Structure-based design of estrogen receptor-beta selective ligands

We present the structure-based optimization of a series of estrogen receptor-beta (ERbeta) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERalpha and ERbeta are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERbeta over ERalpha. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERbeta relative to ERalpha when measured using a competitive radioligand binding assay.     

Room-temperature,excitation wavelength-dependent fluorescence at surfaces: a potential method for studying the micro-heterogeneity of surface environments

The fluorescence maxima at room temperature of 5-dimethylamino-1-naphthalenesulfonamide (dansylamide) groups covalently attached to the surface of silica particles in dry form and slurried in acetonitrile exhibit varying degrees of dependence upon excitation wavelength. This dependence is attributed to the micro-heterogeneity of the surface itself and varying degrees of accessibility of the fluorophore to solvent. The observed effect may prove useful in investigations of surface environment heterogeneity at the molecular level.     

Hydrolysis of mustard derivatives. remarkable tosylate/chloride and chloride/dinitrophenolate rate ratios

Comparisons of leaving group solvolytic rate ratios for mustard derivatives with other substrate types reveals unusual OTs/Cl and Cl/ODNP rate ratios for mustards. A very tight transition state is suggested.     

Solid‐state NMR spectroscopy of Pb‐rich apatite

Pb‐containing hydroxylapatite phases synthesized under aqueous conditions were investigated by X‐ray diffraction and solid‐state nuclear magnetic resonance (NMR) techniques to determine the Pb, Ca distribution. ³¹P and ¹H magic‐angle spinning (MAS) NMR results indicate slight shifts of the isotropic chemical shift with increased Ca content and complex lineshapes at compositions with near equal amounts of Ca and Pb. ³¹P{²⁰⁷Pb} and ¹H{²⁰⁷Pb} rotational‐echo double resonance (REDOR) results for intermediate compositions show that resolved spectral features cannot be assigned simply in terms of local Ca, Pb configurations or coexisting phases. ²⁰⁷Pb MAS NMR spectra are easily obtained for these materials and contain well‐resolved resonances for crystallographically unique A1 and A2 Pb sites. Splitting of the A1 and A2 ²⁰⁷Pb resonances for pure hydroxyl‐pyromorphite (Pb₁₀(PO₄)₆(OH)₂) compared to natural pyromorphite (Pb₅(PO₄)₃Cl) suggests symmetry reduced from hexagonal. We find that ²⁰⁷Pb{¹H} CP/MAS NMR is impractical in Pb‐rich hydroxylapatites due to fast ²⁰⁷Pb relaxation. Copyright © 2009 John Wiley & Sons, Ltd.     

Discrete network models of interacting nephrons

The kidney is one of the major organs involved in whole-body homeostasis, and exhibits many of the properties of a complex system. The functional unit of the kidney is the nephron, a complex, segmented tube into which blood plasma is filtered and its composition adjusted. Although the behaviour of individual nephrons can fluctuate widely and even chaotically, the behaviour of the kidney remains stable.In this paper, we investigate how the filtration rate of a multi-nephron system is affected by interactions between nephrons. We introduce a discrete-time multi-nephron network model. The tubular mechanisms that have the greatest effect on filtration rate are the transport of sodium and water, consequently our model attempts to capture these mechanisms. Multi-nephron systems also incorporate two competing coupling mechanisms–vascular and hemodynamic–that enforce in-phase and anti-phase synchronisations respectively. Using a two-nephron model, we demonstrate how changing the strength of the hemodynamic coupling mechanism and changing the arterial blood pressure have equivalent effects on the system. The same two-nephron system is then used to demonstrate the interactions that arise between the two coupling mechanisms. We conclude by arguing that our approach is scalable to large numbers of nephrons, based on the performance characteristics of the model.     

A novel class of azatricyclononanes: pentasubstituted cyclopropanes from an uncatalysed reaction

The direct and versatile stereoselective synthesis of a novel class of cyclopropyl derivatives of pyroglutamic acid is reported, using substituted diaryldiazo compounds. The course of the reaction has been investigated, and yields of substituted fluorenylcyclopropanes are greater than those of diphenylmethylcyclopropane analogues.