What Is Wrong with Hyaluronic Acid Chemistry? A 15N/13C Solid-State NMR Re-Evaluation of Its Dopamine Conjugates.

In this work, a systematic 15N/13C solid-state NMR investigation is performed on three dopamine (DA) conjugates of hyaluronic acid, considered in both its native (HA) and NaIO4-oxidized (HAOx) forms. Two of them, here named HAEDC-DA and HAOx-DA, have been previously introduced as covalent conjugates involving DA amine nitrogen: the former by EDC-mediated amide bond formation, and the latter by reaction of the Schiff base with the aldehyde moieties presumed to exist in HAOx. The third conjugate, HA-DA, is reported here for the first time; it is obtained by simply mixing hyaluronan with DA∙HCl at pH 5. The 15N ss-NMR spectra were found to be consistent in all the systems, and the DA molecules were found to be in their charged -NH3+ form, which contradicts the HAEDC-DA/HAOx-DA covalent bonding schemes proposed in the literature. The 13C ss-NMR results add useful new insights into the structure and interaction patterns of the conjugates. All of our findings are relevant for future practical applications, for instance in developing novel HA-based hydrogels. In addition, the present study demonstrates the importance of using the most appropriate analytical tools when investigating composite systems due to the complexity of hyaluronic acid conjugates. Solid-state NMR proved essential to answering the question in the title: actually, there is nothing wrong with hyaluronic acid chemistry; the claimed covalent bonds between DA and the HA(HAOx) chain do not exist in these systems, because the conditions for their formation do not hold in practice.

Polydopamine conjugated SiO2 nanoparticles as potential drug carriers for melanoma treatment.

Silica nanoparticles (SiO2) are increasingly investigated for biomedical applications. Aim: This study aimed to analyze the potential use of a SiO2 nanoparticles coated with biocompatible polydopamine (SiO2@PDA) as a potential chemotherapeutic drug carrier. Materials & methods: SiO2 morphology and PDA adhesion was analyzed by dynamic light scattering, electron microscopy and nuclear magnetic resonance. Cytotoxicity studies and morphology analyses (immunofluorescence, scanning and transmission electron microscopy) were used to assess the cellular reaction to the SiO2@PDA nanoparticles and to identify a biocompatible (safe use) window. Results & conclusion: Concentrations above 10 µg/ml and up to 100 µg/ml SiO2@PDA showed the best biocompatibility on human melanoma cells at 24 h and represent a potential drug carrier template for targeted melanoma cancer treatment.

Tiny particles can be small enough to enter cells. This is why they may be useful in the treatment of cancer. We made particles in a way that is friendly for human cells, then we analyzed their effects on cancer cells. Our tests showed that these particles could be useful for treatment because they do not worsen cancer cells. This is important because sometimes after treatment, cancer cells can become more dangerous. This way, even if the drug did not work, the cancer will not worsen.

Structural studies of various olmesartan solvates.

Seven solvates of the angiotensin II receptor blocker agent olmesartan (C24H26N6O3), namely, the methanol (C24H26N6O3·CH4O), ethanol (C24H26N6O3·C2H6O), isopropanol (C24H26N6O3·C3H8O), isobutanol (C24H26N6O3·C4H10O), 2-ethoxyethanol (C24H26N6O3·C4H10O2), chloroform (C24H26N6O3·CHCl3) and acetonitrile (C24H26N6O3·C2H3N) solvates, were successfully obtained. The crystal structures were determined using the single-crystal X-ray diffraction technique and the structural features are described, each solvate containing one molecule of olmesartan and one of solvent in the asymmetric unit. The samples were also analyzed by powder X-ray diffraction. Total lattice energies and binding energies between the olmesartan and solvent molecules were evaluated, which can be partitioned into electrostatic, polarization, dispersion and repulsion components. Hirshfeld and fingerprint plot analysis was performed to highlight the intermolecular contacts. Hydrogen bonding and supramolecular arrangements were comparatively studied for the seven solvates.

