Vinylic MIDA Boronates: New Building Blocks for the Synthesis of Aza‐Heterocycles

A two‐step synthesis of structurally diverse pyrrole‐containing bicyclic systems is reported. ortho‐Nitro‐haloarenes coupled with vinylic N‐methyliminodiacetic acid (MIDA) boronates generate ortho‐vinyl‐nitroarenes, which undergo a “metal‐free” nitrene insertion, resulting in a new pyrrole ring. This novel synthetic approach has a wide substrate tolerance and it is applicable in the preparation of more complex “drug‐like” molecules. Interestingly, an ortho‐nitro‐allylarene derivative furnished a cyclic β‐aminophosphonate motif.     

Catalytic Homologation-Allylboration Sequence for Diastereo- and Enantioselective Synthesis of Densely Functionalized β-Fluorohydrins with Tertiary Fluoride Stereocenters

Homologation of trisubstituted fluoroalkenes followed by allylboration of aldehyde, ketone and imine substrates is suitable for synthesis of β-fluorohydrin and amine products. In the presence of (R)-iodo-BINOL catalyst enantioselectivities up to 99 % can be achieved by formation of a single stereoisomer with adjacent stereocenters, of which one is a tertiary C−F center.     

Stability Enhancement of a Dimeric HER2-Specific Affibody Molecule through Sortase A-Catalyzed Head-to-Tail Cyclization

Natural backbone-cyclized proteins have an increased thermostability and resistance towards proteases, characteristics that have sparked interest in head-to-tail cyclization as a method to stability-enhance proteins used in diagnostics and therapeutic applications, for example. In this proof-of principle study, we have produced and investigated a head-to-tail cyclized and HER2-specific Z_HER2:342 Affibody dimer. The sortase A-mediated cyclization reaction is highly efficient (>95%) under optimized conditions, and renders a cyclic Z_HER3:342-dimer with an apparent melting temperature, T_m, of 68 °C, which is 3 °C higher than that of its linear counterpart. Circular dichroism spectra of the linear and cyclic dimers looked very similar in the far-UV range, both before and after thermal unfolding to 90 °C, which suggests that cyclization does not negatively impact the helicity or folding of the cyclic protein. The cyclic dimer had an apparent sub-nanomolar affinity (K_d ~750 pM) to the HER2-receptor, which is a ~150-fold reduction in affinity relative to the linear dimer (K_d ~5 pM), but the anti-HER2 Affibody dimer remained a high-affinity binder even after cyclization. No apparent difference in proteolytic stability was detected in an endopeptidase degradation assay for the cyclic and linear dimers. In contrast, in an exopeptidase degradation assay, the linear dimer was shown to be completely degraded after 5 min, while the cyclic dimer showed no detectable degradation even after 60 min. We further demonstrate that a site-specifically DyLight 594-labeled cyclic dimer shows specific binding to HER2-overexpressing cells. Taken together, the results presented here demonstrate that head-to-tail cyclization can be an effective strategy to increase the stability of an Affibody dimer.     

Asymmetric Organocatalytic Homologation: Access to Diverse Chiral Trifluoromethyl Organoboron Species

A broad range of aliphatic, aromatic, and heterocyclic boronic acids were successfully homologated using trifluorodiazoethane in the presence of BINOL derivatives to provide the corresponding chiral trifluoromethyl containing boronic acid derivatives in high yields and excellent enantioselectivity. The in situ conversion of the chiral transient boronic acids to the corresponding alcohols or β-CF3 carboxylates are also demonstrated.     

Theoretical prediction of the protein–protein interaction between Arabidopsis thaliana COP1 and UVR8

In plants, ultraviolet-B radiation (280–315 nm) regulates gene expression and plant morphology through the UV RESPONSE LOCUS 8 (UVR8) photoreceptor. The first signaling event after quantal absorbance is the interaction of the UVR8 C-terminus with the E3 ubiquitin ligase CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1). The nature of the interaction between these two proteins is hitherto unknown. A protein homology model of the Arabidopsis thaliana COP1 seven-bladed propeller WD40 repeat domain and de novo folds of the C-terminal 27 amino acid (amino acids 397–423) peptide of Arabidopsis UVR8 (UVR8^397?423) is herein reported. Using a theoretical computational docking protocol, the interaction between COP1 and UVR8 was predicted. A core motif was identified in UVR8^397?423 comprising adjacent hydrophobic residues V410 and P411 together with a charged residue D412, homologous to corresponding motifs in other COP1-binding proteins, such as ELONGATED HYPOCOTYL 5 (HY5), cryptochrome 1 (CRY1), and salt tolerance proteins STO/STH. The protein–protein interaction between the COP1 WD40 repeat domain and UVR8^397?423 reveals binding within a region of COP1 overlapping with the binding site for HY5 and the other COP1-interacting proteins. This study provides a framework for understanding docking between UVR8 and COP1, which in turn gives clues for experimental testing of UVR8/COP1 interaction.     

