range corrected exchange‐correlation functionals (LC‐BOP12+LRD and LCgau‐BOP+LRD) on the interaction energy for the complexes in the recently compiled S66 database and found to be comparable with the high‐level wave function‐based methods reported in ?ezá? et al. (J. Chem. Theory Comput. 2011 , 7, 2427). Our calculations with the S66 intermolecular complexes at equilibrium geometries suggests that the LC‐BOP12+LRD and LCgau‐BOP+LRD are well‐balanced and lower cost alternatives to the methods reported in the database. Further, test on the S66X8 database (with eight nonequilibrium points) and the HBC6 and NBC10 database shows LC+LRD method with newly optimized parameters is a promising candidate for dealing such weak interactions. Finally, the new parameterized LC+LRD method was tested on X40 benchmark halogenated complexes.Copyright © 2013 Wiley Periodicals, Inc.     

A simple,rapid and reliable liquid chromatography–mass spectrometry method for determination of methotrexate in human plasma and its application to therapeutic drug monitoring

A simple, rapid and reliable liquid chromatography–electrospray ionization tandem mass spectrometry method was established and validated for the determination of methotrexate in human plasma. After a straightforward protein precipitation by acetonitrile–water (70:30, v/v), methotrexate (MTX) and p‐aminoacetophenone (used as internal standard, IS) were separated on a Column C₁₈ column (50 × 2.1 mm, 3 µm; Column Technology, Fremont, CA, USA) using a gradient elution with mobile phase of acetonitrile and 0.03% acetic acid aqueous solution at a flow rate of 0.5 mL/min. The total chromatographic runtime was 5 min for each injection. Quantification detection was performed in a triple‐quadruple tandem mass spectrometer under positive mode monitoring the following mass transitions: m/z 455.3 → 308.3 for MTX and m/z 136.1 → 94.4 for IS. The calibration curve was linear over the range of 0.05–25.0 µmol/L with a lower limit of quantification of 0.05 µmol/L. The intra‐ and interday precisions were <5.2%, the accuracy varied from ?4.1 to 4.5%. The recovery was >94%. The LC‐MS/MS method showed an excellent agreement with the existing HPLC‐UV method using Passing–Bablok regression and Bland–Altman difference plot analysis. The validated LC‐MS/MS can be successfully applied to the routine therapeutic drug monitoring of MTX in clinical laboratories. Copyright © 2015 John Wiley & Sons, Ltd.