Structural and sorption characteristics of an aerogel composite material loaded with flufenamic acid: insights from MAS NMR and high-pressure NOESY studies.

The structural and sorption characteristics of a composite material consisting of a silica aerogel loaded with flufenamic acid were investigated using a variety of nuclear magnetic resonance techniques. The composite structure was analyzed using magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy, which revealed significant interactions between the aerogel matrix and the FFA molecules. Solid-state 29Si NMR provided insights into the aerogel's stability, while 1H and 13C NMR confirmed the presence of FFA in the matrix, with signals from FFA molecules observed alongside tetraethoxysilane (TEOS) groups. Ethanol-induced desorption of FFA led to narrowed spectral lines, suggesting the breaking of intermolecular hydrogen bonds. 19F MAS NMR spectra indicated changes in FFA local environments upon loading into AG pores. Evaluation of CO2 sorption characteristics using 13C NMR demonstrated a slower sorption rate for AG + FFA than that for pure AG, attributed to decreased pore volume. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) was employed to explore the conformational behavior of FFA within the aerogel matrix. The results indicated a shift in conformer populations, particularly those related to the rotation of one cyclic fragment relative to the other. These findings provide insights into the structural and sorption characteristics of the AG + FFA composite, which are valuable for developing novel drug solid forms.

Influence of Solvent Polarity on the Conformer Ratio of Bicalutamide in Saturated Solutions: Insights from NOESY NMR Analysis and Quantum-Chemical Calculations.

The study presents a thorough and detailed analysis of bicalutamide's structural and conformational properties. Quantum chemical calculations were employed to explore the conformational properties of the molecule, identifying significant energy differences between conformers. Analysis revealed that hydrogen bonds stabilise the conformers, with notable variations in torsion angles. Conformers were classified into 'closed' and 'open' types based on the relative orientation of the cyclic fragments. NOE spectroscopy in different solvents (CDCl3 and DMSO-d6) was used to study the conformational preferences of the molecule. NOESY experiments provided the predominance of 'closed' conformers in non-polar solvents and a significant presence of 'open' conformers in polar solvents. The proportions of open conformers were 22.7 ± 3.7% in CDCl3 and 59.8 ± 6.2% in DMSO-d6, while closed conformers accounted for 77.3 ± 3.7% and 40.2 ± 6.2%, respectively. This comprehensive study underscores the solvent environment's impact on its structural behaviour. The findings significantly contribute to a deeper understanding of conformational dynamics, stimulating further exploration in drug development.

meso-Bromination of cyano- and aquacobalamins facilitates their processing into Co(II)-species by glutathione.

Cyanocobalamin (CNCbl), a medicinal form of vitamin B12, is resistant to glutathione (GSH), and undergoes intracellular processing via reductive decyanation producing the Co(II)-form of Cbl (Cbl(II)) mediated by the CblC-protein. Alteration of the CblC-protein structure might inhibit CNCbl processing. Here, we showed that introducing a bromine atom to the C10-position of the CNCbl corrin ring facilitates its reaction with GSH leading to the formation of Cbl(II) and cyanide dissociation. In a neutral medium, the reaction between C10-Br-CNCbl and GSH proceeds via the complexation of the reactants further leading to dimethylbenzimidazole (DMBI) substitution and electron transfer from GSH to the Co(III)-ion. The reaction is accelerated upon the GSH thiol group deprotonation. The key factors explaining the higher reactivity of C10-Br-CNCbl compared with unmodified CNCbl towards GSH are increasing the electrode potential of CNCbl two-electron reduction upon meso-bromination and the substantial labilization of DMBI, which was shown by comparing their reactions with cyanide and the pKa values of DMBI protonation (pKa base-off). Aquacobalamin (H2OCbl) brominated at the C10-position of the corrin reacts with GSH to give Cbl(II) via GSH complexation and subsequent reaction of this complex with a second GSH molecule, whereas unmodified H2OCbl generates glutathionyl-Cbl, which is resistant to further reduction by GSH.

Accurate prediction of 11B NMR chemical shift of BODIPYs via machine learning.

In this article, we present the results of developing a model based on an RFR machine learning method using the ISIDA fragment descriptors for predicting the 11B NMR chemical shift of BODIPYs. The model is freely available at https://ochem.eu/article/146458. The model demonstrates the high quality of predicting the 11B NMR chemical shift (RMSE, 5CV (FINALE training set) = 0.40 ppm, RMSE (TEST set) = 0.14 ppm). In addition, we compared the "cost" and the user-friendliness for calculations using the quantum-chemical model with the DFT/GIAO approach. The 11B NMR chemical shift prediction accuracy (RMSE) of the model considered is more than three times higher and tremendously faster than the DFT/GIAO calculations. As a result, we provide a convenient tool and database that we collected for all researchers, that allows them to predict the 11B NMR chemical shift of boron-containing dyes. We believe that the new model will make it easier for researchers to correctly interpret the 11B NMR chemical shifts experimentally determined and to select more optimal conditions to perform an NMR experiment.

