Optimized scale up of 3-pyrimidinylpyrazolo[1,5-a]pyridine via Suzuki coupling; a general method of accessing a range of 3-(hetero)arylpyrazolo[1,5-a]pyridines

We have developed an improved synthesis of 3-(hetero)aryl pyrazolo[1,5-a]pyridines (such as 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (8)) via an optimized synthesis and Suzuki coupling of 3-pyrazolo[1,5-a]pyridine boronic ester 10. These conditions are applicable to both high throughput chemistry and large scale synthesis of these medicinally important compounds. The scope of this chemistry has been further extended to include the synthesis and coupling of a novel boronic ester, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (43).     

Identification of cloud phase from PICASSO-CENA lidar depolarization: a multiple scattering sensitivity study

A fast Monte Carlo simulation scheme is developed to assess the impact of multiple scattering on space-based lidar backscattering depolarization measurements. The specific application of our methodology is to determine cloud thermodynamic phase from satellite-based lidar depolarization measurements. Model results indicate that multiple scattering significantly depolarizes backscatter return from water clouds. Multiple scattering depolarization is less significant for non-spherical particles. There are sharp contrasts in the depolarization profile between a layer of spherical particles and a layer of non-spherical particles. Although it is not as obvious as ground-based lidar observations, it is likely that we can identify cloud phase not only for a uniform cloud layer, but also for overlapping cloud layers where one layer contains ice and the other water droplets.     

Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.     

The structure of oxygen on Cu(1 0 0) at low and high coverages

The local adsorption structure of oxygen on Cu(1 0 0) has been studied using O 1s scanned-energy mode photoelectron diffraction. A detailed quantitative determination of the structure of the 0.5 ML (√2×2√2)R45°-O ordered phase confirms the missing-row character of this reconstruction and agrees well with earlier structural determinations of this phase by other methods, the adsorbed O atoms lying only approximately 0.1 Å above the outermost Cu layer. At much lower coverages, the results indicate that the O atoms adopt unreconstructed hollow sites at a significantly larger O–Cu layer spacing, but with some form of local disorder. The best fit to these data is achieved with a two-site model involving O atoms at Cu–O layer spacings of 0.41 and 0.70 Å in hollow sites; these two sites (also implied by an earlier electron-energy-loss study) are proposed to be associated with edge and centre positions in very small c(2×2) domains as seen in a recent scanning tunnelling microscopy investigation.     

Layer-by-layer assembly of pH-responsive, compositionally controlled (co)polyelectrolytes synthesized via RAFT

Homo- and block copolyelectrolytes that have well-defined structures and are responsive to pH were synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization and employed to produce layer-by-layer (LBL) films. Acrylamido monomers with carboxylate, sulfonate, and amine functionality were utilized to provide both strong and weak homopolyelectrolytes and mixed strong/weak copolyelectrolyte systems. Multilayer films were prepared under specified conditions of pH and ionic strength and analyzed via atomic force microscopy and ellipsometry to study the effects of changes in the local molecular environment on film morphologies. The pH responsiveness and integrity of the multilayer assemblies were investigated by exposing films to solutions of varying pH in a fluid cell and performing in situ AFM analysis. The multilayer dimensions, morphology, and integrity were found to depend on the molecular architecture of the polyelectrolytes, with changes in segmental type and repeating unit distribution producing dramatic differences in film characteristics. These results suggest the possibility of producing LBL assemblies of precisely controlled dimensions and properties by specifically tailoring copolymer structure. To our knowledge, this is the first report of LBL assembly of RAFT-synthesized homo- and copolyelectrolyte multilayer complexes.     

Adsorption to metal oxides of the Pseudomonas aeruginosa siderophore pyoverdine and implications for bacterial biofilm formation on metals

The initiation of biofilm formation is poorly understood, and in particular, the contribution of chemical bond formation between bacterial cells and metal surfaces has received little attention. We have previously used in situ infrared spectroscopy to show, during the initial stages of Pseudomonas aeruginosa biofilm formation, the formation of coordinate covalent bonds between titanium dioxide particle films and pyoverdine, a mixed catecholate and hydroxamate siderophore. Here we show using infrared spectroscopy that pyoverdine can also form covalent bonds with particle films of Fe2O3, CrOOH, and AlOOH. Adsorption to the metal oxides through the catechol-like 2,3-diamino-6,7-dihydroxyquinoline part of pyoverdine was most evident in the infrared spectrum of the adsorbed pyoverdine molecule. Weaker infrared absorption bands that are consistent with the hydroxamic acids of pyoverdine binding covalently to TiO2, Fe2O3, and AlOOH surfaces were also observed. The adsorption of pyoverdine to TiO2 and Fe2O3 surfaces showed a pH dependence that is indicative of the dominance of the catechol-like ligand of pyoverdine. Infrared absorption bands were also evident for pyoverdine associated with the cells of P. aeruginosa on TiO2 and Fe2O3 surfaces and were notably absent for genetically modified cells unable to synthesize or bind pyoverdine at the cell surface. These studies confirm the generality of pyoverdine-metal bond formation and suggest a wider involvement of siderophores in bacterial biofilm initiation on metals.     

Investigation of the high-p<Subscript>T</Subscript> strange baryon anomalies at RHIC

Results from RHIC have shown that there is an enhanced baryon/meson ratio in the intermediate transverse momentum range (2<p_T<6 GeV/c) in Au+Au collisions at both  =130 and 200 GeV. This was initially demonstrated by measurements of the p̄/π^- ratio which was then extended in p_T by the Λ/K⁰ _S ratio. The data were successfully described by models utilising different hadronization mechanisms: those having recombination of quarks and others having an interplay between flow, jet quenching and incorporating baryon junction loops. The strange particle data from the first Au+Au run at  =200 GeV gave tantalising hints that the observed enhancement of baryons compared to mesons was diminished by a p_T of 6 GeV/c, but a lack of statistics in this range made a definitive statement impossible. Here we present an extended analysis of identified strange baryons and mesons in Au+Au collisions at  =200 GeV using data obtained by the STAR experiment from the 2004 running period. The increase in statistics extends the measurement of Λ hyperons out to at least 7 GeV/c and K⁰ _S mesons out to 9 GeV/c. This data allows us to place limits on the range where in-vacuum fragmentation functions are applicable and the effect of baryon dominance is reduced. We also discuss the prospects for making these measurements using multiply-strange baryons and mesons (Ω and ϕ).