Molecular recognition at the active site of catechol-O-methyltransferase (COMT): adenine replacements in bisubstrate inhibitors

L-Dopa, the standard therapeutic for Parkinson's disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrüggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar IC(50) values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and Mg(2+) confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group.     

Vitrifying star-shaped liquid crystals: synthesis and application in cholesteric polymer networks

In this paper, the formation of glass-forming reactive mesogens, that do not crystallize upon cooling, but vitrify and form supercooled LC phases, is described. These molecules exhibit broad range LC phases and enable us to carry out photopolymerization in a broad range of temperatures. From such reactive mesogens densely crosslinked networks in which the liquid crystalline order is permanently fixed are formed by photopolymerization. For this purpose eight novel low molecular mass LC materials with photopolymerizable acrylate groups have been synthesized and the detailed experimental procedures are given. The molecules have a star-shaped topology with three and four arms. The mesogenic units were varied by the addition of lateral groups in different positions. Comparing the twin molecules which we have described before with the novel three- and four-armed stars, we found that the supercooled LC phase in the three-armed stars has a stability superior to that in both twin molecules and four-armed stars. In the three-armed star triple-4 with a suitable substituent pattern, the supercooled nematic phase is stable at room temperature for at least nine months. Photo-DSC experiments show that the final conversion after 10 min of UV-irradiation for the threearmed star molecule triple-4 is as high as for the smaller molecules twin-4 and mono-4 over the whole temperature range. Doped with a suitable chiral molecule the novel nematics formed cholesteric phases which were used to make cholesteric polymer networks by photopolymerization.     

1,6-Anhydrofurawosen,XX.1 Synthese von Zuei 1,6:2,3-Dianhydrohexofuranosen Durch Payne-Oxidation von 1,6-Anhydro-5-O-Benzoyl-2,3-Didesoxy-β-D-Erythro- uno -α-L-Threo-Hex-2-Enofuranose

Abstract

The 5-0-benzoyl derivatives 3 and 4 derived from 1,6-anhydro-β-D-mannpfuranose and -α-L-gulofuranose are suitable educts for the preparation of the isomeric olefins 7 and 8 by Corey-Winter elimination via the thionocarbonates 5 and 6, respectively. 8 was prepared in higher yields also from 5-α-Benzoyl-1,6-anhydro-α-L-talofuranose (14) via 15. Payne oxidation of the unsaturated compounds 7 and 8 gave the exo epoxides 9 and 10 with D-allo and L-talo configuration.     

SModelS: a tool for interpreting simplified-model results from the LHC and its application to supersymmetry

We present a general procedure to decompose Beyond the Standard Model (BSM) collider signatures presenting a $\mathbb {Z}_2$ symmetry into Simplified Model Spectrum (SMS) topologies. Our method provides a way to cast BSM predictions for the LHC in a model independent framework, which can be directly confronted with the relevant experimental constraints. Our concrete implementation currently focusses on supersymmetry searches with missing energy, for which a large variety of SMS results from ATLAS and CMS are available. As show-case examples we apply our procedure to two scans of the minimal supersymmetric standard model. We discuss how the SMS limits constrain various particle masses and which regions of parameter space remain unchallenged by the current SMS interpretations of the LHC results.     

Size effect of gold nanoparticles supported on carbon nanotube as catalysts in selected organic reactions

Carbon nanotube-supported gold nanoparticles of different sizes (diameter of 3 or 20 nm) were evaluated as catalysts in four selected organic transformations. The nanohybrids were shown to efficiently catalyze the investigated reactions, regardless of the size of the supported gold nanoparticles. However, some differences were observed as regards turnover frequency values although size effect turned out to be less significant when only gold surface atoms were considered.     

Automated quantum mechanical total line shape fitting model for quantitative NMR-based profiling of human serum metabolites

An automated quantum mechanical total line shape (QMTLS) fitting model was implemented for quantitative nuclear magnetic resonance (NMR)-based profiling of 42 metabolites in ultrafiltrated human serum samples. Each metabolite was described by a set of chemical shifts, J-couplings, and line widths. These parameters were optimized for each metabolite in each sample by iteratively minimizing the difference between the calculated and the experimental spectrum. In total, 92.0 to 98.1 % of the signal intensities in the experimental spectrum could be explained by the calculated spectrum. The model was validated by comparison to signal integration of metabolites with isolated signals and by means of standard additions. Metabolites present at average concentration higher than 50 μM were quantified with average absolute relative error less than 10 % when using different initial parameters for the fitting procedure. Furthermore, the biological applicability of the QMTLS model was demonstrated on 287 samples from an intervention study in 37 human volunteers undergoing an exercise challenge. Our automated QMTLS model was able to cope with the large dynamic range of metabolite concentrations in serum and proved to be suitable for high-throughput analysis.

Self-assembled zinc chlorin rod antennae powered by peripheral light-harvesting chromophores

The multichromophoric dyads 1, 2 and triad 3 have been synthesized by coupling of the appropriately functionalized chlorin derivative with naphthalene diimide dyes through esterification, and subsequent metalation of the chlorin center with zinc acetate. The self-assembly properties of naphthalene diimide (NDI)-zinc chlorin (ZnChl) dyads 1, 2 and triad 3 have been studied in nonpolar, aprotic solvents by UV-vis, CD, and steady-state emission spectroscopy, revealing formation of rod-like structures by noncovalent interactions of zinc chlorin units, while the appended naphthalene diimide dyes do not aggregate at the periphery of the rod antennae. In all these systems, photoexcitation of the enveloping naphthalene diimides at 540 and 620 nm, respectively, leads to highly efficient energy-transfer processes (FRET; phiET > or = 0.99) to the inner zinc chlorin backbone, as explored by time-resolved fluorescence spectroscopy on the picosecond time scale. The efficiencies of zinc chlorin rod aggregates for the harvesting of solar light are markedly increased from 26% for dyad 2 up to 63% for triad 3, compared to the LH capacity of the monochromophoric aggregates of model system ZnChl 6a. Thus, with the self-assembled zinc chlorin rod antenna based on triad 3, a highly efficient artificial LH system has been achieved.     

Supramolecular self-assembly of amphiphiles on carbon nanotubes: a versatile strategy for the construction of CNT/metal nanohybrids, application to electrocatalysis

Homogeneous coating of carbon nanotubes with metallic nanoparticles was achieved using supramolecular auto-organization of amphiphilic molecules as template. The resulting Pd nanoparticles/carbon nanotube nanohybrids were then evaluated in electrocatalysis experiments, showing superior activity in ethanol oxidation compared to analogous systems.