Amine-Reactive BODIPY Dye: Spectral Properties and Application for Protein Labeling.

A boron-dipyrromethene (BODIPY) derivative reactive towards amino groups of proteins (NHS-Ph-BODIPY) was synthesized. Spectroscopic and photophysical properties of amine-reactive NHS-Ph-BODIPY and its non-reactive precursor (COOH-Ph-BODIPY) in a number of organic solvents were investigated. Both fluorescent dyes were characterized by green absorption (521-532 nm) and fluorescence (538-552 nm) and medium molar absorption coefficients (46,500-118,500 M-1·cm-1) and fluorescence quantum yields (0.32 - 0.73). Solvent polarizability and dipolarity were found to play a crucial role in solvent effects on COOH-Ph-BODIPY and NHS-Ph-BODIPY absorption and emission bands maxima. Quantum-chemical calculations were used to show why solvent polarizability and dipolarity are important as well as to understand how the nature of the substituent affects spectroscopic properties of the fluorescent dyes. NHS-Ph-BODIPY was used for fluorescent labeling of a number of proteins. Conjugation of NHS-Ph-BODIPY with bovine serum albumin (BSA) resulted in bathochromic shifts of absorption and emission bands and noticeable fluorescence quenching (about 1.5 times). It was demonstrated that the sensitivity of BSA detection with NHS-Ph-BODIPY was up to eight times higher than with Coomassie brilliant blue while the sensitivity of PII-like protein PotN (PotN) detection with NHS-Ph-BODIPY and Coomassie brilliant blue was almost the same. On the basis of the molecular docking results, the most probable binding sites of NHS-Ph-BODIPY in BSA and PotN and the corresponding binding free energies were estimated.

Mechanism of cyanocobalamin chlorination by hypochlorous acid.

Hypochlorous acid (HOCl) is a strong oxidant produced by myeloperoxidase. Previous work suggested that HOCl modifies the corrin ring of cobalamins to yield chlorinated species via mechanisms that are incompletely understood. Herein, we report a mechanistic study on the reaction between cyanocobalamin (CNCbl, vitamin B12) and HOCl. Under weakly acidic, neutral and weakly alkaline conditions, the reaction produces the c-lactone derivative of CNCbl chlorinated at the C10-position of corrin ring (C10-Cl-CNCbl-c-lactone). Formation of C10-Cl-CNCbl-c-lactone was not observed at pH ≥ 9.9. The chlorination of CNCbl by HOCl proceeds via two pathways involving one and two HOCl molecules: the reaction is initiated by the very fast formation of a complex between CNCbl and HOCl, which either undergoes slow transformation to chlorinated species, or rapidly reacts with a second HOCl molecule to produce C10-Cl-CNCbl. Subsequent reaction of C10-Cl-CNCbl with HOCl proceeds rapidly toward lactone ring formation by H-atom abstraction at position C8. This work uncovered mechanisms and products of the reaction of a biologically active and therapeutically used cobalamin, CNCbl and the endogenous oxidant HOCl. Binding and reactivity studies of C10-Cl-CNCbl and C10-Cl-CNCbl-c-lactone with relevant proteins of the cobalamin pathway and with cultured cells are necessary to elucidate the potential physiological effects of these species.

La(III), Ce(III), Gd(III), and Eu(III) Complexation with Tris(hydroxymethyl)aminomethane in Aqueous Solution.

Lanthanides such as cerium(III), europium(III), and gadolinium(III) are widely used for designing fluorescent probes or magnetic resonance imaging contrasting agents for biological systems. The synthesis and study of lanthanide complexes in buffer solutions imitating biological fluids are often complicated because of a lack of data on the lanthanide interactions with buffer solution components. Therefore, Ln(III) [where Ln(III) = La(III), Ce(III), Gd(III), Eu(III)] complexation with a widely used buffer agent, tris(hydroxymethyl)aminomethane (Tris), in aqueous solution is studied using potentiometry, spectrofluorimetry, and 139La NMR spectroscopy. The stoichiometric composition of complexes is determined using mass spectrometry. The thermodynamic stability constants of Ln(III)-Tris complexes are calculated from potentiometric and spectral data; the difficulties in the study of these systems, reliability, and accuracy of the obtained constants are discussed. The possible structures of free Tris and its complexes with lanthanides(III) are optimized on the density functional theory/PBE0 level; the peculiarities of metal-ligand bonds were studied by Quantum Theory Atoms in Molecules analysis.

