Reacciones de formación de sistemas policíclicos: I. Síntesis de taxoesteroides mediante metátesis de dieninos. II. Estudios teóricos de reacciones de ciclación de metátesis y reacciones de cicloadición [3+2] catalizadas por Pd

Polycyclic systems containing medium size rings are present in a high number of compounds and constitute the basic skeleton of natural and non natural products of great importance. The construction of these systems continues being a challenge in the Synthetic Organic Chemistry. Transition metals have become ideal candidates for their synthesis, because of their multiple advantages: all functional groups can coordinate to some transition metals, and after that, the reactivity of this functional group is incredibly changed very often. Besides, most of the reactions can be carried out in a very specifically way, and it is possible to distinguish between similar positions into the same molecule. Another advantage is that transition metals can participate in domino or tandem reactions, where more than one bond can be formed at the same time. However, the mechanisms of these transformations are often complicated and difficult to understand. This fact, more than a disadvantage can be considered a great chance for the development of new chemical transformations. This memory describes the results obtained from the investigation of two important reactions catalyzed by a transition metal: metathesis and cycloaddition reactions. Both transformations constitute big synthetic tools and allow achieving a big molecular complexity in only one step; this is why they are so useful in the construction of polycyclic systems

Hydrazone-modulated peptides for efficient gene transfection

Gene transfection continues to be a major challenge in chemistry, biology and materials sciences. New methodologies and recent breakthroughs have renewed the interest in the discovery and development of new tools for efficient gene transfection. Hydrazone formation between a cationic head and hydrophobic tails has emerged as one of the most promising techniques for nucleotide delivery. In this contribution, we have exploited hydrazone formation to modulate the transfection activity of a parent linear peptide in combination with a plasmid DNA cargo. This strategy allowed the straightforward preparation, under physiologically compatible conditions, of a discrete library of amphiphilic modulated penetrating peptides. Without the requirement of any isolation or purification steps, these modulated amphiphilic peptides were combined with a plasmid DNA and screened in transfection experiments of human HeLa cells. Three of these hydrazone-conjugated peptides were identified as excellent vectors for plasmid delivery with comparable, or even higher, efficiencies and lower toxicity than the commercial reagents employed in routine transfection assaysWe are thankful to Dr. Irene Lostalé-Seijo for cell culture assistance and discussions. We acknowledge funding from the Spanish Government MINECO: [CTQ2014-59646-R] and [CTQ2015-74621-JIN], the Xunta de Galicia (ED431G/09), the ERDF and the CESGA. R. G.-F. received a FCT Investigator Grant from Portugal (IF/01133/2015). J.M. received a Ramon y Cajal (RYC-2013-13784) and an ERC Starting Investigator Grant (DYNAP-677786)S

Aggregation versus inclusion complexes to solubilize drugs with cyclodextrins. A case study using sulphobutylether-β-cyclodextrins and remdesivir

The formation of small hybrid aggregates between excipient and drug molecules is one of the mechanisms that contributes to the solubilization of active principles in pharmaceutical formulations. The characterization of the formation, governing interactions and structure of such entities is not trivial since they are highly flexible and dynamic, quickly exchanging molecules from one to another. In the case of cyclodextrins, this mechanism and the formation of inclusion complexes synergistically cooperate to favour the bioavailability of drugs. In a previous study we reported a detailed characterization of the possible formation of inclusion complexes with 1:1 stoichiometry between remdesivir, the only antiviral medication currently approved by the United States Food and Drug Administration for treating COVID-19, and sulphobutylether-β-cyclodextrins. Here we extend our study to assess the role of the spontaneous aggregation in the solubilization of the same drug, by molecular dynamics simulations at different relative concentrations of both compounds. The number of sulphobutylether substitutions in the cyclodextrin structure and two different protonation states of the remdesivir molecule are considered. We aim to shed light in the solubilization mechanism of sulphobutylether-β-cyclodextrins, broadly used as an excipient in many pharmaceutical formulations, in particular in the case of remdesivir as an active compoundR.G.-F thanks to the Spanish Agencia Estatal de Investigación (AEI) and the ERDF (RTI2018-098795-A-I00) and for a “Ramón y Cajal” contract (RYC-2016-20335), to Xunta de Galicia (ED431F 2020/05) and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund - ERDF). Á. P. thanks to the Ministerio de Ciencia e Innovación (PID2019-111327 GB-I00)S

Remdesivir interactions with sulphobutylether-β-cyclodextrins: a case study using selected substitution patterns

