Asymmetric synthesis of densely functionalized medium-ring carbocycles and lactones through modular assembly and ring-closing metathesis of sulfoximine-substituted trienes and dienynes

An asymmetric synthesis of densely functionalized 7-11-membered carbocycles and 9-11-membered lactones has been developed. Its key steps are a modular assembly of sulfoximine-substituted C- and O-tethered trienes and C-tethered dienynes and their Ru-catalyzed ring-closing diene and enyne metathesis (RCDEM and RCEYM). The synthesis of the C-tethered trienes and dienynes includes the following steps: 1) hydroxyalkylation of enantiomerically pure titanated allylic sulfoximines with unsaturated aldehydes, 2) α-lithiation of alkenylsulfoximines, 3) alkylation, hydroxy-alkylation, formylation, and acylation of α-lithioalkenylsulfoximines, and 4) addition of Grignard reagents to α-formyl(acyl)alkenylsulfoximines. The sulfoximine group provided for high asymmetric induction in steps 1) and 4). RCDEM of the sulfoximine-substituted trienes with the second-generation Ru catalyst stereoselectively afforded the corresponding functionalized 7-11-membered carbocyles. RCDEM of diastereomeric silyloxy-substituted 1,6,12-trienes revealed an interesting difference in reactivity. While the (R)-diastereomer gave the 11-membered carbocyle, the (S)-diastereomer delivered in a cascade of cross metathesis and RCDEM 22-membered macrocycles. RCDEM of cyclic trienes furnished bicyclic carbocycles with a bicyclo[7.4.0]tridecane and bicyclo[9.4.0]pentadecane skeleton. Selective transformations of the sulfoximine- and bissilyloxy-substituted carbocycles were performed including deprotection, cross-coupling reaction and reduction of the sulfoximine moiety. Esterification of a sulfoximine-substituted homoallylic alcohol with unsaturated carboxylic acids gave the O-tethered trienes, RCDEM of which yielded the sulfoximine-substituted 9-11-membered lactones. RCEYM of a sulfoximine-substituted 1,7-dien-10-yne showed an unprecedented dichotomy in ring formation depending on the Ru catalyst. While the second-generation Ru catalyst gave the 9-membered exo 1,3-dienyl carbocycle, the first-generation Ru catalyst furnished a truncated 9-membered 1,3-dieny carbocycle having one CH(2) unit less than the dienyne.     

Ped_Outlier software for automatic identification of within-family outliers

A high-throughput resequencing technology has brought family based studies back into genetic research focus. Within-family outliers (the individuals whose phenotype is very much unlike the phenotype of relatives) may carry rare variants of large effects and thus resequencing of these provides a highly powered strategy for rare variants detection. On the other hand, such outliers may complicate search for common variants of smaller effects, because they may obscure a real linkage signal. We have developed a program Ped_Outlier allowing automatic detection of within-family outliers in a sample of pedigrees of arbitrary structure and size. We tested our program by identification of within-family outliers for adult height and intracranial volume in large pedigree. Results of linkage analysis of these traits demonstrated that identification of within-family outliers is one of the important steps of pedigree analysis. The program Ped_outlier is freely available at http://mga.bionet.nsc.ru/soft/index.html.     

Multiplexed immunoassays for the analysis of breast cancer biopsies

Within the last decade, protein microarray technology has been successfully used for the simultaneous quantification of target proteins from minimal amounts of samples in basic and applied proteome research. The robustness and appropriate sensitivity of these miniaturized assays have been demonstrated and thus the transfer to routine and high-throughput applications is now possible. In this study, multiplexed bead-based sandwich immunoassays were used to determine the concentrations of 54 protein analytes, including HER 2 and the estrogen receptor, from ultrasound-guided large-core needle biopsies (LCNBs) from breast cancer patients. Expression levels for HER 2, estrogen receptors and progesterone receptors were also assessed by immunohistochemical routine staining, performed in the clinic on corresponding biopsy samples. The high concordance of the data sets generated with the bead-based protein arrays and by conventional immunohistochemical assessment of HER 2 and the estrogen receptor expressed by breast cancer cells present in the biopsies was demonstrated.     

