New glucosamine-based TLR4 agonists: design, synthesis, mechanism of action, and in vivo activity as vaccine adjuvants

20 p.-15 fig.-1 graph. abst.We disclose here a panel of small-molecule TLR4 agonists (the FP20 series) whose structure is derived from previously developed TLR4 ligands (FP18 series). The new molecules have increased chemical stability and a shorter, more efficient, and scalable synthesis. The FP20 series showed selective activity as TLR4 agonists with a potency similar to FP18. Interestingly, despite the chemical similarity with the FP18 series, FP20 showed a different mechanism of action and immunofluorescence microscopy showed no NF-κB nor p-IRF-3 nuclear translocation but rather MAPK and NLRP3-dependent inflammasome activation. The computational studies related a 3D shape of FP20 series with agonist binding properties inside the MD-2 pocket. FP20 displayed a CMC value lower than 5 μM in water, and small unilamellar vesicle (SUV) formation was observed in the biological activity concentration range. FP20 showed no toxicity in mouse vaccination experiments with OVA antigen and induced IgG production, thus indicating a promising adjuvant activity.The authors acknowledge the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie, project BactiVax (www.bactivax.eu) grant agreement no. 860325; the consortium CINMPIS; the project of excellence CHRONOS, CHRonical multifactorial disorders explored by NOvel integrated Strategies of the Department of Biotechnology and Biosciences; the Agencia Estatal de Investigacion (Spain) for project PID2021-126130OB-I00 (N.G.A.A.), PID2020-113588RB-I00 (S.M.-S.), PRE2018-086249 (A.M.-R), PRE2021-097247 (M.M.-T.); and project FEDER MINECO, the EM-platform at the CIC bioGUNE for support in cryo-EM imaging. J.J.-B. also thanks funding by CIBERES, an initiative of Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Perkin-Elmer Italia is also acknowledged for providing the cell imaging reagents.Peer reviewe

Intramolecular π–hole interactions with nitro aromatics

A thorough evaluation of the CSD and DFT computations were conducted to assess if intramolecular π–hole interactions can stabilize a conformer of nitro aromatics. It was found that this can only be the case when the nitro N-atom and an interacting electron-rich atom are separated by at least four bonds. Data from the solid state correspond well to the gas phase calculations and stabilizing energies were estimated to be as large as about 2–3 kcal mol−1, which is in the order of weak hydrogen bonding interactions

Unexpected chalcogen bonds in tetravalent sulfur compounds

In this manuscript we have combined a CSD (Cambridge Structural Database) analysis with theoretical calculations (RI-MP2/def2-TZVP level of theory) to study the importance of polarizability in chalcogen bonding interactions. It is well known that chalcogen bonds are stronger for less electronegative chalcogen atoms, i.e., S < Se < Te, and in the presence of electron-withdrawing substituents at the chalcogen. Herein, we report experimental and theoretical evidence (RI-MP2/def2-TZVP) that the chalcogen bond acceptor (Lewis base) has a preference in some cases for the σ-hole that is opposite to the more polarizable group instead of the more electron withdrawing one, as confirmed by Natural Bond Orbital (NBO) and Bader's theory of "atoms-in-molecules" computational tools

Highly efficient hydroamination of phenylacetylenes with anilines catalysed by gold nanoparticles embedded in nanoporous polymer matrix: Insight into the reaction mechanism by kinetic and DFT investigations

The synthesis of aromatic ketimines via hydroamination of phenylacetylenes (PAs) with anilines (ANs) has been accomplished in high yields and with excellent regio- and stereo-selectivity using gold nanoparticles (AuNPs) embedded in crystalline syndiotactic polystyrene-cis-1,4-polybutadiene (sPSB) multiblock copolymer matrix. The performances of the AuNPs-sPSB catalyst exceed those of the other commercial gold catalysts as a result of the physical chemical properties of the nanoporous polystyrenic support which allows excellent activity, thermal stability and recyclability of the catalyst. Electron donating (EDGs) and electron withdrawing (EWGs) substituents onto the aromatic group of ANs and PAs yield, in all examined cases, high selectivity in the formation of the thermodynamic favoured E stereoisomer of the aromatic ketimines. Kinetic investigation of the reaction mechanism in the presence of AN and of the deuterated analogue, AN-N,N-d2, highlighted a new reaction pathway for the hydroamination reaction, which was also supported by DFT calculations. Actually, the formation of AN aggregates stabilized by hydrogen bonding interactions produces a favourable transition state for the nucleophilic attack of AN to PA, coordinated/activated onto AuNPs surface. Moreover, an additional AN molecule cooperatively assists the 1,3-hydrogen shuttling from the N atom to the Cβ of the coordinated enamine intermediate to produce the kinetically favoured Z-ketimine intermediate that in turn evolves into the thermodynamically stable E-aromatic ketimine. The first order kinetics observed for AN, along with the experimental energetic barrier (ΔG‡ = 26.6 ± 0.7 kcal mol−1; ΔH‡ = 13.4 ± 1.8 kcal mol−1; ΔS‡ = −0.04 ± 0.04 kcal mol−1 K−1) found in good agreement with the energy of the transition state calculated for the 1,3-hydrogen shift in the DFT modelling, strongly support that the latter is the rate determining step in the gold catalysed hydroamination of AN with PA

