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Two literature-known sulfido vanadates, Na 3 [VS 4 ] and K 3 [VS 4 ], were obtained through a straightforward and scalable synthetic method. Highly crystalline powders of both compounds were obtained from the homogeneous molten phases of starting materials via a─comparably rapid─solid-state technique. Low-temperature structure determination, ambient temperature powder diffraction, and solid-state NMR spectroscopy verify previous structural reports and indicate purity of the obtained samples. Both compounds show semiconductivity with the optical band gap values in the range of 2.1 to 2.3 eV. Experimental values of the ionic conductivity and dielectric constants are σ = 2.41·10 -5 mS·cm -1 , k = 76.52 and σ = 1.36·10 -4 mS·cm -1 , k = 103.67 at ambient temperature for Na 3 [VS 4 ] and K 3 [VS 4 ], respectively. It is demonstrated that Na 3 [VS 4 ] depicts second-order nonlinear optical properties, i.e., second harmonic generation over a broad wavelength spectrum. The results introduce new aspects of sulfido vanadates as multifunctional candidates for potential optical and electrical applications.

There are various commercially available setups for studying drug permeation, which differ in cost and manual labor. We explore an artificial membrane in an NMR tube to assess drug permeation with automated measurements. NMR-based concentrations were validated with HPLC and compared to a conventional setup. Setup-specific challenges and workarounds as well as future setup-designs for this and other applications are discussed.

Hydrogen bonds (H-bonds) are highly sensitive to the surrounding environments owing to their dipolar nature, with polar solvents kown to significantly weaken H-bonds. Herein, the stability of the H-bonding motif ureidopyrimidinone (UPy) is investigated, embedded into a highly polar polymeric ionic liquid (PIL) consisting of pendant pyrrolidinium bis(trifluoromethylsulfonyl)imide (IL) moieties, to study the influence of such ionic environments on the UPy H-bonds. The content of the surrounding IL is changed by addition of an additional low molecular weight IL to further boost the IL content around the UPy moieties in molar ratios of UPy/IL ranging from 1/4 up to 1/113, thereby promoting the polar microenvironment around the UPy-H-bonds. Variable-temperature solid-state MAS NMR spectroscopy and FT-IR spectroscopy demonstrate that the UPy H-bonds are largely present as (UPy-) dimers, but sensitive to elevated temperatures (>70 °C). Subsequent rheology and DSC studies reveal that the ILs only solvate the polymeric chains but do not interfere with the UPy-dimer H-bonds, thus accounting for their high stability and applicability in many material systems., (© 2023 The Authors. Macromolecular Rapid Communications published by Wiley-VCH GmbH.)

Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.

Drug loading of polymer micelles can have a profound effect on their particle size and morphology as well as their physicochemical properties. In turn, this influences performance in biological environments. For oral delivery of drugs, the intestinal environment is key, and consequently, a thorough structural understanding of what happens at this material-biology interface is required to understand in vivo performance and tailor improved delivery vehicles. In this study, we address this interface in vitro through a detailed structural characterization of the colloidal assemblies of polymeric micelles based on poly(2-oxazolines) with three different guest loadings with the natural product curcumin (17-52 wt %) in fed-state simulated intestinal fluids (FeSSIF). For this, we employ NMR spectroscopy, in particular, 1 H NMR, 1 H- 1 H-NOESY, and 1 H DOSY experiments complemented by quantum chemical calculations and cryo-TEM measurements. Through this mixture of methods, we identified curcumin-taurocholate interactions as central interaction patterns alongside interactions with the polymer and lipids. Furthermore, curcumin molecules can be exchanged between polymer micelles and bile colloids, an important prerequisite for their uptake. Finally, increased loading of the polymer micelles with curcumin resulted in a larger number of vesicles as taurocholate─through coordination with Cur─is less available to form nanoparticles with the lipids. The loading-dependent behavior found in this study deviates from previous work on a different drug substance highlighting the need for further studies including different drug molecules and polymer types to improve the understanding of events on the molecular level.

