Polymer network comprised of steroidal rotors as promising storage material.

In this paper, we report a new generation of polymeric networks as potential functional material based on changes in molecular dynamics in the solid state. The material is obtained by free radical polymerization of a diacrylate derivative bearing a steroid (stator) and a 1,4-diethynyl-phenylene-d4 fragment (rotator). Polymer research using the PALS technique complements the knowledge about nanostructural changes occurring in the system in the temperature range -115 °C - +190 °C. It indicates the presence of two types of free nanovolumes in the system and the occurrence of phase transitions. The polymer is characterized using 1 H NMR, 2 H Solid Echo NMR, ATR-FTIR and Raman spectroscopies, thermal analysis, and porosimetry. It is proved that the applied procedure leads to the formation of a novel porous organic material containing multiple molecular rotors.

Polymer Network Comprised of Steroidal Rotors as a Promising Storage Material.

The front cover artwork is provided by Dr habil. Izabella Jastrzebska's group from the University of Bialystok, Poland. The image shows a polymeric network with molecular rotors (MR) as crosslinks. The MR rotation is slowed or inhibited when a molecule of stored gas is placed inside the polymer material. Read the full text of the Research Article at 10.1002/cphc.202300793.

Rapid diazotransfer for selective lysine labelling.

Azide functionalization of protein and peptide lysine residues allows selective bioorthogonal labeling to introduce new, site selective functionaltiy into proteins. Optimised diazotransfer reactions under mild conditions allow aqueous diazotransfer to occur in just 20 min at pH 8.5 on amino acid, peptide and protein targets. In addition, conditons can be modified to selectively label a single lysine residue in both protein targets investigated. Finally, we demonstrate selective modification of proteins containing a single azidolysine using copper(I)-catalyzed triazole formation.

Structure and Microbiological Activity of 1H-benzo[d]imidazole Derivatives.

Three new crystal structures of 1H-benzo[d]imidazole derivatives were determined. In the structures of these compounds, an identical system of hydrogen bonds, C(4), was observed. Solid-state NMR was applied for testing the quality of the obtained samples. All of these compounds were tested for in vitro antibacterial activity against Gram-positive bacteria and Gram-negative bacteria, as well as antifungal activity, by checking their selectivity. ADME calculations indicate that the compounds can be tested as potential drugs.

Solid-State Study of the Structure, Dynamics, and Thermal Processes of Safinamide Mesylate─A New Generation Drug for the Treatment of Neurodegenerative Diseases.

Safinamide mesylate (SM), the pure active pharmaceutical ingredient (API) recently used in Parkinson disease treatment, recrystallized employing water-ethanol mixture of solvents (vol/vol 1:9) gives a different crystallographic form compared to SM in Xadago tablets. Pure SM crystallizes as a hemihydrate in the monoclinic system with the P21 space group. Its crystal and molecular structure were determined by means of cryo X-ray crystallography at 100 K. SM in the Xadago tablet exists in anhydrous form in the orthorhombic crystallographic system with the P212121 space group. The water migration and thermal processes in the crystal lattice were monitored by solid-state NMR spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. SM in Xadago in the high-humidity environment undergoes phase transformation to the P21 form which can be easily reversed just by heating up to 80 °C. For the commercial form of the API, there is also a reversible thermal transformation observed between Z' = 1 ↔ Z' = 3 crystallographic forms in the 0-20 °C temperature range. Analysis of molecular motion in the crystal lattice proves that the observed conformational polymorphism is forced by intramolecular dynamics. All above-mentioned processes were analyzed and described employing the NMR crystallography approach with the support of advanced theoretical calculations.

New salts of teriflunomide (TFM) - Single crystal X-ray and solid state NMR investigation.

