No abstract

Amyloid is a term for extracellular protein fibril deposits that have characteristic tinctorial and structural properties. Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction. Heparan sulphate interacts with the AA amyloid precursor and the beta-peptide of Alzheimer's amyloid, imparting characteristic secondary and tertiary amyloid structural features. These observations suggest that molecules that interfere with this interaction may prevent or arrest amyloidogenesis. We synthesized low-molecular-weight (135-1,000) anionic sulphonate or sulphate compounds. When administered orally, these compounds substantially reduced murine splenic AA amyloid progression. They also interfered with heparan sulphate-stimulated beta-peptide fibril aggregation in vitro.

We report a comprehensive variable-temperature solid-state 17 O NMR study of three 17 O-labeled crystalline sulfonic acids: 2-aminoethane-1-sulfonic acid (taurine, T), 3-aminopropane-1-sulfonic acid (homotaurine, HT), and 4-aminobutane-1-sulfonic acid (ABSA − groups in these compounds undergo a 3-fold rotational jump mechanism but also extracted the corresponding jump rates (10 2 −10 5 s −1 ) and the associated activation energies (E a ) for this process (E a =4 8± 7, 42 ± 3, and 45 ± 1 kJ mol −1 for T, HT, and ABSA, respectively). This is the first time that SO 3 − rotational dynamics have been directly probed by solid-state 17 O NMR. Using the experimental activation energies for SO 3 − rotation, we were able to evaluate quantitatively the total hydrogen bond energy that each SO 3 − group is involved in within the crystal lattice. The activation energies also correlate with calculated rotational energy barriers. This work provides a clear illustration of the utility of solid-state 17 O NMR in quantifying dynamic processes occurring in organic solids. Similar studies applied to selectively 17 O-labeled biomolecules would appear to be very feasible.

We report solid-state NMR characterization of the 17 O quadrupole coupling (QC) and chemical shift (CS) tensors in five site-specifically 17 O-labeled samples of salicylic acid and o-acetylsalicylic acid (Aspirin). High-quality 17 O NMR spectra were obtained for these important pharmaceutical compounds under both static and magic angle spinning (MAS) conditions at two magnetic fields, 14.0 and 21.1 T. A total of 14 17 O QC and CS tensors were experimentally determined for the seven oxygen sites in salicylic acid and Aspirin. Although both salicylic acid and Aspirin form hydrogen bonded cyclic dimers in the solid state, we found that the potential curves for the concerted double proton transfer in these two compounds are significantly different. In particular, while the double-well potential curve in Aspirin is nearly symmetrical, it is highly asymmetrical in salicylic acid. This difference results in quite different temperature dependencies in 17 O MAS spectra of the two compounds. A careful analysis of variabletemperature 17 O MAS NMR spectra of Aspirin allowed us to obtain the energy asymmetry (ΔE) of the double-well potential, ΔE = 3.0 ± 0.5 kJ/mol. We were also able to determine a lower limit of ΔE for salicylic acid, ΔE > 10 kJ/mol. These asymmetrical features in potential energy curves were confirmed by plane-wave DFT computations, which yielded ΔE = 3.7 and 17.8 kJ/mol for Aspirin and salicylic acid, respectively. To complement the solid-state 17 O NMR data, we also obtained solid-state 1 H and 13 C NMR spectra for salicylic acid and Aspirin. Using experimental NMR parameters obtained for all magnetic nuclei present in salicylic acid and Aspirin, we found that plane-wave DFT computations can produce highly accurate NMR parameters in welldefined crystalline organic compounds.

We demonstrate that high-quality solid-state 17O (I = 5/2) NMR spectra can be successfully obtained for paramagnetic coordination compounds in which oxygen atoms are directly bonded to the paramagnetic metal centers. For complexes containing V(III) (S = 1), Cu(II) (S = 1/2), and Mn(III) (S = 2) metal centers, the 17O isotropic paramagnetic shifts were found to span a range of more than 10000 ppm. In several cases, high-resolution 17O NMR spectra were recorded under very fast magic-angle spinning (MAS) conditions at 21.1 T. Quantum chemical computations using density functional theory (DFT) qualitatively reproduced the experimental 17O hyperfine shift tensors.