Pyrimidine acyclo-C-nucleosides by ring transformations of 2-formyl-L-arabinal

The protected 2-formyl-L-arabinal 2 reacted with thiourea and cyanamide in the presence of sodium hydride to afford via ring transformations the 5-[1R,2S-1,2- bis(benzyloxy)-3-hydroxypropyl]-1,2-dihydropyrimidines 3 and 4, respectively. Similarly, treatment of 2 with 3-amino-2H-1,2,4-triazole yielded 6-[1R,2S-1,2- bis(benzyloxy)-3-hydroxypropyl][1,2,4]-triazolo[1,5-a]pyrimidine (5).     

Pore structural characterization of monolithic silica columns by inverse size-exclusion chromatography

In this work, a parallel pore model (PPM) and a pore network model (PNM) are developed to provide a state-of-art method for the calculation of several characteristic pore structural parameters from inverse size-exclusion chromatography (ISEC) experiments. The proposed PPM and PNM could be applicable to both monoliths and columns packed with porous particles. The PPM and PNM proposed in this work are able to predict the existence of the second inflection point in the experimental exclusion curve that has been observed for monolithic materials by accounting for volume partitioning of the polymer standards in the macropores of the column. The appearance and prominence of the second inflection point in the exclusion curve is determined to depend strongly on the void fraction of the macropores (flow-through pores), (b) the nominal diameter of the macropores, and (c) the radius of gyration of the largest polymer standard employed in the determination of the experimental ISEC exclusion curve. The conditions that dictate the appearance and prominence of the second inflection point in the exclusion curve are presented. The proposed models are applied to experimentally measured ISEC exclusion curves of six silica monoliths having different macropore and mesopore diameters. The PPM and PNM proposed in this work are able to determine the void fractions of the macropores and silica skeleton, the pore connectivity of the mesopores, as well as the pore number distribution (PND) and pore volume distribution (PVD) of the mesopores. The results indicate that the mesoporous structure of all materials studied is well connected as evidenced by the similarities between the PVDs calculated with the PPM and the PNM, and by the high pore connectivity values obtained from the PNM. Due to the fact that the proposed models can predict the existence of the second inflection point in the exclusion curves, the proposed models could be more applicable than other models for ISEC characterization of chromatographic columns with small diameter macropores (interstitial pores) and/or large macropore (interstitial pore) void fractions. It should be noted that the PNM can always be applied without the use of the PPM, since the PPM is an idealization that considers an infinitely connected porous medium and for materials having a low (<6) pore connectivity the PPM would force the PVD to a lower average diameter and larger distribution width as opposed to properly accounting for the network effects present in the real porous medium.     

Momentum-resolved lifetimes of image-potential states on Ag(001)

Binding energies and decay rates of image potential states at an Ag(001) surface have been investigated with time-resolved two-photon photoemission. For the first four image potential states the binding energies are determined to be 561, 170, 72 and 37 meV with respect to the vacuum level. Lifetimes of the first three states are extracted to be 57, 165 and 380 fs at k_∥ = 0. With increasing parallel momentum k_∥ the lifetime of the n = 1 state decreases such that the inverse lifetime scales proportional to the kinetic energy within the parallel motion with 34 meV/eV. As light source for the pump-probe photoemission experiments a novel all fiber based femtosecond laser system with a repetition rate of 1.5 MHz has been used.     

Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1)

FAH domain containing protein 1 (FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced. The synthesis of drug-like scaffolds afforded first-generation FAHD1-inhibitors with activities in the low micromolar IC₅₀ range. The investigations disclosed structures competing with the substrate for binding to the metal cofactor, as well as scaffolds, which may have a novel binding mode to FAHD1.     

Challenges in protein folding simulations: Timescale, representation, and analysis

Experimental studies of protein folding processes are frequently hampered by the fact that only low resolution structural data can be obtained with sufficient temporal resolution. Molecular dynamics simulations offer a complementary approach, providing extremely high resolution spatial and temporal data on folding processes. The effectiveness of such simulations is currently hampered by continuing questions regarding the ability of molecular dynamics force fields to reproduce the true potential energy surfaces of proteins, and ongoing difficulties with obtaining sufficient sampling to meaningfully comment on folding mechanisms. We review recent progress in the simulation of three common model systems for protein folding, and discuss how recent advances in technology and theory are allowing protein folding simulations to address their current shortcomings.     

Flexibility of phenylene oligomers revealed by single molecule spectroscopy

The rigidity of a p-phenylene oligomer (p-terphenyl) has been investigated by single molecule confocal fluorescence microscopy. Two different rylene diimide dyes attached to the terminal positions of the oligomer allowed for wavelength selective excitation of the two chromophores. In combination with polarization modulation the spatial orientation of the transition dipoles of both end groups could be determined independently. We have analyzed 597 single molecules in two different polymer hosts, polymethylmethacrylate and Zeonex. On average we find a 22 degrees deviation from the linear gas phase geometry (T = 0 K), indicating a rather high flexibility of the p-phenylene oligomer independent of the matrix. To substantiate our experimental results, we have performed quantum chemical calculations at the density functional theory level for the molecular geometry and the electronic excitations. Our findings are in agreement with former experiments on the persistence length of poly(p-phenylenes).     

Zur photometrischen Bestimmung von Germanium(IV), Zirkonium(IV) und Titan(IV) mit Phenylfluoronderivaten

Ohne Zusammenfassung     

Bioactive unnatural somatostatin analogues through bioorthogonal iodo- and ethynyl-disulfide intercalators

Iodo- and ethynyl-containing bisalkylating bioconjugation agents 5 and 8 were achieved and allow the introduction of reactive unnatural substituents into proteins and peptides whilst the bioactive 3D structure is retained. Derivatives of the peptide hormone somatostatin bearing a single iodo or ethynyl group were prepared through intercalation into the disulfide bridge. For the first time, the exact reaction mechanism of the intercalation was elucidated by applying 2D NMR experiments and it was shown that, during the reaction, somatostatin diastereomers were formed. Site-directed modification of the ethynyl-modified peptide with a coumarin chromophore was achieved through a [1,3] dipolar Huisgen cycloaddition reaction; this suggests that such a derivative could serve as an attractive platform to prepare artificial somatostatin compound libraries. The biological activity and specificity of a representative modified somatostatin derivative was demonstrated and efficient receptor-mediated cell uptake occurred in a dose-dependent manner into receptor positive cells only. The iodo and ethynyl bioconjugation reagents presented herein could be applied for introducing such substituents into alternative peptides and proteins and, in principle, could facilitate the efficient design of a broad variety of artificial protein and peptide analogues with previously unknown bioactivities.