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Modulable monosulfonyl squaramides have been shown to exert activation of gold(I) chloride complexes through H-bonding in an intermolecular way. Combinations of (PPh3)AuCl or IPrAuCl complexes and an optimal sulfonyl squaramide cocatalyst bearing two 3,5-bis(trifluoromethyl)phenyl groups efficiently catalyzed diverse heterocyclizations and a cyclopropanation reaction, avoiding in all cases undesired side reactions. Computational studies indicate that the Au–Cl bond breaks by transligation to the triple bond in a ternary complex formed by the actual AuCl···HBD catalyst and the substrate.

The deacetylative aldol reaction of N-methyl-3-acetyl-3-fluoro-2-oxindole is optimized with benzaldehyde and the most appropriate conditions are used for the survey of the scope of this transformation with different aldehydes. The relative configuration of the resulting compounds is also confirmed. The reaction is diastereoselective and affords the syn-stereoisomer in good yields. DFT calculations are used for the explanation of this diastereoselectivity through a traditional chair-like transition state.

We have demonstrated that the catalytic and enantioselective vinylcyclopropane-cyclopentene rearrangement can be carried out on (vinylcyclopropyl)acetaldehydes through activation via enamine intermediates. The reaction makes use of racemic starting materials that, upon ring opening facilitated by the catalytic generation of a donor-acceptor cyclopropane, deliver an acyclic iminium ion/dienolate intermediate in which all stereochemical information has been deleted. The final cyclization step forms the rearrangement product, showing that chirality transfer from the catalyst to the final compound is highly effective and leads to the stereocontrolled formation of a variety of structurally different cyclopentenes. Grants PID2019-104090RB-100 and PID2020-118422GB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” are gratefully acknowledged together with the Basque Government (Grupos IT1558-22) and the Government of Aragón (Grupos Consolidados, E34-20R and a fellowship to M. P.). G. G. also thanks the Spanish Ministerio de Universidades for an FPU grant. The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo”, technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

Piperidine-based photoswitchable derivatives have been developed as putative pharmacological chaperones for glucocerebrosidase (GCase), the defective enzyme in Gaucher disease (GD). The structure-activity study revealed that both the iminosugar and the light-sensitive azobenzene are essential features to exert inhibitory activity towards human GCase and a system with the correct inhibition trend (IC50 of the light-activated form lower than IC50 of the dark form) was identified. Kinetic analyses showed that all compounds are non-competitive inhibitors (mixed or pure) of GCase and the enzyme allosteric site involved in the interaction was identified by means of MD simulations. A moderate activity enhancement of mutant GCase assessed in GD patients' fibroblasts (ex vivo experiments) carrying the most common mutation was recorded. This promising observation paves the way for further studies to improve the benefit of the light-to-dark thermal conversion for chaperoning activity.

The ability of cyclooctatetraene oxide to undergo two sequential ring contraction events under mild conditions, using Brønsted acid catalysis, has been studied in detail. We have found that the selectivity can be controlled by the acidity of the catalyst and by the temperature, being able to obtain selectively either the cycloheptatriene carbaldehyde product, arising from a single ring-contraction event, or phenylacetaldehyde that is formed after a second ring contraction process. A complete mechanistic picture of the reaction and a rationale behind the influence of the catalyst is provided based on both experimental and computational data. Finally, this acid-catalyzed ring contraction has been coupled with an in situ enantioselective allylation reaction, delivering enantioenriched cycloheptatrienyl-substituted homoallylic alcohols when it is carried out in the presence of a chiral phosphoric acid catalyst. These homoallylic alcohols have also been converted into enantioenriched oxaborinanes through copper-catalyzed nucleophilic borylation/cyclization protocol. Grants PID2019-104090RB-100, PID2019-109674GB−I00 and PID2020-118422GB−I00 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” are gratefully acknowledged together with the Basque Government (Grupos IT1558-22) and the Government of Aragón (Grupos Consolidados, E34_20R and a fellowship to M. P.). O. S. thanks MF-URV for a predoctoral grant and J. S. thanks Grant PRE2018-083532 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future” for an FPI fellowship. The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo” and technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