New salts of teriflunomide TFM (drug approved for Multiple Sclerosis treatment) with inorganic counterions: lithium (TFM_Li), sodium (TFM_Na), potassium (TFM_K), rubidium (TFM_Rb), caesium (TFM_Cs) and ammonium (TFM_NH4) were prepared and investigated employing solid state NMR Spectroscopy, Powder X-ray Diffraction PXRD and Single Crystal X-ray Diffraction (SC XRD). Crystal and molecular structures of three salts: TFM_Na (CCDC: 2173257), TFM_Cs (CCDC: 2165288) and TFM_NH4 (CCDC: 2165281) were determined and deposited. Compared to the native TFM, for all crystalline salt structures, a conformational change of the teriflunomide molecule involving about 180-degree rotation of the end group, forming an intramolecular hydrogen bond N-H⋯O is observed. By applying a complementary multi-technique approach, employing 1D and 2D solid state MAS NMR techniques, single and powder X-ray diffraction measurements, as well as the DFT-based GIPAW calculations of NMR chemical shifts for TFM_Na and TFM_Cs allowed to propose structural features of TFM_Li for which it was not possible to obtain adequate material for single crystal X-Ray measurement.

Combining heteronuclear correlation NMR with spin-diffusion to detect relayed Cl-H-H and N-H-H proximities in molecular solids.

Analysis of short-to-intermediate range intermolecular interactions offers a great way of characterizing the solid-state organization of small molecules and materials. This can be achieved by two-dimensional (2D) homo- and heteronuclear correlation NMR spectroscopy, for example, by carrying out experiments at high magnetic fields in conjunction with fast magic-angle spinning (MAS) techniques. But, detecting 2D peaks for heteronuclear dipolar coupled spin pairs separated by greater than 3 Å is not always straightforward, particularly when low-gamma quadrupolar nuclei are involved. Here, we present a 2D correlation NMR experiment that combines the advantages of heteronuclear-multiple quantum coherence (HMQC) and proton-based spin-diffusion (SD) pulse sequences using radio-frequency-driven-recouping (RFDR) to probe inter and intramolecular 1H-X (X = 14N, 35Cl) interactions. This experiment can be used to acquire 2D 1H{X}-HMQC filtered 1H-1H correlation as well as 2D 1H-X HMQC spectra. Powder forms of dopamine·HCl and l-histidine·HCl·H2O are characterized at high fields (21.1 T and 18.8 T) with fast MAS (60 kHz) using the 2D HMQC-SD-RFDR approach. Solid-state NMR results are complemented with NMR crystallography analyses using the gauge-including projector augmented wave (GIPAW) approach. For histidine·HCl·H2O, 2D peaks associated with 14N-1H-1H and 35Cl-1H-1H distances of up to 4.4 and 3.9 Å have been detected. This is further corroborated by the observation of 2D peaks corresponding to 14N-1H-1H and 35Cl-1H-1H distances of up to 4.2 and 3.7 Å in dopamine·HCl, indicating the suitability of the HMQC-SD-RFDR experiments for detecting medium-range proximities in molecular solids.

Cytotoxic Activity against A549 Human Lung Cancer Cells and ADMET Analysis of New Pyrazole Derivatives.

Two new pyrazole derivatives, namely compound 1 and compound 2, have been synthesized, and their biological activity has been evaluated. Monocrystals of the obtained compounds were thoroughly investigated using single-crystal X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy. The results gathered from all three techniques are in good agreement, provide complete information about the structures of 1 and 2, and confirm their high purity. Thermal properties were studied using thermogravimetric analysis; both 1 and 2 are stable at room temperature. In order to better characterize 1 and 2, some physicochemical and biological properties have been evaluated using ADMET analysis. The cytotoxic activity of both compounds was determined using the MTT assay on the A549 cell line in comparison with etoposide. It was determined that compound 2 was effective in the inhibition of human lung adenocarcinoma cell growth and may be a promising compound for the treatment of lung cancer.

Porous Molecular Capsules as Non-Polymeric Transducers of Mechanical Forces to Mechanophores.