Identification of Compounds that Selectively Stabilize Specific G‐Quadruplex Structures by Using a Thioflavin T‐Displacement Assay as a Tool

Small molecules are used in the G‐quadruplex (G4) research field in vivo and in vitro, and there are increasing demands for ligands that selectively stabilize different G4 structures. Thioflavin T (ThT) emits an enhanced fluorescence signal when binding to G4 structures. Herein, we show that ThT can be competitively displaced by the binding of small molecules to G4 structures and develop a ThT‐displacement high‐throughput screening assay to find novel and selective G4‐binding compounds. We screened approximately 28 000 compounds by using three different G4 structures and identified eight novel G4 binders. Analysis of the structural conformation and stability of the G4 structures in presence of these compounds demonstrated that the four compounds enhance the thermal stabilization of the structures without affecting their structural conformation. In addition, all four compounds also increased the G4‐structure block of DNA synthesis by Taq DNA polymerase. Also, two of these compounds showed selectivity between certain Schizosaccharomyces pombe G4 structures, thus suggesting that these compounds or their analogues can be used as selective tools for G4 DNA studies.     

Solvent‐Dependent Structure of the I3− Ion Derived from Photoelectron Spectroscopy and Ab Initio Molecular Dynamics Simulations

Ab initio molecular dynamics (MD) simulations of the solvation of LiI₃ in four different solvents (water, methanol, ethanol, and acetonitrile) are employed to investigate the molecular and electronic structure of the I₃^? ion in relation to X‐ray photoelectron spectroscopy (XPS). Simulations show that hydrogen‐bond rearrangement in the solvation shell is coupled to intramolecular bond‐length asymmetry in the I₃^? ion. By a combination of charge analysis and I 4 d core‐level XPS measurements, the mechanism of the solvent‐induced distortions has been studied, and it has been concluded that charge localization mediates intermolecular interactions and intramolecular distortion. The approach involving a synergistic combination of theory and experiment probes the solvent‐dependent structure of the I₃^? ion, and the geometric structure has been correlated with the electronic structure.     

Surface integral analogy approaches for predicting noise from 3D high-lift low-noise wings

Three surface integral approaches of the acoustic analogies are studied to predict the noise from three concep- tual configurations of three-dimensional high-lift low-noise wings. The approaches refer to the Kirchhoff method, the Ffowcs Williams and Hawkings （FW-H） method of the permeable integral surface and the Curle method that is known as a special case of the FW-H method. The first two approaches are used to compute the noise generated by the core flow region where the energetic structures exist. The last approach is adopted to predict the noise specially from the pressure perturbation on the wall. A new way to con- struct the integral surface that encloses the core region is proposed for the first two methods. Considering the local properties of the flow around the complex object-the actual wing with high-lift devices-the integral surface based on the vorticity is constructed to follow the flow structures. The surface location is discussed for the Kirchhoff method and the FW-H method because a common surface is used for them. The noise from the core flow region is studied on the basis of the dependent integral quantities, which are indicated by the Kirchhoff formulation and by the FW-H formulation. The role of each wall component on noise contribution is analyzed using the Curle formulation. Effects of the volume integral terms of Lighthill＇s stress tensors on the noise pre-diction are then evaluated by comparing the results of the Curle method with the other two methods.     

Electronic structure of platinum at ultrahigh pressure

Abstract

Platinum is studied, theoretically, under very high compression. The calculated equation of state is found to agree well with the recent experimental data. At V/V₀ = 0.4, where V₀ is the experimental equilibrium volume, we find a transition from the face centered cubic structure (fcc), found at ambient pressure, to the body centered cubic structure (bcc). The calculated transition pressure is 26 Mbar. The stabilization of the bcc structure is explained by the eigen value sum.     

Cone motion viscosity and optical second harmonic generation of ferroelectric liquid crystalline dendrimers

We report second harmonic generation in a ferroelectric liquid crystalline trimer and ferroelectric liquid crystalline dendrimers of first, second and third generation. Thin cells were filled with the compounds by capillary forces at elevated temperature, and cooled from the surface stabilized ferroelectric state to below the glass transition temperature, while kept in an electric field. The cone motion viscosity and the threshold electric field for unwinding of the helix axis of the chiral tilted smectic mesophases were studied separately at elevated temperature, and these data were used to optimize the preparation of the films. The measured response time was between 0.3 and 3ms, which corresponds to a cone motion viscosity between 0.5 and 50 Pa s. Second harmonic generation was studied both at elevated temperature with an electric field and at room temperature with and without electric field. The first generation dendrimer exhibited a strong increase in the second order non-linear optical response with time at room temperature. The d ₂₃-coefficient of this dendrimer was approximately four times larger than for the other macromolecules and was 0.045 pm V^-1. The relatively large d-coefficient of the first generation dendrimer is ascribed to crystallization, which improved the orientation of the molecular dipoles.