N-Acetylgalactosamine (GalNAc)-type O-glycosylation is an essential posttranslational modification (PTM) that plays fundamental roles in biology. Malfunction of this PTM is exemplified by the presence of truncated O-glycans in cancer. For instance, the glycoprotein MUC1 is overexpressed in many tumor tissues and tends to carry simple oligosaccharides that allow for the presentation of different tumor-associated antigens, such as the Tn or sTn antigens (GalNAc-α-1-O-Thr/Ser and Neu5Acα2-6GalNAcα1-O-Ser/Thr, respectively). In other cases, such as tumoral calcinosis associated with O-glycosylation of the fibroblast growth factor 23, O-glycans are absent or less abundant. Significant progress has been made in determining the three-dimensional structures of biomolecules that recognize GalNAc, such as antibodies, lectins, mucinases, GalNAc-transferases, and other glycosyltransferases. Analysis of the complexes between these entities and GalNAc-containing glycopeptides, in most cases derived from crystallographic or NMR analysis, provides an understanding of the key structural elements that control molecular recognition of these glycopeptides. Here, we describe and compare the binding sites of these proteins in detail, focusing on how the GalNAc moieties interact selectively with them. We also summarize the differences and similarities in GalNAc recognition. In general, the recognition of GalNAc-containing glycopeptides is determined by hydrogen bonds between hydroxyl groups and the N-acetyl group of GalNAc with proteins, as well as CH-π contacts in which the hydrophobic α-face of the sugar and the methyl group of NHAc can be involved. The latter interaction usually provides the basis for selectivity. It is worth noting that binding of these glycopeptides depends primarily on recognition of the sugar moiety, with some exceptions such as a few anti-MUC1 antibodies that primarily recognize the peptide backbone and use the sugar to facilitate shape complementarity or to establish a limited number of interactions with the protein. Focusing specifically on the GalNAc moiety, we can observe that there is some degeneracy of interactions within the same protein families, likely due to substrate flexibility. However, when all studied proteins are considered together, despite the commonalities within each protein family, no pattern can be discerned between the different families, apart from the presence of common residues such as Tyr, His, or Asp, which are responsible for hydrogen bonds. The lack of a pattern can be anticipated, given the diverse functions of mucinases, glycosyltransferases, antibodies, and lectins. Finally, it is important to point out that the conformational differences observed in solution in glycopeptides bearing GalNAc-α-1-O-Ser or GalNAc-α-1-O-Thr also can be found in the bound state. This unique characteristic is exploited, for instance, by the enzyme C1GalT1 to broadly glycosylate both acceptor substrates. The findings summarized in this review may contribute to the rational structure-guided development of therapeutic vaccines, novel diagnostic tools for early cancer detection, and new cancer treatments for cancer with tailored anti-Tn or anti-STn antibodies or new drugs to inhibit GalNAc-T isoenzymes.

Acylcyclopropanes are employed as useful donor–acceptor cyclopropanes that undergo formal (4 + 2) cyclocondensation with N-unprotected 3-substituted indoles in the presence of a Brønsted acid catalyst. The reaction involves the simultaneous alkylation of both the N and C-2 positions of the indole and provides access to the 8,9-dihydropyrido[1,2-a]indole scaffold that is the central core of several biologically relevant indole alkaloids in excellent yields and good selectivities., This research was supported by the Spanish MINECO (PID2019-104090RB-100 and FEDER-CTQ2016-76155-R), Basque Government (IT908-16), UPV/EHU (fellowship to A.O.), and Government of Aragón (Grupos Consolidados, E34_20R).

En este artículo presentamos el modelo matemático de tipo compartimental con individuos asintomáticos utilizado por el Centro de Modelización Matemática (MODEMAT) para estudiar la propagación del SARS-CoV-2 en Ecuador, así como el esquema variacional de tipo bayesiano desarrollado para estimar los diferentes parámetros del modelo, en presencia de incertidumbre de los datos observados. Esta estimación permite realizar actualizaciones periódicas del número efectivo de reproducción, así como proyecciones a corto plazo, mediante métodos de ensamble de la incidencia de la epidemia.

