Theoretical insights into the regioselectivity of a Pictet‐Spengler reaction: Transition state structures leading to salsolinol and isosalsolinol

The mechanism of the cyclization step of the Pictet‐Spengler reaction between acetaldehyde and dopamine to give salsolinol and isosalsolinol was studied computationally, using density functional theory. The preferential formation in acidic media of salsolinol, the product of para‐cyclization, and the requirement of a neutral pH for the formation of the ortho‐cyclized isosalsolinol are explained in terms of 2 different mechanistic routes with an iminium ion or a phenolate‐iminium zwitterion as starting reactants.     

Tuning the Catalytic Activity of a Pincer Complex of Rhodium(I) by Supramolecular and Redox Stimuli

We report the rhodium(I) complex [Rh(CNC−NDI)(CO)]⁺, in which CNC−NDI refers to a pincer-CNC ligand decorated with a naphthalenediimide moiety. Due to the presence of the planar CNC ligand and the naphthalenediimide moiety, the electronic nature of the complex can be modulated by means of supramolecular and redox stimuli, respectively. The metal complex shows a strong π–π-stacking interaction with coronene. This interaction has an impact on the electron-richness of the metal, as demonstrated by the shifting of the ν(CO) stretching band to a lower frequency. The addition of tetrabutylammonium fluoride facilitates the sequential one- and two-electron reduction of the NDI moiety of the ligand, thus resulting in a situation in which the ligand can increase its electron-donor strength in two levels. The nature of the interaction with the fluoride anion was studied computationally. The catalytic activity of the [Rh(CNC−NDI)(CO)]⁺ complex was tested in the cycloisomerization of alkynoic acids, where it is observed that the activity of the catalyst can be modulated between four levels of activity, which correspond to i) the use of the unmodified catalyst, ii) catalyst+coronene, iii) catalyst+2 equivalents of fluoride, and iv) catalyst+5 equivalents of fluoride.     

Supramolecular Control of the Oxidative Addition as a Way To Improve the Catalytic Efficiency of Pincer-Rhodium (I) Complexes

¹H NMR studies using a cationic complex with a pyridine-di-imidazolylidene pincer ligand of formula [Rh(CNC)(CO)]⁺ revealed that this compound showed high binding affinity with coronene in CH₂Cl₂. The interaction between coronene and the planar Rh^I complex is established by means of π-stacking interactions. This interaction has a strong impact on the electron-donating strength of the pincer CNC ligand, which is increased significantly, as demonstrated by the shifting of the ν(CO) stretching bands to lower frequencies. The addition of coronene increases the reaction rate of the nucleophilic attack of methyl iodide on the rhodium (I) pincer complex, and also has a positive effect on the performance of the complex as a catalyst in the cycloisomerization of 4-pentynoic acid. These findings highlight the importance of supramolecular interactions for tuning the reactivity and catalytic activity of square-planar metal complexes.     

MiniAp‐4: A Venom‐Inspired Peptidomimetic for Brain Delivery

Drug delivery across the blood–brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non‐invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactam‐bridged peptidomimetic MiniAp‐4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human‐cell‐based BBB model. Furthermore, MiniAp‐4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice.     

Fast detection of Piscirickettsia salmonis in Salmo salar serum through MALDI‐TOF‐MS profiling

Piscirickettsia salmonis is a pathogenic bacteria known as the aetiological agent of the salmonid rickettsial syndrome and causes a high mortality in farmed salmonid fishes. Detection of P. salmonis in farmed fishes is based mainly on molecular biology and immunohistochemistry techniques. These techniques are in most of the cases expensive and time consuming. In the search of new alternatives to detect the presence of P. salmonis in salmonid fishes, this work proposed the use of MALDI‐TOF‐MS to compare serum protein profiles from Salmo salar fish, including experimentally infected and non‐infected fishes using principal component analysis (PCA). Samples were obtained from a controlled bioassay where S. salar was challenged with P. salmonis in a cohabitation model and classified according to the presence or absence of the bacteria by real time PCR analysis. MALDI spectra of the fish serum samples showed differences in its serum protein composition. These differences were corroborated with PCA analysis. The results demonstrated that the use of both MALDI‐TOF‐MS and PCA represents a useful tool to discriminate the fish status through the analysis of salmonid serum samples. Copyright © 2016 John Wiley & Sons, Ltd.     

Error bounds in high-order Sobolev norms for POD expansions of parameterized transient temperatures

In this work, we analyze the convergence of the POD expansion for the solution to the heat conduction parameterized with respect to the thermal conductivity coefficient. We obtain error bounds for the POD approximation in high-order norms in space that assure an exponential rate of convergence, uniformly with respect to the parameter whenever it remains within a compact set of positive numbers. We present some numerical tests that confirm this theoretical accuracy.     

Exploring Multi-Subsite Binding Pockets in Proteins: DEEP-STD NMR Fingerprinting and Molecular Dynamics Unveil a Cryptic Subsite at the GM1 Binding Pocket of Cholera Toxin B

Ligand-based NMR techniques to study protein–ligand interactions are potent tools in drug design. Saturation transfer difference (STD) NMR spectroscopy stands out as one of the most versatile techniques, allowing screening of fragments libraries and providing structural information on binding modes. Recently, it has been shown that a multi-frequency STD NMR approach, differential epitope mapping (DEEP)-STD NMR, can provide additional information on the orientation of small ligands within the binding pocket. Here, the approach is extended to a so-called DEEP-STD NMR fingerprinting technique to explore the binding subsites of cholera toxin subunit B (CTB). To that aim, the synthesis of a set of new ligands is presented, which have been subject to a thorough study of their interactions with CTB by weak affinity chromatography (WAC) and NMR spectroscopy. Remarkably, the combination of DEEP-STD NMR fingerprinting and Hamiltonian replica exchange molecular dynamics has proved to be an excellent approach to explore the geometry, flexibility, and ligand occupancy of multi-subsite binding pockets. In the particular case of CTB, it allowed the existence of a hitherto unknown binding subsite adjacent to the GM1 binding pocket to be revealed, paving the way to the design of novel leads for inhibition of this relevant toxin.     

Reversible Hydride Migration from C5Me5 to RhI Revealed by a Cooperative Bimetallic Approach

The use of cyclopentadienyl ligands in organometallic chemistry and catalysis is ubiquitous, mostly due to their robust spectator role. Nonetheless, increasing examples of non-innocent behaviour are being documented. Here, we provide evidence for reversible intramolecular C−H activation at one methyl terminus of C₅Me₅ in [(η-C₅Me₅)Rh(PMe₃)₂] to form a new Rh−H bond, a process so far restricted to early transition metals. Experimental evidence was acquired from bimetallic rhodium/gold structures in which the gold center binds either to the rhodium atom or to the activated Cp* ring. Reversibility of the C−H activation event regenerates the Rh^I and Au^I monometallic precursors, whose cooperative reactivity towards polar E−H bonds (E=O, N), including the N−H bonds in ammonia, can be understood in terms of bimetallic frustration.     

Multi-molecule reaction of serum albumin can occur through thiol-yne coupling

The free-radical hydrothiolation of alkynes (thiol-yne coupling, TYC) unites two thiol fragments across the carbon-carbon triple bond to give a dithioether derivative with exclusive 1,2-addition; this reaction can be used for modification of peptides and proteins allowing glycoconjugation and fluorescent labeling. These results have implications not only as a flexible strategy for attaching two modifications at a single site in proteins but also for unanticipated side-reactions of reagents (such as cycloalkynes) used in other protein coupling reactions.