Mechanical grinding/milling can be regarded as historically the first technology for changing the properties of matter. Mechanically activated molecular units (mechanophores) can be present in various structures: polymers, macromolecules, or small molecules. However, only polymers have been reported to effectively transduce energy to mechanophores, which induces breakage of covalent bonds. In this paper, a second possibility is presented-molecular capsules as stress-sensitive units. Mechanochemical encapsulation of fullerenes in cystine-based covalent capsules indicates that complexation takes place in the solid state, despite the fact that the capsules do not possess large enough entrance portals. By using a set of solvent-free MALDI (sf-MALDI) and solid-state NMR (ss-NMR) experiments, it has been proven that encapsulation proceeds during milling and in this process hydrazones and disulfides get activated for breakage, exchange, and re-forming. The capsules are porous and therefore prone to collapse under solvent-free conditions and their conformational rigidity promotes the collapse by the breaking of covalent bonds.

The use of variable temperature 13 C solid-state MAS NMR and GIPAW DFT calculations to explore the dynamics of diethylcarbamazine citrate.

Experimental 13 C solid-state magic-angle spinning (MAS) Nuclear Magnetic Resonance (NMR) as well as Density-Functional Theory (DFT) gauge-including projector augmented wave (GIPAW) calculations were used to probe disorder and local mobility in diethylcarbamazine citrate, (DEC)+ (citrate)- . This compound has been used as the first option drug for the treatment of filariasis, a disease endemic in tropical countries and caused by adult worms of Wuchereria bancrofti, which is transmitted by mosquitoes. We firstly present 2D 13 C─1 H dipolar-coupling-mediated heteronuclear correlation spectra recorded at moderate spinning frequency, to explore the intermolecular interaction between DEC and citrate molecules. Secondly, we investigate the dynamic behavior of (DEC)+ (citrate)- by varying the temperature and correlating the experimental MAS NMR results with DFT GIPAW calculations that consider two (DEC)+ conformers (in a 70:30 ratio) for crystal structures determined at 293 and 235 K. Solid-state NMR provides insights on slow exchange dynamics revealing conformational changes involving particularly the DEC ethyl groups.

Competent Geometric Semantic Genetic Programming for Symbolic Regression and Boolean Function Synthesis.

Program semantics is a promising recent research thread in Genetic Programming (GP). Over a dozen semantic-aware search, selection, and initialization operators for GP have been proposed to date. Some of these operators are designed to exploit the geometric properties of semantic space, while others focus on making offspring effective, that is, semantically different from their parents. Only a small fraction of previous works aimed at addressing both of these features simultaneously. In this article, we propose a suite of competent operators that combine effectiveness with geometry for population initialization, mate selection, mutation, and crossover. We present a theoretical rationale behind these operators and compare them experimentally to operators known from literature on symbolic regression and Boolean function synthesis benchmarks. We analyze each operator in isolation as well as verify how they fare together in an evolutionary run, concluding that the competent operators are superior on a wide range of performance indicators, including best-of-run fitness, test-set fitness, and program size.

Correction: Analysis of local molecular motions of aromatic sidechains in proteins by 2D and 3D fast MAS NMR spectroscopy and quantum mechanical calculations.

Correction for 'Analysis of local molecular motions of aromatic sidechains in proteins by 2D and 3D fast MAS NMR spectroscopy and quantum mechanical calculations' by Piotr Paluch et al., Phys. Chem. Chem. Phys., 2015, 17, 28789-28801.

Analysis of local molecular motions of aromatic sidechains in proteins by 2D and 3D fast MAS NMR spectroscopy and quantum mechanical calculations.

We report a new multidimensional magic angle spinning NMR methodology, which provides an accurate and detailed probe of molecular motions occurring on timescales of nano- to microseconds, in sidechains of proteins. The approach is based on a 3D CPVC-RFDR correlation experiment recorded under fast MAS conditions (ν(R) = 62 kHz), where (13)C-(1)H CPVC dipolar lineshapes are recorded in a chemical shift resolved manner. The power of the technique is demonstrated in model tripeptide Tyr-(d)Ala-Phe and two nanocrystalline proteins, GB1 and LC8. We demonstrate that, through numerical simulations of dipolar lineshapes of aromatic sidechains, their detailed dynamic profile, i.e., the motional modes, is obtained. In GB1 and LC8 the results unequivocally indicate that a number of aromatic residues are dynamic, and using quantum mechanical calculations, we correlate the molecular motions of aromatic groups to their local environment in the crystal lattice. The approach presented here is general and can be readily extended to other biological systems.

