Glicoquímica y reconocimiento molecular: influencia de las interacciones de apilamiento CH/π sobre la reactividad de glicósidos

La interacción de apilamiento carbohidrato/aromático constituye un motivo estructural recurrente en el reconocimiento molecular de glicósidos porreceptores, tanto naturales como sintéticos. Curiosamente, residuos de triptófano, fenilalanina y tirosina son comunes también en los centros catalíticos de glicosidasas y glicosiltransferasas. Esta observación plantea la cuestión de si, además de contribuir al reconocimiento del sustrato, dichos residuos podrían asistir la formación o ruptura de enlaces glicosídicos mediante la estabilización de intermedios o estados de transición catiónicos, a través de interacciones CH/. Si bien la relevancia del apilamiento carbohidrato/aromático en el reconocimiento molecular de glicósidos es incuestionable, su impacto sobre la reactividad de los mismos es, a día de hoy, desconocido..

Photocurable Thiol–yne Alginate Hydrogels for Regenerative Medicine Purposes

Every year millions of people worldwide undergo surgical interventions, with the occur- rence 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 cul- ture 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.Laura Montalvillo-Jiménez, Paula Bosch, Raquel Cue-López, and Enrique Martínez- Campos acknowledge the Spanish National Research Council—CSIC Interdisciplinary Thematic Platform Salud Global+ (PTI-SALUDGLOBAL+) for providing financial support.Peer reviewe

Aromatic Interactions in Glycochemistry: From Molecular Recognition to Catalysis

Aromatic platforms are ubiquitous recognition motifs occurring in protein carbohydrate-binding domains (CBDs), RNA receptors and enzymes. They stabilize the glycoside/ receptor complexes by participating in stacking CH/π interactions with either the α-or β-face of the corresponding pyranose units. In addition, the role played by aromatic units in the stabilization of glycoside cationic transition states has started being recognized in recent years. Extensive studies carried out during the last decade have allowed the dissection of the main contributing forces that stabilize the carbohydrate/aromatic complexes, while helping delineate not only the standing relationship between the glycoside/ aromatic chemical structures and the strength of this interaction but also their potential influence on glycoside reactivity.This study was supported by research grants of the Spanish “Plan Nacional” (MINECO) CTQ2016-79255- P and PID2019-107476GB-I00, as well as an EU commission MSCA-IF postdoctoral fellowship. Spanish Ministerio de Economía, Industria y Competitividad and Ministerio de Ciencia, Innovación y Universidades provided an FPI fellowship each (BES-2014- 070232 and BES-2017-080618

Impact of Aromatic Stacking on Glycoside Reactivity: Balancing CH/πand Cation/πInteractions 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/πinteractions. 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.This investigation was supported by research grants of the Spanish “Plan Nacional” CTQ2016-79255-P/CTQ2015- 66702-R and the Mizutani Foundation for Glycoscience 17- 0045. A.G.S. and L.M.-J. acknowledge the Spanish Ministerio de Economía , Industria y Competitividad for a Juan de la Cierva contract (IJCI-2016-29785) and for a FPI contract (BES-2014-070232), respectively.Peer Reviewe

De novo design of selective quadruplex–duplex junction ligands and structural characterisation of their binding mode: targeting the G4 hot‐spot

10 pags., 6 figs. -- In memory of Enrique PedrosoTargeting 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.This investigation was supported by research grants from the Ministerio de Ciencia, Innovación y Universidades (CTQ2016-79255-P, PID2019-107476GB-I00, BFU2017-89707-P and RTI2018-099592-B-C21). A.G.S. acknowledges the Ministerio deCiencia, Innovación y Universidades for a Juan de la Cierva contract. L.D.-C., I. S-R and L.M.-J. acknowledge the Ministeriode Ciencia, Innovación y Universidades for FPI contracts. NMR experiments were performed in the ‘‘Manuel Rico’’ NMR laboratory (LMR), a node of the Spanish Large-Scale National Facility (ICTS R-LRB).Peer reviewe

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

10 pags., 6 figs. -- In memory of Enrique PedrosoTargeting 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.This investigation was supported by research grants from the Ministerio de Ciencia, Innovación y Universidades (CTQ2016-79255-P, PID2019-107476GB-I00, BFU2017-89707-P and RTI2018-099592-B-C21). A.G.S. acknowledges the Ministerio deCiencia, Innovación y Universidades for a Juan de la Cierva contract. L.D.-C., I. S-R and L.M.-J. acknowledge the Ministeriode Ciencia, Innovación y Universidades for FPI contracts. NMR experiments were performed in the ‘‘Manuel Rico’’ NMR laboratory (LMR), a node of the Spanish Large-Scale National Facility (ICTS R-LRB).Peer reviewe

Single-Step Glycosylations with 13C-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 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.This investigation was supported by research grants of the Spanish “Plan Nacional” (MINECO)CTQ2016-79255-P,PID2019- 107476GB-I00 and RTI2018-094862-B-100. A.G.S. thanks the EU commission for aMSCA-IF postdoctoral fellowsh ip (H2020- MSCA-IF-2018, 841824). L.M.-J.and L.D.-C. thank the Spanish Ministerio de Economía, Industria y Competitividad and Minis- terio de Ciencia,Innovación y Universidades foranFPI fellow- ship each (BES-2014-070232 and BES-2017-080618)