The Phenomenon of Self-Induced Diastereomeric Anisochrony and Its Implications in NMR Spectroscopy

Nuclear magnetic resonance (NMR) spectroscopy is an analytical technique largely applied in the analysis of discrimination processes involving enantiomeric substrates and chiral agents, which can interact with the analyte either via covalent bonding or via formation of diastereomeric solvates. However, enantiodiscrimination has been observed, in some cases, even in the absence of any additional chiral selector. The reasons behind this phenomenon must be found in the capability of some chiral substrates to interact with themselves by forming diastereomeric solvates in solution that can generate nonequivalences in the NMR spectra of enantiomerically enriched mixtures. As a result, differentiation of enantiomers is observed, thus allowing the quantification of the enantiomeric composition of the mixture under investigation. The tendency of certain substrates to self-aggregate and to generate diastereomeric adducts in solution can be defined as Self-Induced Diastereomeric Anisochrony (SIDA), but other acronyms have been used to refer to this phenomenon. In the present work, an overview of SIDA processes investigated via NMR spectroscopy will be provided, with a particular emphasis on the nature of the substrates involved, on the interaction mechanisms at the basis of the phenomenon, and on theoretical treatments proposed in the literature to explain them

Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics

: Silylated-acetylated cyclodextrin (CD) derivatives have recently been investigated, via nuclear magnetic resonance (NMR) spectroscopy, as chiral sensors for substrates that are endowed and devoid of fluorine atoms, and the importance of Si-F interaction in the discrimination phenomena has been assessed. Here, the contributions of both superficial interactions and inclusion processes were further evaluated by extending the records to other chiral fluorinated substrates of interest for pharmaceutical applications. Non-equivalences were measured for both the 1H and 19F resonances in equimolar mixtures with the CDs; the promising results also supported the use of chiral sensors in sub-stoichiometric amounts. Finally, the occurrence of inclusion processes was evaluated by analyzing the intermolecular dipolar interactions by means of ROESY (Rotating-frame Overhauser Enhancement Spectroscopy) experiments. The study confirmed that the γCD derivative is the best chiral solvating agent for the fluorinated substrates investigated, likely due to the higher number of silyl moieties that can be involved in Si-F interactions. The contribution of inclusion processes to the enantiodiscrimination was also confirmed by comparison with the α- and β-analogues. Overall, the CD derivatives proved to be able to discriminate fluorinated substrates even when used in sub-stoichiometric amounts

Role of nanostructured aggregation of chitosan derivatives on [5-methionine]enkephalin affinity

Affinities of quaternary ammonium-chitosan conjugates, their thiolated derivatives and corresponding nanostructured aggregates towards the hydrophilic drug [5-methionine]enkephalin were compared by Nuclear Magnetic Resonance (NMR) spectroscopic methods based on proton selective relaxation rate measurements. Nanoaggregates showed enhanced drug affinity in comparison with corresponding polymers, especially in the case of thiolated systems

NMR Investigation of the Interaction of Three Non-Steroidal Anti-Inflammatory Drugs with Human Serum Albumin

The understanding of the interaction between non-steroidal anti-inflammatory drugs and human serum albumin plays a fundamental role in the development of new drugs and new therapeutic strategies. Several studies have been performed, nevertheless, the interaction phenomena are still not fully understood. In this work, high-field solution Nuclear Magnetic Resonance (NMR) spectroscopy was applied to compare the strength of the interaction of diclofenac sodium salt, ketorolac tris salt and flurbiprofen sodium salt toward albumin. To this aim, mono- and bi-selective relaxation rate measurements were performed by applying selective π-pulses at the selected frequencies and by following magnetization recovery. On the basis of the dependence of relaxation parameters on albumin concentration, normalized affinity indexes were calculated for several protons of the drugs. Affinity indexes for diclofenac were about five-fold higher in comparison with ketorolac and flurbiprofen. Aromatic moieties of the three drugs and methine protons at the chiral centers of ketorolac and flurbiprofen were more involved in the interaction with albumin. In conclusion, NMR spectroscopy allows not only for the comparison of drug-to- protein affinities but also points out the nature of the drug sites that are more extensively involved in the interaction

Regio- and stereoselective behavior of l-arabinal-derived vinyl epoxide in nucleophilic addition reactions. Comparison with conformationally restricted d-galactal-derived analogs

Abstract The regio- and stereoselectivity of the addition reactions of O-, C-, N-, and S-nucleophiles to l-arabinal-derived vinyl epoxide 2, the simplest non-conformationally restricted glycal-derived vinyl epoxide, has been examined and compared with the corresponding, conformationally restricted d-galactal-derived analogs 1β and 1β-Me. Results indicated that the 1,4-/1,2-regioselectivity ratio and the related syn-1,4-/anti-1,2-stereoselectivity observed in glycal-derived vinyl oxiranes is independent of the presence of substituents on the six-membered unsaturated ring, and the absence of conformational freedom: it depends only on the ability of the nucleophile to give a coordination process with the oxirane oxygen in the form of a hydrogen bond or through a coordinating cation

A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-β-cyclodextrin conjugate forming inclusion complexes with dexamethasone

The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-β-cyclodextrin (MCD) on quaternary ammonium chitosan (QA-Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water-soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices

Efficient Ligand Passivation Enables Ultrastable CsPbX3 Perovskite Nanocrystals in Fully Alcohol Environments

Halide perovskite nanocrystals (PNCs) have demonstrated their wide potential to fabricate efficient optoelectronic devices and to prepare promising photocatalysts for solar-driven photo(electro)chemical reactions. However, their use in most of the practical applications is limited due to the instability of PNCs in polar environments. Here, the preparation of non-encapsulated CsPbX3 nanocrystals dispersed in fully alcohol environments, with outstanding stability through surface defect passivation strategy is reported. By using didodecyldimethylammonium bromide (DDAB) during material post-treatment, highly luminescent CsPbBr3 PNCs with remarkable stability in methanol/butanol medium up to 7 months with near-unity photoluminescence quantum yield are achieved. This approach is extrapolated to stabilize iodine-based CsPbBr3-xIx and CsPbI3 PNCs, showing an improvement of their photoluminescence features and stability in these high polar alcohols up to 6 h. DDAB mediates the defect suppression through ligand exchange and avoids the full permeation of alcohol to be in contact with the PNCs. In this context, DDAB induces ionization of alcohol molecules to strengthen the surface passivation. The findings open the door to the development of long-term stable CsPbX3 PNCs with high optical performance to be used in polar environments.This work was supported by the European Innovation Council (EIC) via OHPERA project (grant agreement 101071010), the Spanish Ministry of Science and Innovation under projects STABLE (PID2019-107314RB-I00) and ECOCAT (PID2020-116093RB-C41), the Spanish Ministry of Science and Innovation under project She-LED (PID2021-122960OA-I00), and the Generalitat Valenciana via Prometeo Grant Q-Solutions (CIPROM/2021/078). C.A.M. acknowledges APOSTD grant (APOSTD/2021/251) for funding. The authors also thank the Ministry of Education, Youth and Sports of the Czech Republic for the financial support of XPS measurements using CEMNAT infrastructure (project LM 2018103). The authors are very grateful to the “Serveis Centrals d'Instrumentació Científica (SCIC)” of the Universitat Jaume I

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling

Chiral mono- and dicarbamates derived from ethyl (S)-lactate: convenient chiral solvating agents for the direct and efficient enantiodiscrimination of amino acid derivatives by 1H NMR spectroscopy

New lactate-based CSAs for 1H NMR enantiodifferentiation of amino acid derivatives