Clear polyurethane coatings with excellent virucidal properties: Preparation, characterization and rapid inactivation of human coronaviruses 229E and SARS-CoV-2.

Commercial polyurethane (PU) coating formulations have been modified with 1-(hydroxymethyl)-5,5-dimethylhydantoin (HMD) both in bulk (0.5 and 1% w/w) and onto the coatings surface as an N-halamine precursor, to obtain clear coatings with high virucidal activity. Upon immersion in diluted chlorine bleaching, the hydantoin structure on the grafted PU membranes was transformed into N-halamine groups, with a high surface chlorine concentration (40-43µg/cm2). Fourier transform infrared spectroscopy (FTIR) spectroscopy, thermogravimetric analysis (TGA), energy-dispersive X-ray (EDX), X-ray photoelectron spectroscopy (XPS) and iodometric titration were used to characterize the coatings and quantify the chlorine contents of the PU membranes after chlorination. Biological evaluation of their activity against Staphylococcus aureus (Gram-positive bacteria) and human coronaviruses HCoV-229E and SARS-CoV-2 was performed, and high inactivation of these pathogens was observed after short contact times. The inactivation of HCoV-229E was higher than 98% for all modified samples after just 30 minutes, whereas it was necessary 12 hours of contact time for complete inactivation of SARS-CoV-2. The coatings were fully rechargeable by immersion in diluted chlorine bleach (2% v/v) for at least 5 chlorination-dechlorination cycles. Moreover, the performance of the antivirus efficiency of the coatings is considered as long-lasting, because experiments of reinfection of the coatings with HCoV-229E coronavirus did not show any loss of the virucidal activity after three consecutive infection cycles without reactivation of the N-halamine groups.

Photocurable Thiol-yne Alginate Hydrogels for Regenerative Medicine Purposes.

Every year millions of people worldwide undergo surgical interventions, with the occurrence of mild or severe post-treatment consequences meaning that rehabilitation plays a key role in modern medicine. Considering the cases of burns and plastic surgery, the pressing need for new materials that can be used for wound patches or body fillers and are able to sustain tissue regeneration and promote cell adhesion and proliferation is clear. The challenges facing next-generation implant materials also include the need for improved structural properties for cellular organization and morphogenic guidance together with optimal mechanical, rheological, and topographical behavior. Herein, we propose for the first time a sodium alginate hydrogel obtained by a thiol-yne reaction, easily synthesized using carbodiimide chemistry in a two-step reaction. The hydrogels were formed in all cases within a few minutes of light irradiation, showing good self-standing properties under solicitation. The mechanical, rheological, topographical, and swelling properties of the gels were also tested and reported. Lastly, no cytotoxicity was detected among the hydrogels. Soluble extracts in culture media allowed cell proliferation, and no differences between samples were detected in terms of metabolic activity and DNA content. These results suggest the potential use of these cytocompatible hydrogels in tissue engineering and regenerative medicine.

De Novo Design of Selective Quadruplex-Duplex Junction Ligands and Structural Characterisation of Their Binding Mode: Targeting the G4 Hot-Spot.

Invited for the cover of this issue are Andrés G. Santana, Carlos González, Juan Luis Asensio and co-workers at Instituto de Química Orgánica General, Instituto de Química-Física Rocasolano and Universidad de La Rioja. The image depicts drug selectivity using a metaphor of an arrow hitting a target. Read the full text of the article at 10.1002/chem.202005026.

De Novo Design of Selective Quadruplex-Duplex Junction Ligands and Structural Characterisation of Their Binding Mode: Targeting the G4 Hot-Spot.

Targeting the interface between DNA quadruplex and duplex regions by small molecules holds significant promise in both therapeutics and nanotechnology. Herein, a new pharmacophore is reported, which selectively binds with high affinity to quadruplex-duplex junctions, while presenting a poorer affinity for G-quadruplex or duplex DNA alone. Ligands complying with the reported pharmacophore exhibit a significant affinity and selectivity for quadruplex-duplex junctions, including the one observed in the HIV-1 LTR-III sequence. The structure of the complex between a quadruplex-duplex junction with a ligand of this family has been determined by NMR methods. According to these data, the remarkable selectivity of this structural motif for quadruplex-duplex junctions is achieved through an unprecedented interaction mode so far unexploited in medicinal and biological chemistry: the insertion of a benzylic ammonium moiety into the centre of the partially exposed G-tetrad at the interface with the duplex. Further decoration of the described scaffolds with additional fragments opens up the road to the development of selective ligands for G-quadruplex-forming regions of the genome.

Single-Step Glycosylations with 13 C-Labelled Sulfoxide Donors: A Low-Temperature NMR Cartography of the Distinguishing Mechanistic Intermediates.