Modified cyclodextrins (CDs) consist of a distribution of different structures with different number and location of the substituted groups. Among the most important applications of these molecules is their use as an enabling excipient in pharmaceutical formulations to provide the necessary solubility, stability and bioavailability for a drug to be effectively used. The most typical interaction mechanism of small molecular groups with CDs is the formation of host–guest inclusion complexes. The thermodynamic affinity constant between CDs and drugs should not be too strong, since then the biological activity could be negated by the formation of the complex. In the opposite scenario, if the affinity constant is too weak, the complex is barely formed and the amount of CD required in the formulation may become too great. Thus, a balance between the affinity of the CD and the drug is necessary for an optimal formulation. Additionally in the case of modified CDs and specific drug complexes there are further questions concerning the effect that the locations and number of substitutions plays in complexation. In the present work, this question is explored by using sulphobutylether-β-cyclodextrin and remdesivir, the only antiviral medication currently approved by the United States Food and Drug Administration for treating COVID-19, as a case study. This paper presents results from an orthogonal study using isothermal titration calorimetry measurements and biased molecular dynamics simulations that provide complementary information. Isothermal titration calorimetry delves into the global impact of the species distribution while molecular dynamics simulations deals with specific chemical structures. The goal is to provide useful information to optimize pharmaceutical formulations based on modified CDs, specifically in the case of remdesivir, used to treat SARS-CoV-2 infection, although the main conclusions could be extended to the interaction of other drugs with modified cyclodextrinsR.G.-F thanks to the Spanish Agencia Estatal de Investigación (AEI) and the ERDF (RTI2018-098795-A-I00) and for a “Ramón y Cajal” contract (RYC-2016-20335), to Xunta de Galicia (ED431F 2020/05) and Centro singular de investigación de Galicia accreditation 2019-2022, ED431G 2019/03) and the European Union (European Regional Development Fund - ERDF). Á. P. thanks to the Ministerio de Ciencia e Innovación (PID2019-111327GB-I00). We thank the “Centro de Supercómputo de Galicia” (CESGA) for computing time as well as for their exceptional technical supportS

Palladium-Catalyzed Conjugate Addition of Terminal Alkynes to Enones

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see: https://pubs.acs.org/doi/10.1021/ol300988nA practical protocol for the hydroalkynylation of enones using Pd catalysis is reported. The reaction proceeds efficiently with a variety of alkynes as well as with several cyclic and acyclic enones, providing synthetically relevant β-alkynyl ketones in good to excellent yieldsThis work was supported by the Spanish MINECO [SAF2007-61015, SAF2010-20822-C02, Consolider Ingenio 2010 CSD2007-00006], the ERDF and the Xunta de Galicia INCITE09209084PR, GRC2010/12. L.V. and R.G.-F. thank the Spanish MEC and MINECO for an FPU fellowship and a Juan de la Cierva contract, respectivelyS

Molecular insights into the effects of focused ultrasound mechanotherapy on lipid bilayers:Unlocking the keys to design effective treatments

Administration of focused ultrasounds (US) represents an attractive complement to classical therapies for a wide range of maladies, from cancer to neurological pathologies, as they are non-invasive, easily targeted, their dosage is easy to control, and they involve low risks. Different mechanisms have been proposed for their activity but the direct effect of their interaction with cell membranes is not well understood at the molecular level. This is in part due to the difficulty of designing experiments able to probe the required spatio-temporal resolutions. Here we use Molecular Dynamics (MD) simulations at two resolution levels and machine learning (ML) classification tools to shed light on the effects that focused US mechanotherapy methods have over a range of lipid bilayers. Our results indicate that the dynamic-structural response of the membrane models to the mechanical perturbations caused by the sound waves strongly depends on the lipid composition. The analyses performed on the MD trajectories contribute to a better understanding of the behavior of lipid membranes, and to open up a path for the rational design of new therapies for the long list of diseases characterized by specific lipid profiles of pathological membrane cells.</p

Rings, Hexagons, Petals, and Dipolar Moment Sink-Sources: The Fanciful Behavior of Water around Cyclodextrin Complexes

The basket-like geometry of cyclodextrins (CDs), with a cavity able to host hydrophobic groups, makes these molecules well suited for a large number of fundamental and industrial applications. Most of the established CD-based applications rely on trial and error studies, often ignoring key information at the atomic level that could be employed to design new products and to optimize their use. Computational simulations are well suited to fill this gap, especially in the case of CD systems due to their low number of degrees of freedom compared with typical macromolecular systems. Thus, the design and validation of solid and efficient methods to simulate and analyze CD-based systems is key to contribute to this field. The behavior of supramolecular complexes critically depends on the media where they are embedded, so the detailed characterization of the solvent is required to fully understand these systems. In the present work, we use the inclusion complex formed by two α-CDs and one sodium dodecyl sulfate molecule to test eight different parameterizations of the GROMOS and AMBER force fields, including several methods aimed to increase the conformational sampling in computational molecular dynamics simulation trajectories. The system proved to be extremely sensitive to the employed force field, as well as to the presence of a water/air interface. In agreement with previous experiments and in contrast to the results obtained with AMBER, the analysis of the simulations using GROMOS showed a quick adsorption of the complex to the interface as well as an extremely exotic behavior of the water molecules surrounding the structure both in the bulk aqueous solution and at the water surface. The chirality of the CD molecule seems to play an important role in this behavior. All together, these results are expected to be useful to better understand the behavior of CD-based supramolecular complexes such as adsorption or aggregation driving forces, as well as to introduce new methods able to speed up general MD simulationsThis work was supported by the Spanish Agencia Estatal de Investigación (AEI) and the ERDF (RTI2018-098795-A-I00), and by the Xunta de Galicia and the ERDF (ED431C 2017/25 and Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09). P.F.G. is funded by a predoctoral research grant (BES-2016-076761) from the Spanish Ministry of Economy and Competitiveness and the European Social Fund. M.C. is funded by a predoctoral fellowship from Xunta de Galicia. R.G.-F. is a “Ramón y Cajal” fellowship (RYC-2016-20335) from the Ministerio de Ciencia, Innovación y UniversidadesS

