Preparation and antitumour properties of the enantiomers of a hypoxia-selective nitro analogue of the duocarmycins

Racemic 2-{[1-(chloromethyl)-5-nitro-3-{5-[2-(dimethylamino)ethoxy]indol-2-carbonyl}-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}aminoethyl dihydrogen phosphate, a synthetic nitro derivative of the duocarmycins, is a hypoxia-selective prodrug active against radiation-resistant tumour cells at nontoxic doses in mice. An intermediate in the synthesis of this prodrug was resolved by chiral HPLC and the absolute configuration assigned by X-ray crystallography. The intermediate was used to prepare the prodrug's enantiomers, and also the enantiomers of the active nitro and amino metabolites. In vitro analysis in the human cervical carcinoma cell line SiHa showed that both nitro enantiomers are hypoxia-selective cytotoxins, but the "natural" S enantiomer is at least 20-fold more potent. Examination of extracellular amino metabolite concentrations demonstrated no enantioselectivity in the hypoxia-selective reduction of nitro to amino. Low levels of amino derivative were also found in aerobic cell suspensions, sufficient to account for the observed oxic toxicity of the nitro form. At an equimolar dose in SiHa-tumour bearing animals, the (-)-R enantiomer of the prodrug was inactive, while the (+)-S enantiomer caused significantly more hypoxic tumour cell kill than the racemate. At this dose, the combination of (+)-S-prodrug and radiation eliminated detectable colony-forming cells in four out of five treated tumour-bearing animals.     

Rapid characterization of lipids by MALDI MS. Part 2: Artifacts,ion suppression,and TLC MALDI imaging

Several new methods have been developed recently that allow the direct detection of lipids without resorting to derivatization or chromatographic separation. The simplest of these is direct MALDI (matrix‐assisted laser desorption/ionization) mass spectrometry. This approach is most useful for mixtures that contain minimal amounts of ion‐suppressing interfering components. However, when such components are present, their effects can often be minimized by using simple separation techniques beforehand, such as solid phase extraction or thin layer chromatography. For example, direct MALDI has been used for rapid screening of lipids and taxonomic identification of the source organisms with no sample pretreatment. Collecting fractions from solid phase extraction cartridges have also been used to avoid the most extreme effects of ion suppression from more complex lipid mixtures. More recently, direct MALDI has been applied to the analysis of TLC plates allowing the detection of TLC‐separated lipids from the complex lipidome. Herein, we briefly describe the application of rapid MALDI MS to some typical research problems involving the characterization of lipids. In Part 1 [1] we covered bacterial taxonomy by direct analysis of intact lipids and the analysis of food oil triacylglycerols . Part 2 will address ion suppression, spontaneous fragmentation, and coupling MALDI with chromatography. The spontaneous fragmentation of protonated lipids in oils by direct MALDI produces artifactual diacylglycerol‐like ions. An understanding of this process and its minimization facilitates monitoring the decomposition of lipids by direct analysis. Suppression also has an impact on direct analysis of lipids, especially when mixtures contain both polar and non‐polar lipids. We demonstrate the use of solid phase extraction and thin layer chromatography to produce fractions or substrates from complex biological samples in which lipids can be detected by direct and rapid MALDI MS analysis.     

Microstructures and abrasive wear performance of PTAW deposited Ni–WC overlays using different Ni-alloy chemistries

The microstructures and performance of Ni–WC (nickel–tungsten carbide) composite overlays deposited by plasma transferred arc welding are studied using a combination of microscopy, hardness, and wear testing. The Ni–WC overlays had microstructures consisting of γ-Ni dendrites, with interdendritic Ni-based eutectics, borides and carbides. Overlays which were produced with a low hardness Ni-alloy matrix contained a smaller fraction of interdendritic phases relative to the high hardness Ni-alloys.The dissolution of WC particles was observed following deposition of the MMCs, and this promoted the formation of secondary carbide phases. Ni-alloys with low carbon and low Cr content exhibited the least dissolution of WC. The Ni–WC overlays produced using these dilute alloys generally performed better in ASTM G65 wear tests. This was due to the increased fraction of retained WC phase, and the reduced fraction of brittle secondary carbide phases when the Ni-alloy contained no Cr.     

