Hydride generation activity of arsenosugars and thioarsenicals

The major arsenosugar compounds have been reported to be hydride-generation-active, however to a lesser extent in comparison with the inorganic arsenicals. We report here for the first time the identity and quantity of the volatile arsenicals generated by As-sugar-SO₃, As-sugar-SO₄, dimethylarsinoyl acetic acid and dimethylarsinoyl ethanol. Only one major volatile compound was identified for all four compounds studied: dimethylarsine. This means that the As–C bond to the longer carbon chain was cleaved during the hydride-generation process. Theoretical calculations at the RHF/6-31G(d,p) ab initio level confirm that this As–C bond is much weaker than the As–CH₃ bonds. Furthermore, it was revealed that the sulphur analogue of dimethylarsinic acid (DMAS ) is hydride-generation-active at pH 7 in contrast to dimethylarsinic acid, despite the fact that arsenic is also pentavalent. This has been substantiated by the calculation of the change in susceptibility of the arsenic towards nucleophilic attack when oxygen is replaced by sulphur. Hence, DMAS can easily be mistaken for a trivalent arsenic species.     

Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds.     

Structural Determination of a Photochemically Active Diplatinum Molecule by Time‐Resolved EXAFS Spectroscopy

Metallica : A large contraction of the Pt? Pt bond in the triplet excited state of the photoreactive [Pt₂(P₂O₅H₂)₄]^4? ion is determined by time‐resolved X‐ray absorption spectroscopy (see picture). The strengthening of the Pt? Pt interaction is accompanied by a weakening of the ligand coordination bonds, resulting in an elongation of the platinum–ligand bond that is determined for the first time.

     

Biosynthesis of the (2S,3R)-3-methyl glutamate residue of nonribosomal lipopeptides

The calcium-dependent antibiotics (CDAs) and daptomycin are therapeutically relevant nonribosomal lipopeptide antibiotics that contain penultimate C-terminal 3-methyl glutamate (3-MeGlu) residues. Comparison with synthetic standards showed that (2S,3R)-configured 3-MeGlu is present in both CDA and daptomycin. Deletion of a putative methyltransferase gene glmT from the cda biosynthetic gene cluster abolished the incorporation of 3-MeGlu and resulted in the production of Glu-containing CDA exclusively. However, the 3-MeGlu chemotype could be re-established through feeding synthetic 3-methyl-2-oxoglutarate and (2S,3R)-3-MeGlu, but not (2S,3S)-3-MeGlu. This indicates that methylation occurs before peptide assembly, and that the module 10 A-domain of the CDA peptide synthetase is specific for the (2S,3R)-stereoisomer. Further mechanistic analyses suggest that GlmT catalyzes the SAM-dependent methylation of alpha-ketoglutarate to give (3R)-methyl-2-oxoglutarate, which is transaminated to (2S,3R)-3-MeGlu. These insights will facilitate future efforts to engineer lipopeptides with modified glutamate residues, which may have improved bioactivity and/or reduced toxicity.     

Structure,biosynthetic origin,and engineered biosynthesis of calcium-dependent antibiotics from Streptomyces coelicolor

The calcium-dependent antibiotic (CDA), from Streptomyces coelicolor, is an acidic lipopeptide comprising an N-terminal 2,3-epoxyhexanoyl fatty acid side chain and several nonproteinogenic amino acid residues. S. coelicolor grown on solid media was shown to produce several previously uncharacterized peptides with C-terminal Z-dehydrotryptophan residues. The CDA biosynthetic gene cluster contains open reading frames encoding nonribosomal peptide synthetases, fatty acid synthases, and enzymes involved in precursor supply and tailoring of the nascent peptide. On the basis of protein sequence similarity and chemical reasoning, the biosynthesis of CDA is rationalized. Deletion of SCO3229 (hmaS), a putative 4-hydroxymandelic acid synthase-encoding gene, abolishes CDA production. The exogenous supply of 4-hydroxymandelate, 4-hydroxyphenylglyoxylate, or 4-hydroxyphenylglycine re-establishes CDA production by the DeltahmaS mutant. Feeding analogs of these precursors to the mutant resulted in the directed biosynthesis of novel lipopeptides with modified arylglycine residues.     

Dynamic fragmentation of powders in spherical geometry

Experimental evidence from a wide range of sources shows that the expanding cloud of explosively disseminated material comprises of “particles” or fragments which have different dimensions from those associated with the original material. Photographic evidence shows jets or fingers behind these expanding fragments. Powders and liquids have often been used to surround explosives to act as blast mitigants; this is the main driver for our research. Other examples of areas where these features are observed include fuel air explosives and enhanced blast explosives as well as quasi-static pressure mitigation systems. In this paper, we consider the processes occurring when an explosive interacts with a surrounding layer of powder in spherical geometry. Results from explosive experiments designed to investigate the effects of powder grain size and powder fill-to-burster charge mass ratio ( \(F\) / \(B\) ) are presented and compared with results from numerical modelling to explore what determines the primary fragment size distribution resulting from explosive dissemination of a layer of material and when this process begins. The evidence clearly shows that the process starts during the first wave transit period of the powder material and, despite the surrounding material initially being a loose powder, shows the characteristics of a brittle fracture mechanism. Later time video evidence shows the same number of jets or fingers as are identified by X-rays of the early, primary fragmentation process. The number of fragments is only a very weak function of the initial grain size of the powder.     

Automorphic vector bundles on connected Shimura varieties

Parts of this work have supported by the National Science Foundation; it was completed while the author was at the sematical Sciences Research Institute, Berkeley     

Auger spectra of aluminium and magnesium induced by caesium-ion bombardment

A caesium ion beam has been used to excite electron emission from Mg, Al, AlAs and GaAs. The portions of the electron emission spectra that result from Auger transitions are compared with previously reported spectra generated with different primary ion beams. It is observed that 10 keV Cs⁺-ion bombardment produces very few excited ions with two 2p vacancies. Evidence for two atomic-like peaks discussed by previous authors, but not unambiguously identified, is also presented.     

Pharmaceutical applications of variable-angle synchronous scanning fluorescence spectroscopy

The development of variable-angle synchronous scanning (v.a.s.s.) in fluorescence spectrometry is reported, based on a computer-aided spectrofluorimeter. The technique permits a linear path to be scanned at any preselected angle through the emission-excitation matrix defined by (I_em, λ_em, λ_ex), by effectively scanning the emission and the excitation monochromators at different speeds under computer control. When applied to pharmaceutical dosage forms, v.a.s.s. gave good selectivity for chlorpromazine in the presence of its principal degradation product, chlorpromazine sulphoxide, and for oxytetracycline in the presence of the additives vitamin C, thiamine, nicotinamide and riboflavin. Good calibration linearity, precision and recovery were observed for both principal drug components. The angle of the scan trajectory can also be varied continuously through the emission-excitation matrix, to describe any desired path under computer control. This novel technique of non-linear v.a.s.s. can provide an improved method for generating diagnostic profiles of drugs, degradation products and metabolites.