Bile solubilization and apparent solubility at resorption sites critically affect the bioavailability of orally administered and poorly water-soluble drugs. Therefore, identification of drug-bile interaction may critically determine the overall formulation success. For the case of the drug candidate naporafenib, drug in solution at phase separation onset significantly improved with polyethylene glycol-40 hydrogenated castor oil (RH40) and amino methacrylate copolymer (Eudragit E) but not with hydroxypropyl cellulose (HPC) in both phosphate-buffered saline (PBS) and PBS supplemented with bile components. Naporafenib interacted with bile as determined by 1 H and 2D 1 H- 1 H nuclear magnetic resonance spectroscopy and so did Eudragit E and RH40 but not HPC. Flux across artificial membranes was reduced in the presence of Eudragit E. RH40 reduced the naporafenib supersaturation duration. HPC on the other side stabilized naporafenib's supersaturation and did not substantially impact flux. These insights on bile interaction correlated with pharmacokinetics (PK) in beagle dogs. HPC preserved naporafenib bile solubilization in contrast to Eudragit E and RH40, resulting in favorable PK.

Poorly water-soluble drugs are frequently formulated with lipid-based formulations including microemulsions and their preconcentrates. We detailed the solidification of drug-loaded microemulsion preconcentrates with the acid-sensitive metal-organic framework ZIF-8 by X-ray powder diffraction and solid-state nuclear magnetic resonance spectroscopy. Adsorption and desorption dynamics were analyzed by fluorescence measurement, high-performance liquid chromatography, dynamic light scattering and 1 H-DOSY experiments using the model compounds Nile Red, Vitamin K 1 , and Lumefantrine. Preconcentrates and drugs were successfully loaded onto ZIF-8 while preserving its crystal structure. The solid powder was pressable to tablets or 3D-printed into oral dosage forms. At low pH, colloidal solutions readily formed, solubilizing the poorly water-soluble compounds. The use of stimuli-responsive metal organic frameworks as carriers for the oral delivery of lipid-based formulations points towards solid dosage forms readily forming colloidal microemulsions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polymer self-assembly leading to cooling-induced hydrogel formation is relatively rare for synthetic polymers and typically relies on H-bonding between repeat units. Here, we describe a non-H-bonding mechanism for a cooling-induced reversible order-order (sphere-to-worm) transition and related thermogelation of solutions of polymer self-assemblies. A multitude of complementary analytical tools allowed us to reveal that a significant fraction of the hydrophobic and hydrophilic repeat units of the underlying block copolymer is in close proximity in the gel state. This unusual interaction between hydrophilic and hydrophobic blocks reduces the mobility of the hydrophilic block significantly by condensing the hydrophilic block onto the hydrophobic micelle core, thereby affecting the micelle packing parameter. This triggers the order-order transition from well-defined spherical micelles to long worm-like micelles, which ultimately results in the inverse thermogelation. Molecular dynamics modeling indicates that this unexpected condensation of the hydrophilic corona onto the hydrophobic core is due to particular interactions between amide groups in the hydrophilic repeat units and phenyl rings in the hydrophobic ones. Consequently, changes in the structure of the hydrophilic blocks affecting the strength of the interaction could be used to control macromolecular self-assembly, thus allowing for the tuning of gel characteristics such as strength, persistence, and gelation kinetics. We believe that this mechanism might be a relevant interaction pattern for other polymeric materials as well as their interaction in and with biological environments. For example, controlling the gel characteristics could be considered important for applications in drug delivery or biofabrication.

The self-assembly of molecular metal oxides, polyoxometalates (POMs), can be controlled using internal or, more rarely, external templates. Here, we explore how the interplay between internal templates (halides, oxoanions) and organic external templates (protonated cyclene species) affect the self-assembly of a model polyoxovanadate cluster, [V 12 O 32 X] n - (X = Cl - , Br - , NO 3 - ). A combination of crystallographic analyses, spectroscopic studies and in situ as well as solid-state 51 V NMR spectroscopy provide critical insights into the initial formation of an intermediate vanadate species formed during the process. Structural and spectroscopic studies suggest that a direct interaction between internal and external templates allows tuning of the internal template position within the cluster cavity. These insights form the basis for further developing the template-driven synthetic chemistry of polyoxovanadates.