Fine refinement of solid state structure of racemic form of phospho-tyrosine employing NMR Crystallography approach.

We present step by step facets important in NMR Crystallography strategy employing O-phospho-dl-tyrosine as model sample. The significance of three major techniques being components of this approach: solid state NMR (SS NMR), X-ray diffraction of powdered sample (PXRD) and theoretical calculations (Gauge Invariant Projector Augmented Wave; GIPAW) is discussed. Each experimental technique provides different set of structural constraints. From the PXRD measurement the size of the unit cell, space group and roughly refined molecular structure are established. SS NMR provides information about content of crystallographic asymmetric unit, local geometry, molecular motion in the crystal lattice and hydrogen bonding pattern. GIPAW calculations are employed for validation of quality of elucidation and fine refinement of structure. Crystal and molecular structure of O-phospho-dl-tyrosine solved by NMR Crystallography is deposited at Cambridge Crystallographic Data Center under number CCDC 1005924.

Influence of heterochirality on the structure, dynamics, biological properties of cyclic(PFPF) tetrapeptides obtained by solvent-free ball mill mechanosynthesis.

Cyclic tetrapeptides c(Pro-Phe-Pro-Phe) obtained by the mechanosynthetic method using a ball mill were isolated in a pure stereochemical form as a homochiral system (all L-amino acids, sample A) and as a heterochiral system with D configuration at one of the stereogenic centers of Phe (sample B). The structure and stereochemistry of both samples were determined by X-ray diffraction studies of single crystals. In DMSO and acetonitrile, sample A exists as an equimolar mixture of two conformers, while only one is monitored for sample B. The conformational space and energetic preferences for possible conformers were calculated using DFT methods. The distinctly different conformational flexibility of the two samples was experimentally proven by Variable Temperature (VT) and 2D EXSY NMR measurements. Both samples were docked to histone deacetylase HDAC8. Cytotoxic studies proved that none of the tested cyclic peptide is toxic.

Magic angle spinning NMR study of interaction of N-terminal sequence of dermorphin (Tyr-d-Ala-Phe-Gly) with phospholipids.

Two modifications of the Tyr-d-Ala-Phe-Gly tetrapeptide with different C-terminal groups (Tyr-d-Ala-Phe-Gly-OH 1 and Tyr-d-Ala-Phe-Gly-NH(2)2) were investigated by various nuclear magnetic resonance sequences under magic angle spinning. The structural constraints obtained from the magic angle spinning nuclear magnetic resonance measurements suggest that both peptides are aligned on the surface of the membrane and that the sandwich-like π-CH(3)-π arrangement of the pharmacophore is preserved. The influence of the chemical modification of the C-terminal residue of 1 and 2 on their interaction with phosphate group of the phospholipid in the subgel phase L(c) and the conformation of the peptides in the liquid crystalline phase L(α) are discussed. The correlation between the X-ray structure of 1 in the solid state and 1 embedded into a membrane in the L(c) phase is presented on the basis of the comparative analysis of the two-dimensional (13)C-(13)C dipolar-assisted rotational resonance cross-peaks and the (13)C isotropic chemical shifts.

NMR crystallography of α-poly(L-lactide).