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 β-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 β-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 β-close ion pair (β-CIP) species, the formation of the α-glycoside is necessarily preceded by a bimolecular α → β 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 β-glycosyl triflates against neutral and anionic acceptors., A.G.S. would like to thank the EU commission for a MSCA-IF postdoctoral fellowship. L.M.-J and L.D.-C thank the Ministerio de Economía , Industria y Competitividad and the Ministerio de Ciencia, Innovación y Universidades the for their FPI fellowships (BES-2014-070232 and BES-2017-080618). This investigation was supported by research grants from the Spanish Ministry of Science and Innovation (CTQ2016−79255-P, PID2019−107476GB-I00, BFU2017−89707-P, RTI2018−094862-B-100, RTI2018−099592−B-C21, PID2019−104090RB-100, RTI2018−094751−B-C22, and RTI2018−099592−B-C22), the Mizutani Foundation forGlycoscience (200077 and 170045), the Aragon Government (Groups 17R-34) and the computational resources from BIFI-ZCAM (Universidad de Zaragoza, Spain).

Acyl group migration affects the synthesis, isolation, manipulation and purification of all acylated organic compounds containing free hydroxyl groups, in particular carbohydrates. While several isolated studies on the migration phenomenon in different buffers have been reported, comprehensive insights into the overall migration process in different monosaccharides under similar conditions have been lacking. Here, we have studied the acyl migration in different monosaccharides using five different acyl groups by a combination of experimental, kinetic and theoretical tools. The results show that the anomeric configuration in the monosaccharide has a major influence on the migration rate, together with the relative configurations of the other hydroxyl groups and the nature of the migrating acyl group. Full mechanistic model, based on computations, demonstrates that the acyl migration proceeds through an anionic stepwise mechanism with linear dependence on the [OH−] and the pKa of the hydroxyl group toward which the acyl group is migrating., Robert Lassfolk thanks the Magnus Ehrnrooth foundation and the Waldemar von Frenckell foundation for financial support. This research was also supported by the Spanish MICIU (PID2019-104090RB-100) and Government of Aragón (Grupos Consolidados, E34_20R and a fellowship to M. P.).

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst., The authors thank the Spanish Ministerio de Ciencia, Innovación y Universidades (FEDER PID2020-118422GB−I00 and FEDER PID2019-104090RB-100), the Basque Government (Grupos IT1558-22 and postdoctoral contract to J.L.-B.) and the Regional Government of Aragon (Grupos 17R-34) for financial support. Predoctoral FPU fellowship to S.R. from the Spanish Ministry of Education and to M.P. from Government of Aragon are also acknowledged. The authors thankfully acknowledge the resources from the super-computers “Memento” and “Cierzo”, technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

Protein O-fucosyltransferase 2 (PoFUT2) is an inverting glycosyltransferase (GT) that fucosylates thrombospondin repeats (TSRs) from group 1 and 2. PoFUT2 recognizes a large and diverse number of TSRs through a dynamic network of water-mediated interactions. By X-ray structural studies of C. elegans PoFUT2 complexed to a TSR of group 2, we demonstrate that this GT recognizes similarly the 3D structure of TSRs from both groups 1 and 2. Its active site is highly exposed to the solvent, suggesting that water molecules might also play an essential role in the fucosylation mechanism. We applied QM/MM methods using human PoFUT2 as a model, and found that HsPoFUT2 follows a classical SN2 reaction mechanism in which water molecules contribute to a great extent in facilitating the release of the leaving pyrophosphate unit, causing the H transfer from the acceptor nucleophile (Thr/Ser) to the catalytic base, which is the last event in the reaction. This demonstrates the importance of water molecules not only in recognition of the ligands but also in catalysis., We thank the Spanish MICINN (grants PID2019-104090RB-100 to P.M. and PID2019-105451GB-I00 to R.H.-G., and predoctoral FPI fellowship to I.S.-M.) for financial support. We also thank ARAID, Gobierno de Aragón (E34_20R to P.M. and LMP58_18 to R.H.-G.) with FEDER (2014-2020) funds for “Building Europe from Aragón” for financial support, and the COST Action CA18103 INNOGLY: Innovation with Glycans new frontiers from synthesis to new biological targets. ALBA (Barcelona, Spain) synchrotron beamline XALOC and resources from the super-computers “Memento” and “Cierzo” provided by BIFI-ZCAM (University of Zaragoza, Spain) are gratefully acknowledged.