The synthesis and detailed characterization of low-viscosity room-temperature ionic liquids (RTILs) and [BnPh 3 P] + salts with the cyano(fluoro)borate anions [BF(CN) 3 ] - (MFB), [BF 2 (CN) 2 ] - (DFB), and [BF 3 (CN)] - as well as the new mixed-substituted anion [BFH(CN) 2 ] - (FHB) is described. The RTILs with [EMIm] + or [BMPL] + as countercations were obtained in yields of up to 98% from readily available alkali metal salts and in high purities that allow application in electrochemical devices. Trends in thermal stability, melting and freezing behavior, density, electrochemical stability, dynamic viscosity, specific conductivity and ion diffusivity have been assessed and compared to those of the related tetracyanoborate- and cyano(hydrido)borate-RTILs. The crystal structure analysis of the [BnPh 3 P] + salts of [BF n (CN) 4- n ] - ( n = 0-4), [BH n (CN) 4- n ] - ( n = 1-3) and [BFH(CN) 2 ] - provided experimental access to anion volumina that together with ion molecular mass, electrostatic potential, shape and chemical stability have been correlated to physicochemical properties. In addition, the cytotoxicity of the [EMIm] + -ILs and potassium or sodium salts was studied.

Although solid-state nuclear magnetic resonance (NMR) is a versatile analytical tool to study polymorphs and phase transitions of pharmaceutical molecules and products, this work summarizes examples of spontaneous and unexpected (and unwanted) structural rearrangements and phase transitions (amorphous-to-crystalline and crystalline-to-crystalline) under magic angle spinning (MAS) conditions, some of them clearly being due to the pressure experienced by the samples. It is widely known that such changes can often be detected by X-ray powder diffraction (XRPD); here, the capability of solid-state NMR experiments with a special focus on 1 H- 13 C frequency-switched Lee-Goldburg heteronuclear correlation (FSLG HETCOR)/MAS NMR experiments to detect even subtle changes on a molecular level not observable by conventional 1D NMR experiments or XRPD is presented. Furthermore, it is shown that a polymorphic impurity combined with MAS can induce a crystalline-to-crystalline phase transition. This showcases that solid-state NMR is not always noninvasive and such changes upon MAS should be considered in particular when compounds are studied over longer time spans., (© 2022 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

Molecular metal oxides are key materials in diverse fields like energy storage and conversion, molecular magnetism and as model systems for solid-state metal oxides. To improve their performance and increase the variety of accessible motifs, new synthetic approaches are necessary. Herein, we report a universal, new precursor to access different metal-functionalized polyoxovanadate (POV) clusters. The precursor is synthesized by a novel solid-state thermal treatment procedure. Solution-phase test reactions at room temperature and pressure show that reaction of the precursor with various metal nitrate salts gives access to a range of metal-functionalized POVs. The first nitrate-templated molecular calcium vanadate cluster is reported. We show that this precursor could open new access routes to POV components for molecular magnetism, energy technologies or catalysis., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Many drugs and drug candidates are poorly water-soluble. Intestinal fluids play an important role in their solubilization. However, the interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz (EFV) as model drug, the triblock copolymers Pluronic® F-127 (PF127) and poly(2-oxazoline) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was however observed if EFV was involved. PF127/EFV formulations in FeSSIF showed concentration dependent aggregation with separate colloids at low formulation concentrations, a merging of individual particles at the solubility limit of EFV in FeSSIF and joint aggregates above this concentration. In the case of pOx/pOzi/EFV formulations, coincident diffusion coefficients for pOx/pOzi, lipids and EFV indicate joint aggregates across the studied concentration range. This demonstrates that separate evaluation of polymers and drugs in biorelevant media is not sufficient and their mixtures need to be studied to learn about concentration and composition dependent behaviour., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Anionic lithium-containing species were predicted to impact ionic liquid-based electrochemical applications but have hitherto never been isolated from ionic liquid systems. Here, we report the first representatives of this class of compounds, ino -chloridolithates, comprising [LiCl 2 ] - and [Li 2 Cl 3 ] - polyanions from ionothermal reactions. Such compounds are obtained at moderate temperatures with imidazolium-based ionic liquids and LiCl. The addition of an auxiliary ammonium salt enhances the lattice energy to yield an ammonium lithate in good yields, which enables extensive investigations including solid-state nuclear magnetic resonance, infrared, and Raman spectroscopy. The structural motifs of ino -lithates are related to ino -silicates, as 1D-extended anionic substructures are formed. Despite this analogy, according to density functional theory calculations with periodic boundary conditions, no evidence of covalent bonding in the anionic moieties is found-indicating packing effects to be the main cause for the formation. Based on an in-depth analysis of the different synthetic parameters, this class of compounds is discussed as an intermediate in ionic liquid applications and could serve as a model system for electrochemical lithium-based systems.