A complementary approach that combines NMR measurements, analysis of X-ray and neutron powder diffraction data and advanced quantum mechanical calculations was employed to study the α-polymorph of L-polylactide. Such a strategy, which is known as NMR crystallography, to the best of our knowledge, is used here for the first time for the fine refinement of the crystal structure of a synthetic polymer. The GIPAW method was used to compute the NMR shielding parameters for the different models, which included the α-PLLA structure obtained by 2-dimensional wide-angle X-ray diffraction (WAXD) at -150 °C (model M1) and at 25 °C (model M2), neutron diffraction (WAND) measurements (model M3) and the fully optimized geometry of the PLLA chains in the unit cell with defined size (model M4). The influence of changes in the chain conformation on the (13)C σ(ii) NMR shielding parameters is shown. The correlation between the σ(ii) and δ(ii) values for the M1-M4 models revealed that the M4 model provided the best fit. Moreover, a comparison of the experimental (13)C NMR spectra with the spectra calculated using the M1-M4 models strongly supports the data for the M4 model. The GIPAW method, via verification using NMR measurements, was shown to be capable of the fine refinement of the crystal structures of polymers when coarse X-ray diffraction data for powdered samples are available.

Amorphization of Ethenzamide and Ethenzamide Cocrystals-A Case Study of Single and Binary Systems Forming Low-Melting Eutectic Phases Loaded on/in Silica Gel.

The applicability of different solvent-free approaches leading to the amorphization of active pharmaceutical ingredients (APIs) was tested. Ethenzamide (ET), an analgesic and anti-inflammatory drug, and two ethenzamide cocrystals with glutaric acid (GLU) and ethyl malonic acid (EMA) as coformers were used as pharmaceutical models. Calcinated and thermally untreated silica gel was applied as an amorphous reagent. Three methods were used to prepare the samples: manual physical mixing, melting, and grinding in a ball mill. The ET:GLU and ET:EMA cocrystals forming low-melting eutectic phases were selected as the best candidates for testing amorphization by thermal treatment. The progress and degree of amorphousness were determined using instrumental techniques: solid-state NMR spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. In each case, the API amorphization was complete and the process was irreversible. A comparative analysis of the dissolution profiles showed that the dissolution kinetics for each sample are significantly different. The nature and mechanism of this distinction are discussed.

Relationship between the Crystal Structure and Tuberculostatic Activity of Some 2-Amidinothiosemicarbazone Derivatives of Pyridine.

Tuberculosis remains one of the most common diseases affecting developing countries due to difficult living conditions, the rapidly increasing resistance of M. tuberculosis strains and the small number of effective anti-tuberculosis drugs. This study concerns the relationship between molecular structure observed in a solid-state by X-ray diffraction and the 15N NMR of a group of pyridine derivatives, from which promising activity against M. tuberculosis was reported earlier. It was found that the compounds exist in two tautomeric forms: neutral and zwitterionic. The latter form forced the molecules to adopt a stable, unique, flat frame due to conjugation and the intramolecular hydrogen bond system. As the compounds exist in a zwitterionic form in the crystal state generally showing higher activity against tuberculosis, it may indicate that this geometry of molecules is the "active" form.

Resolving Atomic-Scale Interactions in Nonfullerene Acceptor Organic Solar Cells with Solid-State NMR Spectroscopy, Crystallographic Modelling, and Molecular Dynamics Simulations.

Fused-ring core nonfullerene acceptors (NFAs), designated "Y-series," have enabled high-performance organic solar cells (OSCs) achieving over 18% power conversion efficiency (PCE). Since the introduction of these NFAs, much effort has been expended to understand the reasons for their exceptional performance. While several studies have identified key optoelectronic properties that govern high PCEs, little is known about the molecular level origins of large variations in performance, spanning from 5% to 18% PCE, for example, in the case of PM6:Y6 OSCs. Here, a combined solid-state NMR, crystallography, and molecular modeling approach to elucidate the atomic-scale interactions in Y6 crystals, thin films, and PM6:Y6 bulk heterojunction (BHJ) blends is introduced. It is shown that the Y6 morphologies in BHJ blends are not governed by the morphology in neat films or single crystals. Notably, PM6:Y6 blends processed from different solvents self-assemble into different structures and morphologies, whereby the relative orientations of the sidechains and end groups of the Y6 molecules to their fused-ring cores play a crucial role in determining the resulting morphology and overall performance of the solar cells. The molecular-level understanding of BHJs enabled by this approach will guide the engineering of next-generation NFAs for stable and efficient OSCs.