It was recently demonstrated by us that acetyl groups in oligosaccharides can migrate not only within one saccharide unit but also between two different saccharide units. Kinetics of this phenomenon were previously investigated in both mannan model compounds and a naturally occurring polysaccharide. In addition to mannans, there are also several other naturally acetylated polysaccharides, such as xyloglucans and xylans. Both xyloglucans and xylans are some of the most common acetylated polysaccharides in nature, displaying important roles in the plant cells. Considering the various biological roles of natural polysaccharides, it could be hypothesized that the intramolecular migration of acetyl groups might also be associated with regulation of the biological activity of polysaccharides in nature. Consequently, a better understanding of the overall migration phenomenon across the glycosidic bonds could help to understand the potential role of such migrations in the context of the biological activity of polysaccharides. Here, we present a detailed investigation on acetyl group migration in the synthesized xylan and glucan trisaccharide model compounds by a combination of experimental and computational methods, showing that the migration between the saccharide units proceeds from a secondary hydroxyl group of one saccharide unit toward a primary hydroxyl group of the other unit., The authors thank the Magnus Ehrnrooth foundation and the Waldemar von Frenckell foundation for financial support. This research was also supported by the Spanish MICIU (PID2019-104090RB-100) and Government of Aragón (Grupos Consolidados, E34_20R and a fellowship to M.P.). The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo”, technical expertise, and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain).

Tactile Internet (TI) refers to the transmission of touch and the real-time control of applications like the remote control for teleoperation of machines, drones or vehicles. Traditional TCP and UDP protocols are not suitable for these applications, because they are mainly designed for content delivery or non real-time interactive applications. Some ideas from transport protocols for real-time multimedia like RTP are closer to Tactile Internet; however, they do not satisfy requirements of low latency and high reliability. In this paper, we present the Multi-connection Tactile Internet Protocol (MTIP), a novel transport protocol on top of the Internet Protocol to support the reliability and latency for Internet applications over multi-homed devices connected to several wireless networks. In order to provide that service, MTIP is based on the combination of sequence numbers and timestamps in packets, enhanced with global clocks and context awareness. The paper focuses on building a state machine based model of MTIP to prove the correct behaviour of the protocol using the SPIN tool to verify a number of relevant correctness properties.

Cruise ships nowadays can carry more than 5500 passengers and 2200 crew members for an average time of seven days per trip. The cruising industry makes up a large proportion of the tourism market, and demand is on the rise. Despite the large numbers of people on board, crime reporting on cruise ships is so far relatively low. While the ship itself faces security threats, activities on board and on shore provide many opportunities for targets and security flaws to be exploited. With the proliferation of activities and data sensors on board, there is an urgent need to develop data fusion algorithms in order to provide a global view of an information environment. The research presented in this paper develops an analysis of current cyber risks at sea, with a specific focus on cruising ships, currently under development with the scope of the H2020 ISOLA project. Several fusion algorithms are described and discussed, while further needs for more secure cyber environments are finally discussed.

A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d]azepines is described. Use of 2′-vinyl-biaryl-2-imines as substrates and in situ formed [CuI/(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereo- and enantioselectivities (>20 : 1 d.r., up to 99% ee). Moreover, the same catalyst was found to facilitate a related borylative cyclization to afford versatile boronic ester derivatives. Both reactions proceed under mild conditions (rt) and are applicable to a variety of substituted aromatic and heterocyclic derivatives., Dibenzo[b,d]azepines featuring axially chiral 7-member-bridged biaryls have been prepared by asymmetric reductive or borylative cyclizations using copper catalysis.