A new approach to monitoring trace element concentrations and speciation in wounds and wound fluids

Combined application of potentiometric stripping analysis (PSA) and computer simulation of speciation analysis has been used to determine the total element concentrations and the proportions of the different chemical species of copper, manganese and zinc present in human would fluids. With samples of 0.5 to 1 cm3 the coefficient of variation lies in the range of 5-10%. In eight patients the concentrations of Cu and Zn were greater than those expected in blood plasma, but for Mn the observed concentrations lay with the range expected for plasma.     

Networks of materials: Construction and structural analysis

Modeling and analysis of the materials universe is an emerging area of research with many important applications in materials science. The main goal is to create a map of materials which allows not only to visualize and navigate the materials space, but also reveal complex relationships and “connections” among materials and potentially find clusters of materials with similar properties. In this paper, we consider the problem of mapping and exploring the materials universe using network science tools and concepts. The networks are based on the open-source materials data repository AFLOW.org where each material is represented as a node, and each pair of nodes is connected by a link if the respective materials exhibit a high level of similarity between their Density of States (DOS) functions. We discuss the importance of similarity measure selection, investigate basic structural properties of the resulting networks, and demonstrate advantages and limitations of the proposed approaches. Materials networks, similarity measures, DOS function, materials informatics, network analysis, clique.     

Contribution of hydrogen and/or covalent bonds on reinforcement of natural rubber latex films with surface modified silica

A macromolecular coupling agent containing hydrophilic and hydrophobic groups is made to react with precipitated silica. Interfacial interactions between  OH groups of silica and  COOH groups of macromolecule are found to be created through either hydrogen bonds alone or through hydrogen bonds and covalent bonds. Aqueous dispersions of unmodified and modified silica are prepared and the colloidal stability and particle size distribution of the dispersions are observed. The dispersions at neutral pH are incorporated into vulcanized/unvulcanized natural rubber latex. The formation of hydrogen bonds and/or covalent bonds is studied via FTIR spectroscopy and their contribution in encouraging filler‐rubber interactions is emphasized through mechanical and swelling properties. Uniform distribution and dispersion of modified filler particles throughout the rubber matrix is confirmed by the microstructures of the latex films cast from filler added natural rubber latex. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40380.     

Rapid characterization of lipids by MALDI MS. Part 1: Bacterial taxonomy and analysis of food oils

Several new methods have been developed recently that allow the direct detection of lipids without resorting to derivatization or chromatographic separation. The simplest of these is direct MALDI (matrix‐assisted laser desorption/ionization) mass spectrometry. This approach is most useful for mixtures that contain minimal amounts of ion‐suppressing interfering components. However, even when such components are present, their effects can often be minimized by using simple separation techniques beforehand, such as solid phase extraction or thin layer chromatography. For example, direct MALDI has been used for rapid screening of lipids and for taxonomic identification of the source organisms with no sample pretreatment. Fractions collected from solid phase extraction cartridges have also been used to avoid the most extreme effects of ion suppression from more complex lipid mixtures. More recently, direct MALDI has been applied to the analysis of TLC plates allowing the detection of TLC‐separated lipids from the complex lipidome. Herein, we briefly describe the application of rapid MALDI MS to some typical research problems involving the characterization of lipids. In Part 1 these include bacterial taxonomy by direct analysis of intact lipids in simple extracts rather than by conversion to fatty acid methyl esters. Food oils such as triacylglycerols can be characterized simply and easily by direct MALDI MS without resort to any sort of separation. Part 2 (in the next issue of Lipid Technology) will cover the spontaneous fragmentation of protonated lipids, ion suppression and the use of solid phase extraction and thin layer chromatography with MALDI MS to characterize complex biological samples.