This study addresses the chemoselectivity of the catalyzed reduction of a series of variously substituted γ-lactams by Et3SiH mediated by a pentamethylcyclopentadienyl iridacyclic acetonitrilo salt derived from benzo[h]quinoline. Introduction of an unsaturation within the 5-membered ring of the γ-lactam annihilates the precedence of the amide function over the capture of the silylium cation, which results in a lower chemoselectivity. Monitoring over time the catalyzed reduction of a γ-lactam bearing a carboxylic ester appendage by 1H NMR spectroscopy revealed pseudo-zero-order kinetics for the prior hydrosilylation of the lactam’s amide. This primary hydrosilylation reaction is followed by the full conversion of the formed intermediate into a pyrrolidine following a pseudo-first-order rate law. Under anhydrous conditions, the hydrosilylation of the pendant ester function occurs only in a late stage once the γ-lactam’s amide function has underwent full reduction of the carbonyl function. DFT investigations show that chemoselectivity is governed (1) by the affinity of the organic substrate for the triethylsilylium cation produced by the electrophilic activation of Et3SiH by the Ir(III) catalyst and (2) by the ability of the in situ-formed hydrido-iridium(III) intermediate to transfer hydride to the activated substrate.

Nuclear magnetic resonance spectroscopy is a technique for the identification and the quantification of chemical molecules in a sample that has been perfectly established for decades. The transition from laboratory NMR to portable NMR for in-field measurements present a quite high number of technological challenges. One of them is the synchronization between signals emitted and received by the device during NMR measurement. With the use of on-the-shelf hardware, such as software defined radio which drastically reduces development costs, distortion might be introduced due to latencies between several Free Induction Decay (FID) recordings, preventing direct FID accumulation for NMR spectrums improvement. The aim of this paper is to study a software method that compensates the latencies, thus enabling NMR signal accumulation. This technique has been tested in simulation and has proved effective even when signal-to-noise ratios are below 0 dB.

An easy-to-handle, highly reusable and efficient [Ru(bpy)3]2+-based heterogeneous photocatalyst was obtained by post-functionalization of a polydopamine-coated open cell polyurethane foam (PDA@PUF) via a silanization process of the mussel-inspired adhesive layer with 3-(triethoxysilyl)propan-1-amine (APTES), followed by an EDC-mediated coupling with [2,2 '-bipyridine]-4-carboxylic acid and further complexation with [Ru(bpy)2Cl2] (bpy = 2,2 '-bypyridine). The successful covalent grafting of APTES on the PDA layer of PUF and functionali-zation all over the foam surface with [Ru(bpy)3]2+ was suggested by 29Si CP-MAS NMR, XPS, ICP-AES and SEM-EDX. The macroscopic photocatalyst proved effective in model benzylic amine homocouplings and cross dehy-drogenative couplings under visible-light irradiation and molecular oxygen, showing good functional group tolerance and excellent reusability in an easy-to-carry "dip-and-play" mode for at least six runs. Impressively, an improvement of the catalytic performances was even observed in both reactions, which most likely results from a modification of the uppermost layer of polydopamine throughout the successive cycles that renders the photo-catalyst more accessible.

The performance of six newly synthesized benzo[h]quinoline-derived acetonitrilo pentamethylcyclopentadienyl iridium(III) tetrakis(3,5-bis-trifluoromethylphenyl)borate salts bearing different substituents -X (-OMe, -H, -Cl, -Br, -NO2 and -(NO2 )2 ) on the heterochelating ligand were evaluated in the dehydro-O-silylation of benzyl alcohol and the monohydrosilylation of 4-methoxybenzonitrile by Et3 SiH, two reactions involving the electrophilic activation of the Si-H bond. The benchmark shows a direct dependence of the catalytic efficiency with the electronic effect of -X, which is confirmed by theoretical assessment of the intrinsic silylicities Π of hydridoiridium(III)-silylium adducts and by the theoretical evaluation of the propensity of hydridospecies to transfer the hydrido ligand to the activated substrate. The revisited analysis of the Ir-Si-H interactions shows that the most cohesive bond in hydridoiridium(III)-silylium adducts is the Ir-H one, while the Ir-Si is a weak donor-acceptor dative bond. The Si…H interaction in all the cases is noncovalent in nature and dominated by electrostatics confirming the heterolytic cleavage of the hydrosilane's Si-H bond in this key catalytically relevant species.

