Antifungal Imidazole‐Decorated Cationic Amphiphiles with Markedly Low Hemolytic Activity

Herein we report that an imidazole‐decorated cationic amphiphile derived from the pseudo‐disaccharide nebramine has potent antifungal activity against strains of Candida glabrata pathogens. In combination with the natural bis‐benzylisoquinoline alkaloid tetrandrine the reported antifungal cationic amphiphile demonstrated synergistic antifungal activity against Candida albicans pathogens. This unique membrane disruptor caused no detectible mammalian red blood cell hemolysis at concentrations up to more than two orders of magnitude greater than its minimal inhibitory concentrations against the tested C. glabrata strains. We provide evidence that potency against C. glabrata may be associated with differences between the drug efflux pumps of C. albicans and C. glabrata. Imidazole decorated‐cationic amphiphiles show promise for the development of less toxic membrane‐disrupting antifungal drugs and drug combinations.     

Chemo- and Regioselective Additions of Nucleophiles to Cyclic Carbonates for the Preparation of Self-Blowing Non-Isocyanate Polyurethane Foams

Polyurethane (PU) foams are indisputably daily essential materials found in many applications, notably for comfort (for example, matrasses) or energy saving (for example, thermal insulation). Today, greener routes for their production are intensively searched for to avoid the use of toxic isocyanates. An easily scalable process for the simple construction of self-blown isocyanate-free PU foams by exploiting the organocatalyzed chemo- and regioselective additions of amines and thiols to easily accessible cyclic carbonates is described. These reactions are first validated on model compounds and rationalized by DFT calculations. Various foams are then prepared and characterized in terms of morphology and mechanical properties, and the scope of the process is illustrated by modulating the composition of the reactive formulation. With impressive diversity and accessibility of the main components of the formulations, this new robust and solvent-free process could open avenues for construction of more sustainable PU foams, and offers the first realistic alternative to the traditional isocyanate route.     

Aromatic 19F–13C TROSY—[19F, 13C]-Pyrimidine Labeling for NMR Spectroscopy of RNA

We present the access to [5-¹⁹F, 5-¹³C]-uridine and -cytidine phosphoramidites for the production of site-specifically modified RNAs up to 65 nucleotides (nts). The amidites were used to introduce [5-¹⁹F, 5-¹³C]-pyrimidine labels into five RNAs—the 30 nt human immunodeficiency virus trans activation response (HIV TAR) 2 RNA, the 61 nt human hepatitis B virus ϵ (hHBV ϵ) RNA, the 49 nt SAM VI riboswitch aptamer domain from B. angulatum, the 29 nt apical stem loop of the pre-microRNA (miRNA) 21 and the 59 nt full length pre-miRNA 21. The main stimulus to introduce the aromatic ¹⁹F–¹³C-spin topology into RNA comes from a work of Boeszoermenyi et al., in which the dipole-dipole interaction and the chemical shift anisotropy relaxation mechanisms cancel each other leading to advantageous TROSY properties shown for aromatic protein sidechains. This aromatic ¹³C–¹⁹F labeling scheme is now transferred to RNA. We provide a protocol for the resonance assignment by solid phase synthesis based on diluted [5-¹⁹F, 5-¹³C]/[5-¹⁹F] pyrimidine labeling. For the 61 nt hHBV ϵ we find a beneficial ¹⁹F–¹³C TROSY enhancement, which should be even more pronounced in larger RNAs and will facilitate the NMR studies of larger RNAs. The [¹⁹F, ¹³C]-labeling of the SAM VI aptamer domain and the pre-miRNA 21 further opens the possibility to use the biorthogonal stable isotope reporter nuclei in in vivo NMR to observe ligand binding and microRNA processing in a biological relevant setting.     

Monopoly

Mathematische Semesterberichte - Die Spielidee des Monopoly-Spiels ist mehr als 100 Jahre alt. Ein Grund für den beständigen Erfolg ist die Anpassungsfähigkeit der Spielidee....     