Glycosyl sulfoxides have gained recognition in the total synthesis of complex oligosaccharides and as model substrates for dissecting the mechanisms involved. Reactions of these donors are usually performed under pre-activation conditions, but an experimentally more convenient single-step protocol has also been reported, whereby activation is performed in the presence of the acceptor alcohol; yet, the nature and prevalence of the reaction intermediates formed in this more complex scenario have comparatively received minimal attention. Herein, a systematic NMR-based study employing both 13 C-labelled and unlabelled glycosyl sulfoxide donors for the detection and monitoring of marginally populated intermediates is reported. The results conclusively show that glycosyl triflates play a key role in these glycosylations despite the presence of the acceptor alcohol. Importantly, the formation of covalent donor/acceptor sulfonium adducts was identified as the main competing reaction, and thus a non-productive consumption of the acceptor that could limit the reaction yield was revealed.

Dissecting the Essential Role of Anomeric ß-Triflates in Glycosylation Reactions.

Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction of glycosidic scaffolds and glycoconjugates of biological and chemical interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the α- and ß-glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only α-glycosyl triflates have been well characterized under representative reaction conditions. Interestingly, the remaining less accessible intermediates, yet to be experimentally described, seem to be particularly relevant in α-selective processes, involving weak acceptors. Herein, we report a detailed analysis of several paradigmatic and illustrative examples of such reactions, employing a combination of chemical, NMR, kinetic and theoretical approaches, culminating in the unprecedented detection and quantification of the true ß-glycosyl triflate intermediates within activated donor mixtures. This achievement was further employed as a stepping-stone for the characterization of the triflate anomerization dynamics, which along with the acceptor substitutions, govern the stereochemical outcome of the reaction. The obtained data conclusively show that, even for highly dissociative reactions involving ß-close ion pair (ß-CIP) species, the formation of the α-glycoside is necessarily preceded by a bimolecular α → ß triflate interconversion, which under certain circumstances becomes the rate-limiting step. Overall, our results rule out the prevalence of the Curtin-Hammett fast-exchange assumption for most glycosylations and highlight the distinct reactivity properties of α- and ß-glycosyl triflates against neutral and anionic acceptors.

Impact of Aromatic Stacking on Glycoside Reactivity: Balancing CH/π and Cation/π Interactions for the Stabilization of Glycosyl-Oxocarbenium Ions.

Carbohydrate/aromatic stacking represents a recurring key motif for the molecular recognition of glycosides, either by protein binding domains, enzymes, or synthetic receptors. Interestingly, it has been proposed that aromatic residues might also assist in the formation/cleavage of glycosidic bonds by stabilizing positively charged oxocarbenium-like intermediates/transition states through cation/π interactions. While the significance of aromatic stacking on glycoside recognition is well stablished, its impact on the reactivity of glycosyl donors is yet to be explored. Herein, we report the first experimental study on this relevant topic. Our strategy is based on the design, synthesis, and reactivity evaluation of a large number of model systems, comprising a wide range of glycosidic donor/aromatic complexes. Different stacking geometries and dynamic features, anomeric leaving groups, sugar configurations, and reaction conditions have been explicitly considered. The obtained results underline the opposing influence exerted by van der Waals and Coulombic forces on the reactivity of the carbohydrate/aromatic complex: depending on the outcome of this balance, aromatic platforms can indeed exert a variety of effects, stretching from reaction inhibition all the way to rate enhancements. Although aromatic/glycosyl cation contacts are highly dynamic, the conclusions of our study suggest that aromatic assistance to glycosylation processes must indeed be feasible, with far reaching implications for enzyme engineering and organocatalysis.

Finding the Right Candidate for the Right Position: A Fast NMR-Assisted Combinatorial Method for Optimizing Nucleic Acids Binders.

Development of strong and selective binders from promiscuous lead compounds represents one of the most expensive and time-consuming tasks in drug discovery. We herein present a novel fragment-based combinatorial strategy for the optimization of multivalent polyamine scaffolds as DNA/RNA ligands. Our protocol provides a quick access to a large variety of regioisomer libraries that can be tested for selective recognition by combining microdialysis assays with simple isotope labeling and NMR experiments. To illustrate our approach, 20 small libraries comprising 100 novel kanamycin-B derivatives have been prepared and evaluated for selective binding to the ribosomal decoding A-Site sequence. Contrary to the common view of NMR as a low-throughput technique, we demonstrate that our NMR methodology represents a valuable alternative for the detection and quantification of complex mixtures, even integrated by highly similar or structurally related derivatives, a common situation in the context of a lead optimization process. Furthermore, this study provides valuable clues about the structural requirements for selective A-site recognition.