The ongoing transition from fossil to renewable feedstocks demands new efficient processes for an economically viable production of biomass-derived commodities and fine chemicals. Novel energy- and material-efficient product purification and separation will play a crucial role due to altered product and feed composition. The present study comprises the synthesis and tests of cross-linked p-vinylphenylboronate polymers for the separation of 18 diols, sugar alcohols, and saccharides, which can be obtained during biomass processing. The separation was based on molecular recognition, that is, esterification of the phenylboronate with vicinal diols. A correlation of the molecular complexation constant, the polymer swelling, and the maximum adsorption capacity was found. The adsorption curves over time were recorded. Preliminary results on competitive adsorption of binary mixtures showed a high potential for the separation of substrates with significantly different complexation constants. Desorption tests implied easier desorption of substrates that only adsorb on the outer polymer shell., (© 2021 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Hydrogels are key components in several biomedical research areas such as drug delivery, tissue engineering, and biofabrication. Here, a novel ABA-type triblock copolymer comprising poly(2-methyl-2-oxazoline) as the hydrophilic A blocks and poly(2-phenethyl-2-oxazoline) as the aromatic and hydrophobic B block is introduced. Above the critical micelle concentration, the polymer self-assembles into small spherical polymer micelles with a hydrodynamic radius of approx 8-8.5 nm. Interestingly, this specific combination of hydrophilic and hydrophobic aromatic moieties leads to rapid thermoresponsive inverse gelation at polymer concentrations above a critical gelation concentration (20 wt %) into a macroporous hydrogel of densely packed micelles. This hydrogel exhibited pronounced viscoelastic solid-like properties, as well as extensive shear-thinning, rapid structure recovery, and good strain resistance properties. Excellent 3D-printability of the hydrogel at lower temperature opens a wide range of different applications, for example, in the field of biofabrication. In preliminary bioprinting experiments using NIH 3T3 cells, excellent cell viabilities of more than 95% were achieved. The particularly interesting feature of this novel material is that it can be used as a printing support in hybrid bioink systems and sacrificial bioink due to rapid dissolution at physiological conditions.

Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as Perphenazine. We detail the impact of Perphenazine concentrations on taurocholate/lecithin colloids using analytical ultracentrifugation, dynamic light scattering, small-angle neutron scattering, nuclear magnetic resonance spectroscopy, coarse-grained molecular dynamics simulations, and isothermal titration calorimetry. Perphenazine impacted colloidal molecular arrangement, structure, and binding thermodynamics in a concentration-dependent manner. At low concentration, Perphenazine was integrated into stable and large taurocholate/lecithin colloids and close to lecithin. Integration of Perphenazine into these colloids was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin colloids had an approximately 5-fold reduction in apparent hydrodynamic size, heat release was less exothermic upon drug integration into the colloids, and Perphenazine interacted with both lecithin and taurocholate. In addition, Perphenazine induced a morphological transition from vesicles to wormlike micelles as indicated by neutron scattering. Despite these surprising colloidal dynamics, these natural colloids successfully ensured stable relative amounts of free Perphenazine throughout the entire drug concentration range tested here. Future studies are required to further detail these findings both on a molecular structural basis and in terms of in vivo relevance.

Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of pharmaceutical polymers on this solubilization interplay using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and by assessing the flux across model membranes. Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point towards a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Shape-persistent conjugated mesogens with oligothiophene arms of different lengths have been synthesized. Such mesogens possess free intrinsic space between their conjugated arms. They form columnar liquid-crystalline phases, in which the void is filled by dense helical packing in the neat phase similar to an oligo(phenylene vinylene) derivative of equal size. The void can also be compensated by the inclusion of the small acceptor molecule 2,4,7-trinitrofluorenone. In solution, the acceptor interacts with the core as the largest π-surface, while in the solid material, it is incorporated between the arms and sandwiched by the star-shaped neighbours along the columnar assemblies. The TNF acceptors are not nanosegregated from the star-shaped donors, thus the liquid crystal structure converts to a nano-reservoir for TNF (endo-receptor). These host-guest arrangements are confirmed by comprehensive X-ray scattering experiments and solid-state NMR spectroscopy. This results in ordered columnar hexagonal phases at high temperatures, which change to helical columnar mesophases or to columnar soft crystals at room temperature., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Amorphous drug-polymer formulations are complex materials and often challenging to characterize, even more so if the small molecule component itself is increasingly complex. In this work, we present 14 N- 1 H HMQC magic-angle spinning (MAS) NMR experiments in the solid state as a promising tool to study amorphous formulations. Poly(2-oxazoline) based polymer micelles loaded with different amounts of the cancer drug paclitaxel serve to highlight the possibilities offered by these experiments: while the dense core of these polymeric micelles prevents NMR spectroscopic analysis in solution and the very similar 15 N chemical shifts hamper a solid-state NMR characterization based on this nucleus, 14 N is a very versatile alternative. 14 N- 1 H HMQC experiments yield well-separated signals, which are spread over a large ppm range, and provide information on the symmetry of the nitrogen environment and probe 14 N- 1 H through-space proximities. In this way, the overall complexity can be narrowed down to specific N-containing environments. The results from the experiments presented here represent a valuable puzzle piece, which helps to improve the structural understanding of drug-polymer formulations. It can be straightforwardly combined with complementary NMR spectroscopic experiments and other analytical techniques.

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as a depot for hydrophobic molecules, and the corona-forming block acts as a stabilizing and solubilizing interface between the core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of micelles, whereas the role of hydrophilic blocks is rarely investigated in this context, with poly(ethylene glycol) (PEG) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A-type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble PEG. The more hydrophobic block B bears either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* is observed for the formulation with two poorly water-soluble compounds, curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various nuclear magnetic resonance spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy, and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important, but previously largely ignored, factor for the rational design of polymeric micelles.

Detailed insight into the internal structure of drug-loaded polymeric micelles is scarce, but important for developing optimized delivery systems. We observed that an increase in the curcumin loading of triblock copolymers based on poly(2-oxazolines) and poly(2-oxazines) results in poorer dissolution properties. Using solid-state NMR spectroscopy and complementary tools we propose a loading-dependent structural model on the molecular level that provides an explanation for these pronounced differences. Changes in the chemical shifts and cross-peaks in 2D NMR experiments give evidence for the involvement of the hydrophobic polymer block in the curcumin coordination at low loadings, while at higher loadings an increase in the interaction with the hydrophilic polymer blocks is observed. The involvement of the hydrophilic compartment may be critical for ultrahigh-loaded polymer micelles and can help to rationalize specific polymer modifications to improve the performance of similar drug delivery systems., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