Catalytic Alkyne Semihydrogenation with Polyhydride Ni/Ga Clusters

The bimetallic, decanuclear Ni₃Ga₇-cluster of the formula [Ni₃(GaTMP)₃(μ²-GaTMP)₃(μ³-GaTMP)] ( 1 , TMP=2,2,6,6-tetramethylpiperidinyl) reacts reversibly with dihydrogen under the formation of a series of (poly-)hydride clusters 2 . Low-temperature 2D NMR experiments at −80 °C show that 2 consist of a mixture of a di- ( 2_Di ), tetra- ( 2_Tetra ) and hexahydride species ( 2_Hexa ). The structures of 2_Di and 2_Tetra are assessed by a combination of 2D NMR spectroscopy and DFT calculations. The cooperation of both metals is essential for the high hydrogen uptake of the cluster. Polyhydrides 2 are catalytically active in the semihydrogenation of 4-octyne to 4-octene with good selectivity. The example is the first of its kind and conceptually relates properties of molecular, atom-precise transition metal/main group metal clusters to the respective solid-state phase in catalysis.     

Pyridine Adducts of Tricyano- and Dicyanoboranes

Cyanoborane adducts of the Lewis acids B(CN)₃, BF(CN)₂, and BH(CN)₂ with pyridine and 4-cyanopyridine have been obtained in high yields. The syntheses were accomplished by oxidation of the readily available potassium salts of the cyano(hydrido)borate anions [BH(CN)₃]⁻ ( MHB ), [BFH(CN)₂]⁻ ( FHB ), and [BH₂(CN)₂]⁻ ( DHB ) with bromine in the presence of the respective pyridine derivative C₅H₅N or 4-CN-C₅H₄N as starting material. All six cyanoborane adducts have been characterized by NMR and vibrational spectroscopy, elemental analysis, and single-crystal X-ray diffraction. The reduction of the cyanoborane adducts has been investigated by cyclic voltammetry and the Lewis acidity of the different cyanoboranes has been assessed using the Gutmann-Beckett method. Selected experimental data and trends are compared to theoretical ones, for example fluoride ion affinities (FIAs).     

Hydrogen Peroxide Production of Individual Nanosecond Pulsed Discharges Submerged in Water of Elevated Conductivity

The production of hydrogen peroxide (H₂O₂) is a key parameter for the performance of pulsed discharges submerged in water utilized as advanced oxidation process. So far, any related assessment of the underlying mechanism was conducted for the application of several hundred discharges, which did not allow for a correlation with physical processes. Moreover, the production was rarely investigated depending on water conductivity as one of the most important parameters for the development of submerged discharges. Accordingly, hydrogen peroxide generation was investigated here for individual single discharge events instigated with 100 ns high-voltage pulses in water with three different conductivities and was associated with the discharge development, i. e. spatial expansion and dissipated electrical energy. The approach necessitated the improvement of an electrochemical flow injection analysis based on the reaction of Prussian blue with H₂O₂. Hydrogen peroxide concentrations were quadratically increasing with propagation time and stable for different water conductivities. H₂O₂ production per unit volume of a discharge was constant over time with an estimated rate constant of 3.2 mol ⋅ m⁻¹ s⁻¹, averaged over the crosssectional area of all discharge filaments. However, the individually dissipated energy increased with conductivity, hence, the production efficiency decreased from 6.1 g ⋅ kWh⁻¹ to 1.4 g ⋅ kWh⁻¹, which was explained by increased resistive losses within the bulk liquid.     

Identification of Structure–Activity Relationships from Screening a Structurally Compact DNA‐Encoded Chemical Library

Methods for the rapid and inexpensive discovery of hit compounds are essential for pharmaceutical research and DNA‐encoded chemical libraries represent promising tools for this purpose. We here report on the design and synthesis of DAL‐100K, a DNA‐encoded chemical library containing 103 200 structurally compact compounds. Affinity screening experiments and DNA‐sequencing analysis provided ligands with nanomolar affinities to several proteins, including prostate‐specific membrane antigen and tankyrase 1. Correlations of sequence counts with binding affinities and potencies of enzyme inhibition were observed and enabled the identification of structural features critical for activity. These results indicate that libraries of this type represent a useful source of small‐molecule binders for target proteins of pharmaceutical interest and information on structural features important for binding.     

Trimethylaluminum: Bonding by Charge and Current Topology

The charge density distribution of the trimethylaluminum dimer was determined by high‐angle X‐ray diffraction of a single crystal and quantum‐chemical methods and analyzed using the quantum theory of atoms in molecules. The data can be interpreted as Al₂Me₆ being predominantly ionically bonded, with clear indications of topological asymmetry for the bridging Al? C bonds owing to delocalized multicenter bonding. This interpretation is supported by the calculated magnetic response currents. The data shed new light on the bonding situation in this basic organometallic molecule, which was previously described by contradicting interpretations of bonding.