Rhodium(III)-catalyzed intramolecular annulations involving amide-directed C–H activations: synthetic scope and mechanistic studies

Alkyne tethered benzamides undergo rhodium(III)-catalyzed intramolecular annulations to give tricyclic isoquinoline derivatives in good yields. DFT calculations suggest that the reaction mechanism involves a migratory insertion of the alkyne into the rhodium–nitrogen bond of the rhodacycle intermediate that results from the initial C–H activation. This contrasts with the pathway proposed for intermolecular cases, which considers an insertion into the rhodium–carbon instead of the rhodium–nitrogen bond. The annulation is also effective with acrylamides; and, while anilides fail to participate in the process, naphthylamides do undergo the intramolecular annulation, albeit the chemoselectivity is different than for the intermolecular reactionsS

Self-Assembly of Silver Metal Clusters of Small Atomicity on Cyclic Peptide Nanotubes

Subnanometric noble metal clusters, composed by only a few atoms, behave like molecular entities and display magnetic, luminescent and catalytic activities. However, non-covalent interactions of molecular metal clusters, lacking of any ligand or surfactant, have not been seen at work. Theoretically attractive and experimentally discernable, van der Waals forces and non-covalent interactions at the metal/organic interfaces will be crucial to understand and develop the next generation of hybrid nanomaterials. Here, we present experimental and theoretical evidence of non-covalent interactions between subnanometric metal (0) silver clusters and aromatic rings and their application in the preparation of 1D self-assembled hybrid architectures with ditopic peptide nanotubes. Atomic force microscopy, fluorescence experiments, circular dichroism and computational simulations verified the occurrence of these interactions in the clean and mild formation of a novel peptide nanotube and metal cluster hybrid materials. The findings reported here confirmed the sensitivity of silver metal clusters of small atomicity towards non-covalent interactions, a concept that could find multiple applications in nanotechnology. We conclude that induced supramolecular forces are optimal candidates for the precise spatial positioning and properties modulation of molecular metal clusters. The reported results herein outline and generalize the possibilities that non-covalent interactions will have in this emerging fieldThis work was supported by the Spanish Ministry of Economy and Competitivity (Mineco) and the ERDF [CTQ2010-15725, CTQ2013-43264-R, MAT2011-28673-C02-01, MAT2012-36754-C02-01], by the Xunta de Galicia (GRC2006/132, GRC2013/044, EM 2012/117). J.M. received a Ramón y Cajal contract from the Mineco. We also thank the ORFEO-CINCA network and Mineco through CTQ2014-51912-REDCS

Short oligoalanine helical peptides for supramolecular nanopore assembly and protein cytosolic delivery

In this work we report a rational design strategy for the identification of new peptide prototypes for the non-disruptive supramolecular permeation of membranes and the transport of different macromolecular giant cargos. The approach targets a maximal enhancement of helicity in the presence of membranes with sequences bearing the minimal number of cationic and hydrophobic moieties. The here reported folding enhancement in membranes allowed the selective non-lytic translocation of different macromolecular cargos including giant proteins. The transport of different high molecular weight polymers and functional proteins was demonstrated in vesicles and in cells with excellent efficiency and optimal viability. As a proof of concept, functional monoclonal antibodies were transported for the first time into different cell lines and cornea tissues by exploiting the helical control of a short peptide sequence. This work introduces a rational design strategy that can be employed to minimize the number of charges and hydrophobic residues of short peptide carriers to achieve non-destructive transient membrane permeation and transport of different macromoleculesThis work was partially supported by the Spanish Agencia Estatal de Investigación (AEI) [SAF2017-89890-R], the Xunta de Galicia (ED431C 2017/25, 2016-AD031 and Centro Singular de Investigación de Galicia accreditation 2019–2022, ED431G 2019/03), the European Union (European Regional Development Fund – ERDF) and the ISCIII (RD16/0008/003). M. P. thanks the Xunta de Galicia (ED481A-2017/142), and M. J. and G. S. thank MINECO for their F. P. I. fellowships (BES-2015-071779; PRE2018-085973). R. G.-F. thanks a RyC (RYC-2016-20335), MINECO (RTI2018-098795-A-I00) and Xunta de Galicia (ED431F 2020/05). J. M. received a RyC (RYC-2013-13784), an ERC-Stg (DYNAP-677786), a HFSP (RGY0066/2017) and ISCIII (COV20/00297). All calculations were carried out at Centro de Supercomputación de Galicia (CESGA)S