We describe the preparation of hydrogels using highly functionalized poly(oxazoline) based polymeric precursors and cross-linking via UV mediated radical thiol-ene chemistry. Random copolymers were synthesized based on the combination of the more hydrophilic 2-methyl-2-oxazoline or the less hydrophilic monomer 2-ethyl-2-oxazoline with 2-(3-butenyl)-2-oxazoline. These copolymers were functionalized via a post-polymerization technique with thiol or cysteine functionality at the side chain. Hence, hydrogels were obtained, for which the thermo-responsive behavior, network density and correlated properties such as swelling and mechanics, as well as the possibility of electrostatic interaction, can be tuned. Cell culture tests demonstrated good cytocompatibility of the synthesized copolymers and hydrogels. A study with two low molecular weight substances, methylene blue and fluorescein sodium, was performed to investigate how the thermo-responsive behavior or the positive charge incorporated by cysteine could influence the interaction with the compounds. It was found that the interaction with the hydrogel network was strongly influenced by the chemical properties of the dye. A hydrophilic and positively charged hydrogel network was shown to be a promising candidate for the uptake and prolonged release of negatively charged low molecular weight substances.

Fragment-based drug discovery and continuous improvement of existing protein inhibitors rely on the knowledge of exactly how and how strongly a range of small molecules bind to their respective protein targets. By increasing the (perdeuterated) protein concentration, WaterLOGSY titration experiments give access to ligand binding modes even in the case of weak binders as well as to the location of protein-bound water in the surroundings of the ligand. On the basis of these findings, specific chemical modifications of the ligand could be shown to yield significantly enhanced binding affinities.

A single-crystal X-ray diffraction structure of a 1:1 cocrystal of two fungicides, namely dithianon (DI) and pyrimethanil (PM), is reported [systematic name: 5,10-dioxo-5H,10H-naphtho[2,3-b][1,4]dithiine-2,3-dicarbonitrile-4,6-dimethyl-N-phenylpyrimidin-2-amine (1/1), C 14 H 4 N 2 O 2 S 2 ·C 12 H 13 N 2 ]. Following an NMR crystallography approach, experimental solid-state magic angle spinning (MAS) NMR spectra are presented together with GIPAW (gauge-including projector augmented wave) calculations of NMR chemical shieldings. Specifically, experimental 1 H and 13 C chemical shifts are determined from two-dimensional 1 H- 13 C MAS NMR correlation spectra recorded with short and longer contact times so as to probe one-bond C-H connectivities and longer-range C...H proximities, whereas H...H proximities are identified in a 1 H double-quantum (DQ) MAS NMR spectrum. The performing of separate GIPAW calculations for the full periodic crystal structure and for isolated molecules allows the determination of the change in chemical shift upon going from an isolated molecule to the full crystal structure. For the 1 H NMR chemical shifts, changes of 3.6 and 2.0 ppm correspond to intermolecular N-H...O and C-H...O hydrogen bonding, while changes of -2.7 and -1.5 ppm are due to ring current effects associated with C-H...π interactions. Even though there is a close intermolecular S...O distance of 3.10 Å, it is of note that the molecule-to-crystal chemical shifts for the involved sulfur or oxygen nuclei are small.

Exploitation of plant lignocellulosic biomass is hampered by our ignorance of the molecular basis for its properties such as strength and digestibility. Xylan, the most prevalent non-cellulosic polysaccharide, binds to cellulose microfibrils. The nature of this interaction remains unclear, despite its importance. Here we show that the majority of xylan, which forms a threefold helical screw in solution, flattens into a twofold helical screw ribbon to bind intimately to cellulose microfibrils in the cell wall. 13 C solid-state magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, supported by in silico predictions of chemical shifts, shows both two- and threefold screw xylan conformations are present in fresh Arabidopsis stems. The twofold screw xylan is spatially close to cellulose, and has similar rigidity to the cellulose microfibrils, but reverts to the threefold screw conformation in the cellulose-deficient irx3 mutant. The discovery that induced polysaccharide conformation underlies cell wall assembly provides new principles to understand biomass properties.