Electrochemiluminescent biosensors are nowadays an established technology in the field of immunosensors and diagnostics. Along with the advent of nanotechnology, the marriage between electrochemiluminescence and nanomaterials results in promising enhancing strategies in many biosensor applications. Among nanomaterials, carbon-based ones are the most used, as (i) scaffolds, (ii) luminophores and (iii) electrode materials of the sensor. In this review, we describe the importance of a rational modification and functionalization of carbon nanomaterials to optimize electrochemiluminescence signal, and we also resume the latest and most relevant applications of electrochemiluminescent biosensors based on carbon nanomaterials.

We propose a local regularization of elliptic optimal control problems which involves the nonconvex $$L^q$$ quasi-norm penalization in the cost function. The proposed Huber type regularization allows us to formulate the PDE constrained optimization instance as a DC programming problem (difference of convex functions) that is useful to obtain necessary optimality conditions and tackle its numerical solution by applying the well known DC algorithm used in nonconvex optimization problems. By this procedure we approximate the original problem in terms of a consistent family of parameterized nonsmooth problems for which there are efficient numerical methods available. Finally, we present numerical experiments to illustrate our theory with different configurations associated to the parameters of the problem.

The addition of 2-bromobenzylmagnesium bromide to chiral N-tert-butanesulfinyl imines derived from tetralone-type ketones proceeds with high levels of diastereocontrol. The resulting sulfinamide derivatives were transformed into dibenzoazaspiro compounds after a palladium-catalyzed intramolecular N-arylation. DFT calculations have been performed to rationalize the stereochemical course of the reaction. Similar results have been obtained considering either diethyl ether or toluene as a solvent, in both cases in an excellent agreement with experimental findings. NCI topological calculations have also been used to evidence crucial noncovalent interactions. In addition, the azaspiro compounds reduced the viability of chronic myeloid leukemia cells in the micromolar range. Notably, both the halogen-substituted (R)- and (S)-8g and -8h as well as (R)-8j were at least two times more effective on a multidrug-resistant derivative than on the parental cell line, exerting a collateral sensitivity effect. We acknowledge the continued financial support from the Spanish Ministerio de Economía y Competitividad (MINECO; project CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-81797-REDC, CTQ2016-76155-R, CTQ2017-85093-P), FEDER, the Generalitat Valenciana (PROMETEOII/2014/017), and the University of Alicante. We thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo” and technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain). We also thank Prof. Vivian M. Rumjanek for providing FEPS cells and Prof. Adriano D. Andricopulo for the preliminary cytotoxicity screening. This study was also financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

This work was supported by the Ministerio de Economia y Competitividad (grants CTQ2013–40855-R to C.C. and CTQ2016–76155-R to P.M.) and the Gobierno de Aragon–FEDER (Biological and Computational Chemistry Group E34_R17 and Amino acids and Peptides Group E19_17R). M.M.J.-A. thanks the Gobierno de Aragon-FSE for predoctoral grant.

This article is part of the themed collection: Mechanistic, computational & physical organic chemistry in OBC., Glycosyl cations are key intermediates in the glycosylation reactions taking place through a SN1-type mechanism. To obtain a reliable description of the glycosylation reaction mechanism a combination of computational studies and experimental data such as kinetic isotopic effects is needed. Computational studies have elucidated SN2-type glycosylation reaction mechanisms, but elucidation of mechanisms in which ion pairs can be formed presents some difficulties because of the recombination of the ions. Recent topological and dynamic studies open the door to the ultimate confirmation of the presence of glycosyl cations in the form of intimate ion pairs during certain glycosylation reactions. This review covers the state-of-the-art tools and applications of computational chemistry mainly developed during the last ten years to understand glycosylation reactions in which an oxocarbenium ion could be involved.