Solid-State and Theoretical Investigations of Some Banister-Type Macrocycles with 2,2'-Aldoxime-1,1'-Biphenyl Units.

In the context of helical chirality, bridging of biphenyl units leads to banister-type compounds and the stability of the resulted atropisomers may increase dramatically if suitable changes are performed in the linker unit that coils around the biphenyl moiety. A rigorous density functional theory (DFT) study was conducted for macrocycles containing rigid oxime ether segments connected to the biphenyl backbone in order to determine how the rotation barriers are influenced by the presence of either a flexible oligoethyleneoxide or a more rigid m-xylylene component in the macrocycle. The calculated values for the racemization barrier were in good agreement with those obtained experimentally and confirm the benefit of introducing a more rigid unit in the macrocycle on the stability of atropisomers. Solid-state data were obtained and computed data were used to assess the contribution brought by supramolecular associations observed in the lattice to the stabilization of the crystal structure. Beside introducing rigidity in the linker, complexation of flexible macrocycles with alkali metal ions is also contributing to the stability of atropisomers, leading to values for the racemization barrier matching that of the rigid macrocycle. Using diethylammonium cation as guest for the macrocycle, a spectacular increase in the barrier to rotation was observed for the resulted pseudo[2]rotaxane.

Hydrogen-Mediated Noncovalent Interactions in Solids: What Can NMR Crystallography Tell About?

Hydrogen atoms play a crucial role in the aggregation of organic (bio)molecules through diverse number of noncovalent interactions that they mediate, such as electrostatic in proton transfer systems, hydrogen bonding, and CH-π interactions, to mention only the most prominent. To identify and adequately describe such low-energy interactions, increasingly sensitive methods have been developed over time, among which quantum chemical computations have witnessed impressive advances in recent years. For reaching the present state-of-the-art, computations had to rely on a pool of relevant experimental data, needed at least for validation, if not also for other purposes. In the case of molecular crystals, the best illustration for the synergy between computations and experiment is given by the so-called NMR crystallography approach. Originally designed to increase the confidence level in crystal structure determination of organic compounds from powders, NMR crystallography is able now to offer also a wealth of information regarding the noncovalent interactions that drive molecules to pack in a given crystalline pattern or another. This is particularly true for the noncovalent interactions which depend on the exact location of labile hydrogen atoms in the system: in such cases, NMR crystallography represents a valuable characterization tool, in some cases complementing even the standard single-crystal X-ray diffraction technique. A concise introduction in the field is made in this mini-review, which is aimed at providing a comprehensive picture with respect to the current accuracy level reached by NMR crystallography in the characterization of hydrogen-mediated noncovalent interactions in organic solids. Different types of practical applications are illustrated with the example of molecular crystals studied by our research group, but references to other representative developments reported in the literature are also made. By summarizing the major concepts and methodological progresses, the present work is also intended to be a guide to the practical potential of this relatively recent analytical tool for the scientists working in areas where crystal engineering represents the main approach for rational design of novel materials.

Ketoconazole-p-aminobenzoic Acid Cocrystal: Revival of an Old Drug by Crystal Engineering.

The 1:1 cocrystal of the antifungal agent ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of disorder. Powder dissolution measurements revealed a 10-fold aqueous solubility increase that induces a 6.7-fold oral bioavailability improvement compared to ketoconazole. In vitro cell assays showed a good toxicity profile of the cocrystal with lower oxidative stress and inflammation and enhanced antifungal activity against several Candida species. The in vivo study of the cocrystal indicated similar pharmacokinetic profiles and liver toxicity with increased transaminases, as reported for ketoconazole. Notably, besides minor signs of inflammation, no morphological changes in liver parenchyma or signs of fibrosis and necrosis were detected. The enhanced solubility and oral bioavailability of the cocrystal over ketoconazole, together with the improved antifungal activity and good in vitro/in vivo toxicity, indicate its potential use as an alternative antifungal agent to the parent drug. Our results bring evidence of cocrystallization as a successful approach for bioavailability improvement of poorly soluble drugs.

A three-armed cryptand with triazine and pyridine units: synthesis, structure and complexation with polycyclic aromatic compounds.

