Determination of the absolute configuration of a chiral oxadiazol-3-one calcium channel blocker, resolved using chiral chromatography, via concerted density functional theory calculations of its vibrational circular dichroism, electronic circular dichroism, and optical rotation

The chiral oxadiazol-3-one 2 has recently been shown to exhibit myocardial calcium entry channel blocking activity, substantially higher than that of diltiazem. To determine the enantioselectivity of this activity, the enantiomers of 2 have been resolved using chiral chromatography. The absolute configuration (AC) of 2 has been determined by comparison of density functional theory (DFT) calculations of its vibrational circular dichroism (VCD) spectrum, electronic circular dichroism (ECD) spectrum, and optical rotation (OR) to experimental VCD, ECD, and OR data. All three chiroptical properties yield identical ACs; the AC of 2 is unambiguously determined to be S(+)/R(-).     

Rates and mechanisms of conversion of ice nanocrystals to hydrates of HCl and HBr: acid diffusion in the ionic hydrates

This FTIR study focuses on solid-state chemistry associated with formation and interconversion of the ionic HX (X = Cl, Br) hydrates. Kinetic data are reported for conversions of ice nanocrystal arrays exposed to the saturation pressure of the acids in the 110 approximately 125 K range. The product is amorphous acid dihydrate in the case of HBr, and amorphous monohydrate for HCl. The rate-determining step is identified as HX diffusion through the hydrate product crust toward the interfacial reaction zone, rather than diffusion through ice, as commonly believed. Slowing of the conversion process is thus observed with increasing thickness of the crust. The diffusion coefficient (D(e)) and activation energy values for HX diffusion through the hydrates were evaluated with the help of the shrinking-core model. Hydrate crystallization occurs as a separate step, upon heating above 130 K. Subsequently, rates of reversible transitions between crystal di- and monohydrates were observed upon exposure to acid vapor and acid evacuation. In conversion from di- to monohydrate, the rate slows after fast formation of several layers; subsequently, diffusion through the product crust appears to be the rate-controlling step. The activation energy for HBr diffusion through crystal dihydrate is found to be significantly higher than that for the amorphous analogue. Conjecture is offered for a molecular mechanism of HX transport through the crystal hydrate, based on (i) spectroscopic/computational evidence for the presence of molecular HX bonded to X(-) in each of the ionic hydrate phases and (ii) the relative E(a) values found for HBr and HCl diffusion. Monte Carlo modeling suggests acid transport to the reaction zone along boundaries between "nanocrystallites" generated by multiple hydrate nucleation events at the particle surfaces. The reverse conversion, of crystalline monohydrate particles to the dihydrate phase, as well as dihydrate to trihydrate, displays nearly constant rate throughout the particle conversion; suggesting desorption of HX from the particle surface as the rate-limiting factor. Like for D(e), the activation energies for desorption were found to be approximately 20% greater for HCl than HBr for related hydrate phases.     

X-ray scattering study of the effect of hydration on the cross-beta structure of amyloid fibrils

We have investigated the effect of sample hydration on the wide-angle X-ray scattering patterns of amyloid fibrils from two different sources, hen egg white lysozyme (HEWL) and an 11-residue peptide taken from the sequence of transthyretin (TTR105-115). Both samples show an inter-strand reflection at 4.7 A and an inter-sheet reflection which occurs at 8.8 and approximately 10 A for TTR105-115 and HEWL fibrils, respectively. The positions, widths, and relative intensities of these reflections are conserved in patterns obtained from dried stalks and hydrated samples over a range of fibril concentrations. In 2D scattering patterns obtained from flow-aligned hydrated samples, the inter-strand and inter-sheet reflections showed, respectively, axial and equatorial alignment relative to the fibril axis, characteristic of the cross-beta structure. Our results show that the cross-beta structure of the fibrils is not a product of the dehydrating conditions typically employed to produce aligned samples, but is conserved in individual fibrils in hydrated samples under dilute conditions comparable to those associated with other biophysical and spectroscopic techniques. This suggests a structure consisting of a stack of two or more sheets whose interfaces are inaccessible to bulk water.