Metal Nodes of Metal-Organic Frameworks can Activate Molecular Hydrogen

Hydrogenation of multiple bonds are among the most general and important organic reactions. Typical heterogeneous catalysts are based on transition metal nanoparticles, including noble metals. Data are presented here showing that metal nodes of MIL-101(Cr) and UiO-66 in the absence of occluded metal nanoparticles can promote hydrogenation of polarized X=Y double bonds of nitro and carbonyl groups. The catalytic activity is a function of the composition of the metal node and the organic linker. It is proposed that the reaction mechanism is based on the operation of frustrated Lewis acid/base pairs.Financial support by the Spanish Ministry of Science and Innovation (Severo Ochoa and PDI2021-126071-OB-CO21) and Generalitat Valenciana (Prometeo 2021-083) are gratefully acknowledged. Authors also thank the Galicia Supercomputing Centre (CESGA) for computational facilities.Peer reviewe

Preparation of chitosan-supported urea materials and their application in some organocatalytic procedures

An efficient and mild procedure was developed for the preparation of three chitosan-supported ureas containing electron-withdrawing groups. These catalysts were characterized and employed as organocatalysts in different transformations, including the enantioselective cyanosilylation of α-ketoesters and aldehydes, the asymmetric addition of formaldehyde tert-butyl hydrazone to prochiral α-ketoesters and a Friedel-Crafts reaction. Several parameters that can affect the activity and selectivity of the reactions were analysed. The supported catalysts can be reused for more than 10 cycles with only a small loss in their properties. Finally, theoretical DFT calculations were carried out to interpret the results of the catalysed reactions.Peer Reviewe

Nanometer-thick defective graphene films decorated with oriented ruthenium nanoparticles. Higher activity of 101 vs 002 plane for silane-alcohol coupling and hydrogen transfer reduction

Pyrolysis of ammonium alginate films containing Ru(NH)Cl leads to the formation of Ru nanoparticles (NPs) supported on defective graphene films. The procedure allows controlling the preferential facet orientation of small Ru NPs (5–20 nm), either 002 when the pyrolysis is carried out under Ar atmosphere or the 002 and 101 planes for pyrolysis in the presence of H. Ru is a metal difficult to prepare in preferential facet orientation compared to noble metals due to its higher reactivity and smaller particle size. Theoretical calculations substantiated the inhibition of Ru(0 0 2) growth by H adsorption, with restructuration to Ru(002–101) NPs. The defective graphene films of about 15 nm thickness containing one of the two types of Ru NPs (150 ng/cm) exhibit distinctive catalytic activity for the dehydrogenative coupling of silanes and alcohols and hydrogen transfer reduction of cyclohexanone. Comparison of turnover frequencies indicates that the 101 facet is more efficient than the 002 plane. Overall, this study illustrates that pyrolysis conditions can control the preferential crystallographic orientation of the growing Ru NPs and the relative catalytic activity of their specific crystallographic planes.Support by the Ministerio de Ciencia e Innovación (Severo Ochoa and RTI2018-098237-B-C21) and Generalitat Valenciana (Prometeo 2017/083) is acknowledged. Thanks are due to Galicia Supercomputing Center. AA thanks UEMF and UPV for an Erasmus + 2019-1-ES01-KA107-062073 Scholarship

Remarkable Activity of 002 Facet of Ruthenium Nanoparticles Grown on Graphene Films on the Photocatalytic CO2 Methanation

In the context of diminishing atmospheric CO emissions, there is an urgent need to develop processes that can be carried out at a scale commensurate with appropriate CO volumes. One possible reaction is the transformation of CO to methane (Sabatier reaction). Due to its chemical stability, catalytic CO hydrogenation to methane is carried out at temperatures of 450 °C or higher and pressures above 5 bars, thus, requiring a significant energy input. One alternative possibility to conventional thermal catalysis is the use of solar light as the primary energy, performing the photocatalytic CO hydrogenation. In this broad context, the present study shows the photocatalytic activity of nanometric films of oriented Ru nanoparticles (NPs) strongly grafted on defective graphene. These graphene films (thinner than 20 nm) containing Ru NPs nanoplatelets (less than 2 nanomol/cm) are among the most active photocatalysts ever prepared for CO hydrogenation and operate through photoinduced charge separation.Support by the Ministerio de Ciencia e Innovación (Severo Ochoa and RTI2018-098237-B-C21) and Generalitat Valenciana (Prometeo 2017/083) was acknowledged. Thanks are due to Galicia Supercomputing Center. A.A. thanks UEMF (Euromed Unniversity Fes) and UPV for an Erasmus+ 2019-1-ES01-KA107-062073 Scholarship. A.P. thanks the Spanish Ministry for a Ramón y Caja