An easy-to-handle eosin Y-based heterogeneous photocatalyst was prepared by post-functionalization of a polydopamine-coated open cell polyurethane foam (PDA@PUF) via the silanization of the adhesive layer with 3-(triethoxysilyl)propan-1-amine (APTES) and the subsequent EDC-mediated coupling of the resulting amino-functionalized foam with eosin Y. The obtained macroscopic material, EY-APTES@PDA@PUF, showed good efficiency and excellent reusability, in an easy-to-carry “dip-and-play” mode for at least six runs as photocatalyst for the aerobic oxidation of 2-methyl-5-nitroisoquinolin-2-ium iodide to the corresponding isoquinolone. Subsequent investigation of the catalytic efficiency of EY-APTES@PDA@PUF for the oxidation of sulfides to sulfoxides, however, evidenced non-negligible eosin Y leaching, leading to a progressive deactivation of the catalytic foam in this case. Two alternative synthetic protocols for the preparation of the macroscopic photocatalyst were next explored to avoid eosin Y leaching. In both cases however, cycling tests also highlighted a progressive deactivation of the catalytic foams in sulfide-to-sulfoxide oxidation reactions.

Miniaturized nuclear magnetic resonance (NMR) devices are a trend in the industry because they allow flexible use within a range of applications that would be otherwise not feasible with standard NMR equipment. However, one of the main obstacles in the development of miniaturized NMR systems is the availability of a static magnetic field $B_{0}$ with enough homogeneity. It is of the utmost interest to be able to evaluate upfront the quality of the static magnetic field of the miniaturized system in order to assess its impact on the NMR spectrum resolution, and its usability for the targeted application. This article proposes an efficient simulator that can compute the deformation of an ideal NMR spectrum due to any $B_{0}$ field inhomogeneity using a coarse discretization of the sample volume. Its validation is performed by comparing the spectrum deformation it provides with the one obtained from an intensive numerical simulation using a high-density discretization of the sample volume. Such intensive simulation is only practical on small sample volumes. Finally, the simulator is applied on a real spectrum and its applicability as well as some improvements are discussed.

The presence of phosphate from different origins (inorganic, bioorganic) is found more and more in calcium carbonate-based biominerals. Phosphate is often described as being responsible for the stabilization of the transient amorphous calcium carbonate phase. In order to specify the composition of the mineral phase deposited at the onset of carbonated shell formation, the present study investigates, down to the nanoscale, the growing shell from the European abalone Haliotis tuberculata , using a combination of solid state nuclear magnetic resonance, scanning transmission electron microscope and spatially-resolved electron energy loss spectroscopy techniques. We show the co-occurrence of inorganic phosphate with calcium and carbonate throughout the early stages of abalone shell formation. One possible hypothesis is that this first-formed mixed mineral phase represents the vestige of a shared ancestral mineral precursor that appeared early during Evolution. In addition, our findings strengthen the idea that the final crystalline phase (calcium carbonate or phosphate) depends strongly on the nature of the mineral-associated proteins in vivo.

Biological mineralized tissues are hybrid materials with complex hierarchical architecture composed of biominerals often embedded in an organic matrix. The atomic-scale comprehension of surfaces and organo-mineral interfaces of these biominerals is of paramount importance to understand the ultrastructure, the formation mechanisms as well as the biological functions of the related biomineralized tissue. In this communication we demonstrate the capability of DNP SENS to reveal the fine atomic structure of biominerals, and more specifically their surfaces and interfaces. For this purpose, we studied two key examples belonging to the most significant biominerals family in nature: apatite in bone and aragonite in nacreous shell. As a result, we demonstrate that DNP SENS is a powerful approach for the study of intact biomineralized tissues. Signal enhancement factors are found to be up to 40 and 100, for the organic and the inorganic fractions, respectively, as soon as impregnation time with the radical solution is long enough (between 12 and 24 h) to allow an efficient radical penetration into the calcified tissues. Moreover, ions located at the biomineral surface are readily detected and identified through P-31 or C-13 HETCOR DNP SENS experiments. Noticeably, we show that protonated anions are preponderant at the biomineral surfaces in the form of HPO42- for bone apatite and HCO32- for nacreous aragonite. Finally, we demonstrate that organo-mineral interactions can be probed at the atomic level with high sensitivity. In particular, reliable C-13-{P-31} REDOR experiments are achieved in a few hours, leading to the determination of distances, molar proportion and binding mode of citrate bonded to bone mineral in native compact bone. According to our results, only 80% of the total amount of citrate in bone is directly interacting with bone apatite through two out of three carboxylic groups.

