Method for the synthesis of multi-epitopic Streptococcus pyogenes lipopeptide vaccines using native chemical ligation

The aim of this study was to investigate methods for the synthesis of highly pure, well-characterized analogues of the lipid core peptide (LCP) system. Difficulties synthesizing and purifying conventional LCP systems have led to the requirement for a technique to produce highly pure, LCP-based vaccines for potential use in human clinical trials. The current study describes methods for the attachment of lipophilic adjuvants onto multi-epitopic peptide vaccines. Described is the synthesis, using native chemical ligation, of a highly pure, tri-epitopic, group A streptococcal (GAS) lipopeptide vaccine candidate. Intranasal immunization of the described tri-epitopic GAS lipopeptide with the mucosal adjuvant cholera toxin B subunit induced high serum IgG antibody titers specific for each of the incorporated peptide epitopes.     

An efficient one-pot construction of substituted pyrimidinones

A concise, scaleable synthesis of building block 10 for p38 kinase inhibitor B is described. The key step is the one-pot construction of 5-aryl-3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one 4 from arylacetic acid ethyl ester 1. Subsequent hydrolysis of the thiomethyl group to the hydroxy group and chlorination provided the key intermediate, 2-chloro-3-methyl-6-pyridin-4-yl-5-aryl-3H-pyrimidin-4-one 10. This class of reactive building blocks enabled the rapid evaluation of a variety of side chains at the 2-position of the pyrimidinone in SAR studies of inhibitors of p38 MAP kinase.     

Cyclic semipeptoids: peptoid-organic hybrid macrocycles

[structure: see text] Cyclic semipeptoids 1 and 2 represent constrained, secondary structure mimics where the R(1) and R(2) side chains correspond to those of amino acids. Solid-phase syntheses and conformational analyses of these compounds are described.     

New lipophilic 3-hydroxy-4-pyridinonate iron(III) complexes: synthesis and EXAFS structural characterisation

New tris-iron(III) chelates of 3-hydroxy-4-pyridinone ligands derived from maltol (3-hydroxy-2-methyl-4-pyrone) or ethylmaltol (2-ethyl-3-hydroxy-4-pyrone), including a variety of N-aryl (phenyl, 4'-tolyl, 4'-(n-butyl)phenyl, 4'-(n-hexyl)phenyl) and N-benzyl (4'-methylbenzyl, 4'-fluorobenzyl and 4'-(trifluoromethyl)benzylamine) substituents on the nitrogen atom of the pyridinone ring, have been prepared. Characterization by C,H,N elemental analysis and thermogravimetric measurements indicates that most of the complexes are obtained as hydrates of general formula ML3.xH2O. Structural characterization of these difficult to crystallize lipophilic complexes has been achieved by EXAFS spectroscopy. Solutions of iron(III) complexes of maltol, ethylmaltol, 1,2-dimethyl-3-hydroxy-4-pyridinone and 1-phenyl-2-methyl-3-hydroxy-4-pyridinone in methanol-water mixtures were also examined by EXAFS. Distances from the central atom to ligand atoms, within 6 A of the metal, have been determined in the solid and solution samples and the results show that the structure observed in the powder is maintained in solution. The local structure around the metal centre, bond distances and bond angles, does not change significantly with variable lipophilicity, thus indicating that ligands may be tailored according to specific needs without altering their chelation properties. EXAFS data analysis for this set of tris-iron(III) compounds illustrates the important contribution of both intra-ligand and inter-ligand multiple scattering pathways through the metal centre to a peak observed in the FT spectrum at twice the metal ligand distance (approximately 4 A). The present results demonstrate that EXAFS features at twice the metal-ligand distance are valuable in the assignment of molecular geometry and that location of hydration water molecules, by EXAFS analysis, is limited by the geometry of the complexes, in particular for those in which ligands containing phenyl rings are present.     

