Oxabicyclo[3.2.1]octane derivatives as highly reactive dienophiles: synthesis of bicyclo[5.n.0] systems

[reaction: see text] We have developed highly versatile, homochiral oxabicyclo[3.2.1]octadiene building blocks for the synthesis of natural products. We have found that these bridged alkenes undergo exceptionally facile Diels-Alder reactions and react faster than several well studied bicyclo[2.2.1]heptene dienophiles. The reaction proceeds with high levels of stereochemical control and in very good to excellent yields, providing access to bicyclo[5.4.0]undecane and bicyclo[5.3.0]decane systems. This reactivity is attributed to strain and homoconjugation effects.     

Investigating 3He diffusion NMR in the lungs using finite difference simulations and in vivo PGSE experiments

Finite difference simulations have been used to model (3)He gas diffusion in simulated lung tissue. The technique has the advantage that a wide range of structural models and diffusion-sensitizing gradient waveforms can be investigated, for which analytical methods would otherwise be virtually impossible. Results from simulations and in vivo pulsed-gradient-spin-echo (PGSE) experiments show that the apparent diffusion coefficient (ADC) is a function of diffusion time and gradient strength, and suggests diffusion is locally anisotropic. The simulations have been compared to recent work on an analytical model that characterizes lung tissue as a series of independent cylinders. The results presented may have clinical implications for (3)He ADC measurements in assessing lung diseases such as chronic-obstructive-pulmonary-disease.     

Lipopeptides incorporated into supported phospholipid monolayers have high specific activity at low incorporation levels

The ability to present cell adhesion molecule (CAM) ligands in controlled amounts on a culture surface would greatly facilitate the control of cell growth and differentiation. Supported lipid monolayer/bilayer systems have previously been developed that allow for presentation of CAM ligands for cell interaction; however, these systems have employed peptide loadings much higher than those used in poly(ethylene glycol) (PEG)-based immobilization systems. We report the development of synthetic methods that can be used for the efficient and versatile creation of many linear and cyclic lipid-linked peptide moieties. Using RGD-based peptides for the alpha5beta1 integrin as a model system, we have demonstrated that these lipopeptides support efficient cell binding and spreading at CAM ligand loadings as low as 0.1 mol %, which is well below that previously reported for supported lipid systems. Engineered lipopeptide-based surfaces offer unique presentation options not possible with other immobilization systems, and the high activity at low loadings we have shown here may be extremely useful in presenting multiple CAM ligands for studying cell growth, differentiation, and signaling.     

The synthesis of symmetrical bis-1,2,5-thiadiazole ligands

We have been engaged in a search for coordination catalysts for the copolymerization of polar monomers (such as vinyl chloride and vinyl acetate) with ethylene. We have been investigating complexes of late transition metals with heterocyclic ligands. In this report we describe the synthesis of a symmetrical bis-thiadiazole. We have characterized one of the intermediates using single crystal X-ray diffraction. Several unsuccessful approaches toward 1 are also described, which shed light on some of the unique chemistry of thiadiazoles.     

Hodge Theory and Geometry

Hodge theory for a smooth algebraic curve includes both theHodge structure (period matrix) on cohomology and the use ofthat Hodge structure to study the geometry of the curve, viathe Jacobian variety. Hodge extended the theory of the periodmatrix to smooth algebraic varieties of any dimension, definingin general a Hodge structure on the cohomology of the variety.He gave a few applications to the geometry of the variety, butthese did not attain the richness of the Jacobian variety. Inrecent years, Hodge theory has been successfully extended toarbitrary varieties, and to families of varieties. In this expositorypaper, some of these developments are reviewed, with specialemphasis on instances where these extensions can be used tostudy the geometry – especially the algebraic cycles –on the variety. 2000 Mathematics Subject Classification 14CDFJ.     

Quantum capping potentials with point charges: a simple QM/MM approach for the calculation of large-molecule NMR shielding tensors

A simple quantum-mechanics/molecular-mechanics (QM/MM) approach for calculating NMR shielding tensors (sigma) is presented. The method involves capping the QM region with quantum capping potentials (QCPs) and representing the MM region with point charges. Test calculations on simple systems without MM charges show that calculated sigma values improve relative to the full QM results with increasing distance between the capped bond and chromophore. Calculations on the histidine amino acid and cytosine monophosphate (CMP) nucleic acid show that the use of QCPs with point charges result in mean errors in the isotropic component of sigma that are less than 1.6 ppm. The results also reveal that, contrary to previous work, the explicit effect of point charges on sigma through coupling with gauge factors, as in the gauge including atomic orbital approach, is minimal for the CMP molecule. The present QM/MM approach for calculating sigma is easy to apply and requires no code modification.     

Accurate mass measurement and tandem mass spectrometry of intact globin chains identify the low proportion variant hemoglobin Lepore-Boston-Washington from the blood of a heterozygote

Within a mixture of proteins, minor polymorphic components are difficult to identify using a conventional proteomic approach. Their identification generally requires multi-dimensional separation steps, before or after proteolytic cleavage, followed by sequence analysis of the proteolytic products. In this study, we investigated the potential of tandem mass spectrometry for protein characterization by identifying the delta-beta hybrid human hemoglobin variant Lepore-Boston-Washington using electrospray ionization tandem mass spectrometry. Hemoglobin Lepore-Boston-Washington occurs mainly in heterozygotes, where it comprises approximately 10% of the total non-alpha-chains, the dominant non-alpha-chain being the normal beta (approximately 90%). Furthermore, Hemoglobin Lepore-Boston-Washington has an average molecular mass (15,865.23 Da) that is only 2 Da lower than that of the normal beta-chain (15,867.24 Da). Consequently, it cannot be resolved from the normal beta-chain by mass spectrometry. Here we show how Hemoglobin Lepore-Boston-Washington was identified directly from the diluted blood of a heterozygote by analyzing the product ions from the Lepore-Boston-Washington and normal beta-chain ions without prior separation of the individual chains. This study shows the potential of the tandem mass spectrometry for identifying a minor component in an unseparated mixture of proteins.     

Sweet success: Ionic liquids derived from non-nutritive sweeteners

The anions of the sweeteners saccharin and acesulfame form ionic liquids when paired with a variety of organic cations.     

Rotational resonance NMR: separation of dipolar coupling and zero quantum relaxation

The solid state NMR technique of rotational resonance (R2) has been used extensively to measure distances approaching 5-6 A between 13C nuclei in a variety of compounds including amyloidogenic peptides and membrane proteins. The accuracy of the distance information extracted from the time-dependent spin dynamics at R2 is often limited by the accuracy with which the relevant zero-quantum lineshape parameters are estimated. Here we demonstrate that measurement of spinning frequency dependent magnetization exchange dynamics provides data from which both distance and zero-quantum relaxation parameters can be extracted independently. In addition to providing more accurate distance information, this technique allows examination of the zero-quantum lineshape, which can indicate the presence of correlated relaxation or chemical shift distributions between dipolar-coupled sites. With this approach we have separated the contribution of dipolar couplings and zero quantum relaxation to R2 exchange curves. Thus, we have significantly improved the accuracy of the measurement of the intramolecular, internuclear distances between a pair of 13C's in two model compounds (N-acetyl-D,L-valine and glycylglycine.HCl) that lie in the distance range 4.6-4.7 A.