The aromatic nucleophilic substitution reaction based synthesis of a three-armed cryptand displaying 2,4,6-triphenyl-1,3,5-triazine units as caps and pyridine rings in the bridges, along with NMR, MS and molecular modelling-based structural analysis of this compound are reported. Appropriate NMR and molecular modelling investigations proved the formation of 1:1 host-guest assemblies between the investigated cryptand and some polynuclear aromatic hydrocarbons or their derivatives.

Novel Palladium(II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells.

New Pd(II) complexes of 1,7-bis(2-methoxyphenyl)hepta-1,6-diene-3,5-dione were synthesized and structurally characterized. The complexes were tested in vitro on human colon and hepatic carcinoma cell lines, normal hepatic cells and hematopoietic progenitor cells. Biological tests proved that Pd(II) complexes 1 and 2 (containing a curcumin derivative) exhibit a strong in vitro antitumor effect against the cells derived from human colorectal carcinoma and the hepatic metastasis of a colorectal carcinoma. Complex 1 has an outstanding inhibitory effect against BRAF-mutant colon carcinoma and hepatocarcinoma cell growth; 1 and 2 are both more active than the free ligand and have the capacity to trigger early apoptotic processes. By flow cytometric measurements, an important decrease of prominin-1 (CD133) molecule expression on tumor cells membrane was identified in cell populations subjected to 1 and 2. Quantitative immune enzymatic assay proved restrictions in stem cell factor (SCF) release by treated tumor cells. Although less cytotoxic, the free ligand inhibits the surface marker CD133 expression in hepatocarcinoma cells, and in HT-29 colon carcinoma. The new synthesized Pd(II) complexes 1 and 2 exhibit an important potential through their selective cytotoxic activity and by targeting the stem-like tumor cell populations, which leads to the tumor growth arrest and prevention of metastasis.

Optimized multi-step NMR-crystallography approach for structural characterization of a stable quercetin solvate.

Herein we report the preparation and solid state structural investigation of the 1,4-dioxane-quercetin solvate. NMR crystallography methods were employed for crystal structure determination of the solvate from microcrystalline powder. The stability of the compound relative to other reported quercetin solvates is discussed and found to be in perfect agreement with the hydrogen bonding networks/supra-molecular architectures formed in each case. It is also clearly shown that NMR crystallography represents an ideal analytical tool in such cases when hydrogen-bonding networks are required to be constrained at a high accuracy level.

Silver(I) 2,2'-(1,2-Phenylenedisulfanediyl)diacetic Acid as a Molecular Building Block for a Silver(I)-Cadmium(II) Coordination Polymer.

Starting from heterotopic multidentate ligand 2,2'-(1,2-phenylenedisulfanediyl)diacetic acid, (RS,RS,RS,RS/SS,SS,SS,SS)-[Ag{1,2-C6H4(SCH2COOH)2-κ2S,S'}2]BF4 (1) was prepared and further used as a building block for the synthesis of heterobimetallic Ag-Cd coordination polymer [Ag2Cd2{1,2-(OOCCH2S)2C6H4}3 (H2O)3·5H2O]n (2). Both complexes were characterized by X-ray structure analysis and conventional spectroscopic techniques.

N-Butyl-4-butyl-imino-2-methyl-pentan-2-aminium (E)-quercetinate.

The title salt, C(14)H(31)N(2) (+)·C(15)H(9)O(7) (-), was obtained in the reaction of quercetin with n-butyl-amine in a mixture of acetone and hexane. The crystal structure determination shows that the quercetin donates one of its phenol H atoms to the N-butyl-4-butyl-imino-2-methyl-pentan-2-amine mol-ecule. The crystal structure of the salt is stabilized by intramolecular (N-H⋯N for the cation and O-H⋯O for the anion) and intermolecular hydrogen bonding (N-H⋯O between cation-anion pairs and O-H⋯O between anions). Quercetin molecules form dimers connected into a two-dimensional network. The dihedral angle between the quercetin ring systems is 19.61 (8)°.