Cognitive, cardiac, and physiological safety studies in ultra high field magnetic resonance imaging

A systematic analysis of the effect of an 8.0 tesla static magnetic field on physiological and/or cognitive function is presented in the normal volunteer and in the swine. A study of ten human subjects revealed no evidence of detectable changes in body temperature, heart rate, respiratory rate, systolic pressure, and diastolic blood pressure after 1 hour of exposure. In addition, no cognitive changes were detected. Important ECG changes were noted which were related both to the position of the subject in the magnet and to the absolute strength of the magnetic field. As such, the ECG tracing at 8 tesla was not diagnostically useful. Nonetheless, all subjects exhibited normal ECG readings both before and following exposure to the 8 tesla field. Cardiac function was also examined in detail in the swine. No significant changes in body temperature, heart rate, left ventricular pressure, left ventricular end diastollic pressure, time rate of change of left ventricular pressure, myocardial stiffness index, cardiac output, systolic volume, troponin, and potassium levels could be detected following 3 h of exposure to a field strength of 8.0 tesla. It is concluded that no short term cardiac or cognitive effects are observed following significant exposure to a magnetic field of up to 8.0 tesla.     

Instability of the Kolmogorov flow in a soap film

We examine the instability of a soap film flow driven by a time-independent force that is spatially periodic in the direction perpendicular to the forcing (Kolmogorov flow). Linear stability analysis of an idealized model of this flow predicts a critical Reynolds number R(c) is approximately equal to the square root of 2. In our soap film experiment, we find a critical value R(c) is approximately equal to 70. This discrepancy can be ascribed to frictional effects from viscous coupling of gas to the film, which is neglected in the idealized model. The kinematic viscosity of the surrounding gas and the thickness of gas layers on each side of the soap film are varied in the experiments to better understand these frictional effects. Our observations indicate that flow in the soap film cannot be decoupled from flow in the surrounding gas.     

Characterization and use of a Raman liquid-core waveguide sensor using preconcentration principles

A novel Raman sensor using a liquid-core optical waveguide is reported, implementing a Teflon-AF 2400 tube filled with water. An aqueous analyte mixture of benzene, toluene and p-xylene was introduced using a 1000 μl sample loop to the liquid-core waveguide (LCW) sensor and the analytes were preconcentrated on the inside surface of the waveguide tubing. The analytes were then eluted from the waveguide using an acetonitrile-water solvent mixture injected via a 30 μl eluting solvent loop. The preconcentration factor was experimentally determined to be 14-fold, in reasonable agreement with the theoretical preconcentration factor of 33 based upon the sample volume to elution volume ratio. Raman spectra of benzene, toluene and p-xylene were obtained during elution. It was found that analytically useful Raman signals for benzene, toluene and p-xylene were obtained at 992, 1004 and 1206 cm⁻¹, respectively. The relative standard deviation of the method was 3% for three replicate measurements. The limit of detection (LOD) was determined to be 730 ppb (parts per billion by volume) for benzene, exceptional for a system that does not resort to surface enhancement or resonance Raman approaches. The Raman spectra of these test analytes were evaluated for qualitative and quantitative analysis utility.     

Cytotoxic 8,9-secokaurane diterpenes from a New Zealand liverwort, Lepidolaena taylorii

The main cytotoxic compound from the liverwort Lepidolaena taylorii is the known ent-8,9-seco-7-hydroxy-kaura-8(14),16-dien-9,15-dione1. The relative stereochemistry of a new cytotoxic compound, 16,17-dihydro derivative 2, was supported by molecular modelling. Another new cytotoxic compound was identified as 8,14-epoxide 3 by preparation from 1. These compounds showed differential cytotoxic activity against human tumor cell lines.     

Oxidative induction of beta-turn conformations in cyclic peptidomimetics: conformational analyses as indicators of configuration

Solid-phase syntheses of the cyclic peptidomimetics 1-4 were performed. Sulfide 1 and sulfoxide 3 did not tend to exist in beta-turn conformations in solution, but the sulfone 2 and the epimeric sulfoxide 4 did. The assignment of configuration of the sulfoxides is based on the conformational analyses.