Structure and dynamic features of an intramolecular frustrated Lewis pair

Di(mesityl)cyclohexenylphosphine undergoes hydroboration with Piers' borane [HB(C₆F₅)₂] to yield the cyclohexylene‐anellated frustrated Lewis pair 5 . This P/B pair splits H₂ with the formation of the product 4 and adds to the C?O double bond of phenyl isocyanate to yield 6 . In the crystal, compound 5 features a puckered four‐membered heterocyclic core structure with a long P? B bond (av. 2.197(5) Å). The activation energy of the P? B cleavage of the frustrated Lewis pair 5 was determined by dynamic ¹⁹F NMR spectroscopy at ΔG^≠(298 K)=12.1±0.3 kcal mol^?1.     

Sobolev spaces on Riemannian manifolds with bounded geometry: General coordinates and traces

We study fractional Sobolev and Besov spaces on noncompact Riemannian manifolds with bounded geometry. Usually, these spaces are defined via geodesic normal coordinates which, depending on the problem at hand, may often not be the best choice. We consider a more general definition subject to different local coordinates and give sufficient conditions on the corresponding coordinates resulting in equivalent norms. Our main application is the computation of traces on submanifolds with the help of Fermi coordinates. Our results also hold for corresponding spaces defined on vector bundles of bounded geometry and, moreover, can be generalized to Triebel‐Lizorkin spaces on manifolds, improving [11].     

Ferroelectricity in mixtures of mesogenic and nonmesogenic compounds

It is shown that by adding potassium nitrate (1 % by weight) to compensated cholesteric mixtures (cholesteryl chloride-cholesteryl myristate 63.63:36.37% by weight and cholesteryl laurate-cholesteryl chloride 35.65% by weight) or to smectic sitosteryl undecilenate, the mixtures exhibit ferroelectric behaviour. Values of P_s = 10-⁹ - 10-⁸ C/cm² were obtained in the high-temperature range. In compensated cholesteric mixtures, the spontaneous polarisation reached a minimum at a temperature corresponding to the cholesteric-nematic transition. The results are explained by assuming coupling between the dipoles of the antiferroelectric KNO₃ and the dipoles of the mesogenic compound.     

Reduced-symmetry two-dimensional solitons in photonic lattices

We demonstrate theoretically and experimentally a novel type of localized beam supported by the combined effects of total internal and Bragg reflection in nonlinear two-dimensional square periodic structures. Such localized states exhibit strong anisotropy in their mobility properties, being highly mobile in one direction and trapped in the other, making them promising candidates for optical routing in nonlinear lattices.     

Solid phase synthesis of 3,4,7-trisubstituted 4,5,8,9-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2-amines

The solid-phase parallel synthesis of 3,4,7-trisubstituted 4,5,8,9-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2-amines starting from resin-bound dipeptides is described. The key synthetic steps involve the cylization of an amino and a guanidino functionality using thiocarbonyldiimidazole and the subsequent transformation of the resulting thiourea moiety to a substituted guanidine group using HgCl(2) and various amines. Following cleavage from the resin, the desired products were obtained in good yields and good to moderate purities, depending on the building blocks employed.     

Photophysics of aminoxanthone derivatives and their application as binding probes for DNA

Xanthones with amino substituents were synthesized to diminish the photoreactivity of the xanthone chromophore with DNA, with the objective of using these molecules to study their binding dynamics with DNA. The aminoxanthones showed a strong solvatochromic effect on their singlet and triplet excited-state photophysics, where polar solvents led to a decrease of the energies for the excited states. Quenching of the triplet excited states by nitrite anions was used to determine the binding dynamics, and a residence time in the microsecond time domain was estimated for the bound 2-aminoxanthone with DNA. The quenching experiments performed showed that this methodology will not be applicable to study the binding dynamics of a wide variety of guests with DNA.     

Modelling and simulation of injecting acrylic bone cement into osteoporotic vertebral bones within percutaneous vertebroplasty

Percutaneous vertebroplasty is a common clinical procedure to treat vertebral compression fractures and osteoporotic vertebral bodies. However, this operation technique is accompanied by different complications due to lack of knowledge about the complicated behaviour of bone cement within the human body. To contribute to a better understanding of the processes that take place inside the body during a vertebroplasty, a detailed model of the thermomechanical behaviour of acrylic bone cement has been developed. All important effects are covered, that influence the behaviour of acrylic bone cement during the injection in a human vertebral body. Implemented in the opensource CFD-code OpenFOAM^®, first results show that this comprehensive simulation of the minimal invasive injection is capable to accurately predict the cement distribution and temperature field of acrylic bone cement inside the vertebral body. (© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)