Correction: Mamardashvili et al. New Polyporphyrin Arrays with Controlled Fluorescence Obtained by Diaxial Sn(IV)-Porphyrin Phenolates Chelation with Cu2+ Cation. Polymers 2021, 13, 829.

In the original publication [...].

C-H-activated Csp2-Csp3 diastereoselective gridization enables ultraviolet-emitting stereo-molecular nanohydrocarbons with mulitple H···H interactions.

Gridization is an emerging molecular integration technology that enables the creation of multifunctional organic semiconductors through precise linkages. While Friedel-Crafts gridization of fluorenols is potent, direct linkage among fluorene molecules poses a challenge. Herein, we report an achiral Pd-PPh3-cataylized diastereoselective (>99:1 d.r.) gridization based on the C-H-activation of fluorene to give dimeric and trimeric windmill-type nanogrids (DWGs and TWGs). These non-conjugated stereo-nanogrids showcase intramolecular multiple H…H interactions with a low field shift to 8.51 ppm and circularly polarized luminescence with high luminescent dissymmetry factors (|gPL | = 0.012). Significantly, the nondoped organic light-emitting diodes (OLEDs) utilizing cis-trans-TWG1 emitter present an ultraviolet electroluminescent peak at ~386 nm (CIE: 0.17, 0.04) with a maximum external quantum efficiency of 4.17%, marking the highest record among nondoped ultraviolet OLEDs based on hydrocarbon compounds and the pioneering ultraviolet OLEDs based on macrocycles. These nanohydrocarbon offer potential nanoscafflolds for ultraviolet light-emitting optoelectronic applications.

Conformational Screening of Arbidol Solvates: Investigation via 2D NOESY.

Understanding of the nucleation process's fundamental principles in saturated solutions is an urgent task. To do this task, it is necessary to control the formation of polymorphic forms of biologically active compounds. In certain cases, a compound can exist in a single polymorphic form, but have several solvates which can appear in different crystal forms, depending on the medium and conditions of formation, and show different pharmaceutical activity. In the present paper, we report on the analysis of Arbidol conformational preferences in two solvents of different polarities-deuterated chloroform and dimethyl sulfoxide-at 25 °C, using the 2D NOESY method. The Arbidol molecule has various solvate forms depending on the molecular conformation. The method based on the nuclear Overhauser effect spectroscopy was shown to be efficient in the analysis of complex heterocyclic compounds possessing conformation-dependent pseudo-polymorphism. It is one of the types of polymorphism observed in compounds forming crystal solvates. Combined use of NMR methods and X-ray data allowed determining of conformer populations of Arbidol in CDCl3 and DMSO-d6 which were found to be 8/92% and 37/63%, respectively. The preferred conformation in solution is the same that appears in stable crystal solvates of Arbidol.

Synthesis and Design of Hybrid Metalloporphyrin Polymers Based on Palladium (II) and Copper (II) Cations and Axial Complexes of Pyridyl-Substituted Sn(IV)Porphyrins with Octopamine.

Supramolecular metalloporphyrin polymers formed by binding tetrapyrrolic macrocycle peripheral nitrogen atoms to Pd(II) cations and Sn(IV)porphyrins extra-ligands reaction centers to Cu(II) cations were obtained and identified. The structure and the formation mechanism of obtained hydrophobic Sn(IV)-porphyrin oligomers and polymers in solution were established, and their resistance to UV radiation and changes in solution temperature was studied. It was shown that the investigated polyporphyrin nanostructures are porous materials with predominance cylindrical mesopores. Density functional theory (DFT) was used to geometrically optimize the experimentally obtained supramolecular porphyrin polymers. The sizes of unit cells in porphyrin tubular structures were determined and coincided with the experimental data. The results obtained can be used to create highly porous materials for separation, storage, transportation, and controlled release of substrates of different nature, including highly volatile, explosive, and toxic gases.

Conformational State of Fenamates at the Membrane Interface: A MAS NOESY Study.