The benefits of the ultrafast magic-angle spinning (MAS) approach for the acquisition of ultrawide-line NMR spectra-spectral simplification, increased mass sensitivity allowing the fast study of small amounts of material, efficient excitation, and application to multiple heavy nuclei-are demonstrated for tin(II) oxide (SnO) and the tin complex [(LB)Sn(II) Cl](+) [Sn(II) Cl3 ](-) [LB=2,6-diacetylpyridinebis(2,6-diisopropylanil)] containing two distinct tin environments. The ultrafast MAS experiments provide optimal conditions for the extraction of the chemical-shift anisotropy tensor parameters, anisotropy, and asymmetry for heavy spin-1/2 nuclei., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An unusual lithium lithiate [Li(diglyme)2][(diglyme)Li2(C4H3S)3], made up from three carbanions, two lithium cations, and a single donor base molecule in the anion and a single lithium cation, coordinated by two donor base molecules, is investigated in a combined study including X-ray diffraction, NMR spectroscopy and computational approaches in solution and the solid state. While the multicomponent lithiate is the only species present in the solid state, solution NMR spectroscopy and computational methods were employed to identify a second species in solution. The dimer [(diglyme)Li(C4H3S)]2 coexists with the lithiate in solution in a 1:1 ratio, the more the higher the polarity of the solvent is. Only the combination of this multitude of methods provides a firm picture of the whole., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Lithium in the gel: The NMR spectroscopic properties of common organolithium and lithium amide reagents are investigated in the anisotropic environment of a stretched polystyrene (PS) gel. PS is stable towards reactive organometallic compounds and can be used at low temperatures. The residual quadrupolar couplings (RQCs) from a single (7)Li NMR spectrum can distinguish between high (hexamer, tetramer) and low (dimer, monomer) aggregation states (see scheme)., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Various 2-thienyllithium derivatives were investigated in the solid state by X-ray diffraction and in solution by 2D NMR experiments. The determined structures of [(Et(2)O)Li(C(4)H(3)S)](4) (1), [(THF)(2)Li(C(4)H(3)S)](2) (2), [(DME)Li(C(4)H(3)S)](2) (3), [(TMEDA)Li(C(4)H(3)S)](2) (4), and [(PMDETA)Li(C(4)H(3)S)] (5) (DME = 1,2-dimethoxyethane, TMEDA = N,N,N',N'-tetramethylethylene-1,2-diamine, and PMDETA = N,N,N',N",N"-pentamethyldiethylenetriamine) were solved in nondonating toluene and provide firm ground for diffusion-ordered NMR spectroscopy as well as heteronuclear Overhauser enhancement NMR spectroscopy. The distance relation of nuclear Overhauser effects with a factor of r(-6) is employed to gain further insight into the aggregation degree of 1-5 in solution. Comparison of the slope provided by the linear region of the buildup curves and of the ∑r(-6) calculated distances from the crystal structures offers a handle to judge the structure retention versus conversion in solution. The structures of 3-5 are maintained in toluene solution. The data of 2, however, indicate a partial dissociation or a rapid exchange between the vertices of a tetrameric core and free THF molecules. Auxiliary exchange spectroscopy investigations showed that the signals of the nitrogen donor base containing compounds 4 and 5 exchange with the signals of nonlithiated thiophene. This is explained by exchange of the deuterium by a hydrogen atom via lithiation of toluene molecules., (© 2011 American Chemical Society)

Largazole 4a and analogues with modifications at the C7 position, as well as 2,4'-bithiazole 5a, have been synthesized using an acyclic cross-metathesis of the corresponding depsipeptide structures assembled by N-C6(O) or C15(O)-N lactam formation. Similar to the parent system 4a, the series of largazole depsipeptides 4b-d, but not 2,4'-bithiazole 5a, showed a marked inhibition of recombinant HDAC1 and selectivity over HDAC4, as well as strong pro-apoptotic effects on the NB4 leukemia cell line, but they failed to induce differentiation to mature granulocytes. Functional assays of the analogues correlated with the in vitro activities, as shown by increased H3 and alpha-tubulin acetylation levels and p21(WAF1/CIP1) up-regulation in NB4 cells. The activity of the natural product HDACi largazole 4a is not significantly altered by the presence of groups of different size (H, Et, Ph) at C7 on the dihydrothiazole ring.