The present work analyzes the 1H NOESY MAS NMR spectra of three fenamates (mefenamic, tolfenamic, and flufenamic acids) localized in the lipid-water interface of phosphatidyloleoylphosphatidylcholine (POPC) membranes. The observed cross-peaks in the two-dimensional NMR spectra characterized intramolecular proximities between the hydrogen atoms of the fenamates as well as intermolecular interactions between the fenamates and POPC molecules. The peak amplitude normalization for an improved cross-relaxation (PANIC) approach, the isolated spin-pair approximation (ISPA) model, and the two-position exchange model were used to calculate the interproton distances indicative of specific conformations of the fenamates. The results showed that the proportions of the A+C and B+D conformer groups of mefenamic and tolfenamic acids in the presence of POPC were comparable within the experimental error and amounted to 47.8%/52.2% and 47.7%/52.3%, respectively. In contrast, these proportions for the flufenamic acid conformers differed and amounted to 56.6%/43.4%. This allowed us to conclude that when they bind to the POPC model lipid membrane, fenamate molecules change their conformational equilibria.

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY.

The search for new forms of already known drug compounds is an urgent problem of high relevance as more potent drugs with fewer side effects are needed. The trifluoromethyl group in flufenamic acid renders its chemical structure differently from other fenamates. This modification is responsible for a large number of conformational polymorphs. Therefore, flufenamic acid is a promising structural modification of well-known drug molecules. An effective approach in this field is micronization, employing "green" supercritical fluid technologies. This research raises some key questions to be answered on how to control polymorphic forms during the micronization of drug compounds. The results presented in this work demonstrate the ability of two-dimensional nuclear Overhauser effect spectroscopy to determine conformational preferences of small molecular weight drug compounds in solutions and fluids, which can be used to predict the polymorphic form during the micronization. Quantitative analysis was carried out to identify the conformational preferences of flufenamic acid molecules in dimethyl sulfoxide-d6 medium at 25 °C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 °C and 9 MPa. The data presented allows predictions of the flufenamic acid conformational preferences of poorly soluble drug compounds to obtain new micronized forms.

The Role of Hidden Conformers in Determination of Conformational Preferences of Mefenamic Acid by NOESY Spectroscopy.

Mefenamic acid has been used as a non-steroidal anti-inflammatory drug for a long time. However, its practical use is quite limited due to a number of side effects on the intestinal organs. Conformational polymorphism provides mefenamic acid with unique properties regarding possible modifications obtained during the micronization process, which can improve pharmacokinetics and minimize side effects. Micronization can be performed by decompression of supercritical fluids; methods such as rapid expansion of the supercritical solution have proven their efficiency. However, this group of methods is poorly applicable for compounds with low solubility, and the modification of the method using a pharmaceutically suitable co-solvent may be useful. In our case, addition of only 2 mol% dimethyl sulfoxide increased the solubility remarkably. Information on the conformational state may be critically important for carrying out micronization. In this work, structural analysis and estimate of conformational preferences of mefenamic acid in dimethyl sulfoxide-d6 (at 25 °C and 0.1 MPa) and in a mixed solvent supercritical carbon dioxide + dimethyl sulfoxide-d6 (45 °C, 9 MPa) were performed based on nuclear Overhauser effect spectroscopy. Results show changes in the conformation fractions depending on the medium used. The importance of allowing for hidden conformers in estimating the conformational state was demonstrated in the analysis. Obtained results may be useful for improving micronization parameters.

Molecular Dynamics and Nuclear Magnetic Resonance Studies of Supercritical CO2 Sorption in Poly(Methyl Methacrylate).

The study of supercritical carbon dioxide sorption processes is an important and urgent task in the field of "green" chemistry and for the selection of conditions for new polymer material formation. However, at the moment, the research of these processes is very limited, and it is necessary to select the methodology for each polymer material separately. In this paper, the principal possibility to study the powder sorption processes using 13C nuclear magnetic resonance spectroscopy, relaxation-relaxation correlation spectroscopy and molecular dynamic modeling methods will be demonstrated based on the example of polymethylmethacrylate and supercritical carbon dioxide. It was found that in the first nanoseconds and seconds during the sorption process, most of the carbon dioxide, about 75%, is sorbed into polymethylmethacrylate, while on the clock scale the remaining 25% is sorbed. The methodology presented in this paper makes it possible to select optimal conditions for technological processes associated with the production of new polymer materials based on supercritical fluids.

Conjugate of meso-carboxysubstituted-BODIPY with thioterpenoid as an effective fluorescent probe: Synthesis, structure, spectral characteristics, and molecular docking.

This paper is devoted to the design of a fluorescent probe based on meso-carboxysubstituted-BODIPY with a thioterpene fragment. The functional replacement of the methoxy group in the BODIPY molecule on a thioterpene fragment was carried out in order to find out the antiplatelet and anticoagulant action mechanisms of thioterpenoids and to assess the membrane and receptor factors contributions. The molecular structure of the conjugate was confirmed via UV/vis-, NMR- and MS-spectra. It is found that the probe is a high fluorescence quantum yield (to âˆ¼ 100%) in the blue-green region at 509-516 nm. Molecular docking of all studied molecules showed that the BODIPY with terpenoid conjugation is an excellent way to increase their affinity to platelet receptor P2Y12.

Design, Spectral Characteristics, Photostability, and Possibilities for Practical Application of BODIPY FL-Labeled Thioterpenoid.

This paper presents the design and a comparative analysis of the structural and solvation factors on the spectral and biological properties of the BODIPY biomarker with a thioterpene fragment. Covalent binding of the thioterpene moiety to the butanoic acid residue of meso-substituted BODIPY was carried out to find out the membranotropic effect of conjugate to erythrocytes, and to assess the possibilities of its practical application in bioimaging. The molecular structure of the conjugate was confirmed via X-ray, UV/vis-, NMR-, and MS-spectra. It was found that dye demonstrates high photostability and high fluorescence quantum yield (to ~100%) at 514-519 nm. In addition, the marker was shown to effectively penetrate the erythrocytes membrane in the absence of erythrotoxicity. The conjugation of BODIPY with thioterpenoid is an excellent way to increase affinity dyes to biostructures, including blood components.

New Polyporphyrin Arrays with Controlled Fluorescence Obtained by Diaxial Sn(IV)-Porphyrin Phenolates Chelation with Cu2+ Cation.

New coordination oligomers and polymers of Sn(IV)-tetra(4-sulfonatophenyl)porphyrin have been constructed by the chelation reaction of its diaxialphenolates with Cu2+. The structure and properties of the synthesized polyporphyrin arrays were investigated by 1H Nuclear Magnetic Resonance (1H NMR), Infra Red (IR), Ultra Violet - Visible (UV-Vis) and fluorescence spectroscopy, mass spectrometry, Powder X-Rays Diffraction (PXRD), Electron Paramagnetic Resonance (EPR), thermal gravimetric, elemental analysis, and quantum chemical calculations. The results show that the diaxial coordination of bidentate organic ligands (L-tyrazine and diaminohydroquinone) leads to the quenching of the tetrapyrrole chromophore fluorescence, while the chelation of the porphyrinate diaxial complexes with Cu2+ is accompanied by an increase in the fluorescence in the organo-inorganic hybrid polymers formed. The obtained results are of particular interest to those involved in creating new 'chemo-responsive' (i.e., selectively interacting with other chemical species as receptors, sensors, or photocatalysts) materials, the optoelectronic properties of which can be controlled by varying the number and connection type of monomeric fragments in the polyporphyrin arrays.

Design, Spectral Characteristics, and Possibilities for Practical Application of BODIPY FL-Labeled Monoterpenoid.

This article describes the design and biological properties of a BODIPY FL-labeled monoterpenoid BF2-meso-(4-((1″R)-6″,6″-dimethylbicyclo[3.1.1]hept-2″-ene-2″)yl-methoxycarbonylpropyl)-3,3',5,5'-tetramethyl-2,2'-dipyrromethene conjugate (BODIPYmyrt). The fluorophore was characterized using X-ray, NMR, MS, and UV/vis spectroscopy. The conjugate exhibits a high quantum yield (to ∼100%) in the region 515-518 nm. BODIPYmyrt effectively penetrates the membranes of the bacterial and fungal cells and therefore can be used to examine the features of a broad spectrum of Gram-positive and Gram-negative bacteria and pathogenic fungi as well. Moreover, BODIPYmyrt exhibits a moderate tropism to the subcellular structures in mammalian cells (e.g., mitochondria), thereby providing an attractive scaffold for fluorophores to examine these particular organelles.

Luminescent properties of new 2,2-, 2,3- and 3,3-CH2-bis(BODIPY)s dyes: Structural and solvation effects.

In this paper the synthesis and spectral properties of three new dimeric bis(BODIPY)s with two indacene domains connected by a methylene (-CH2-) spacer at 2,2-, 2,3- or 3,3- positions were reported. It was found bis(BODIPY)s exhibit a high sensitivity of fluorescence to the medium properties. To interpret solvatochromic effects of bis(BODIPY)s, a multilinear correlation analysis of bis(BODIPY)s fluorescence quantum yields with respect to solvent different parameters was carried out. To understand the features of the spectral properties of bis(BODIPY)s, we carried out a thorough quantum-chemical analysis of the structural, conformational, and spectral characteristics of bis(BODIPY)s. The obtained bis(BODIPY)s have a high potential for application as sensors of medium polarity.