Polydopamine-coated polyurethane open cell foams are used as structured supports for molecular catalysts through the covalent anchoring of alkoxysilyl arms by the catechol groups of the mussel-inspired layer. This strong bonding prevents their leaching. No alteration of the mechanical properties of the flexible support is observed after repeated uses of the catalytic materials.

A family of histidine-rich peptides LAH4 was designed using linear cationic peptides such as magainins as a template. These designed peptides have been shown to exhibit considerable antimicrobial, nucleic acid transfection as well as cell penetrating activities. In contrast to their natural templates their membrane interactions are strongly pH dependent. The delivery of cargo by these peptides is complex, involving many steps, which we investigated on a structural and biophysical level. Recently, vectofusin-1, a member of the family of LAH4 peptides has been shown to spontaneously self-assemble into helical coiled-coil structures, spherical aggregates, that further assemble into annular and extended nanofibrils and hydrogels as a function of phosphate and in a pH-dependent manner. This bears considerable interest for the design of biomaterials. Furthermore, the peptide has a strong capacity to enhance the gene transfer by lenti- and adeno associated viruses into the cell interior. Thereby, the fibers formed by this short peptide have gene therapeutic applications ranging from monogenic and infectious diseases to cancer, by enhancing transduction levels of target cells and reducing the amount of lentivirus for greater safety and reduced costs. Vectofusin-1 promotes the entry of several retroviral pseudotypes into target cells when added to the culture medium, without cytotoxicity. These associate with viral particles allowing them to be easily pelleted. These fibrils have a unique coiled-coil α-helical structure whereas most other viral transduction enhancers form β-amyloid fibrils. Our observations define vectofusin-1 as a member of a new class of α-helical lentiviral transduction enhancers. Its coiled-coil fibril formation is reversible which bears considerable advantages in handling the peptide in conditions well-adapted to scalable gene therapy protocols. References: J PepSci 21, 346 (2015), JPC B 119, 9678 (2015), JBC 291, 2161 (2016), Acta Biomat (2017 in press), SciRep 7:9585 (2017).

The synthetic LAH4 peptides were designed to investigate the interactions that determine the membrane topology of helical peptides (1). Their core consists of alanines, leucine and four histidines arranged to form an amphipathic helix, as well as two lysines at each terminus. Through protonation of its histidines (pKs between 5.4 and 6.0) the alignment of the helices is transmembrane at neutral pH and in-plane at pH <5.5 (1). The LAH4 peptides exhibit membrane pore-formation and antimicrobial action at both neutral and at acidic pH including against clinical isolates where the low pH configuration is more active (2). The LAH4 peptides have been found to also exhibit potent DNA and siRNA transfection activities (3). Therefore they can act as a non-viral vector and has indeed been used for the delivery of quantum dots or protein-based vaccines. Furthermore, transduction by adeno-associated viruses or lentiviruses is enhanced by LAH4 (4) or non-peptidic mimetics of this family of peptides (5). Recent and ongoing biophysical, structural and cell biological investigations will be reported which aim to understand these activities at atomic resolution (3, 6-8). (1) B. Bechinger, J.Mol.Biol. 263, 768 (1996). (2) A. J. Mason, et al., J. Biol. Chem. 284, 119 (2009). (3) B. Bechinger, et al. J Pept Sci (2017, in prep.). (4) S. Majdoul, Seye, A.K., Kichler, A., Holic, N., Galy, A., Bechinger, B., Fenard, D., J. Biol. Chem., 291, 2161 (2016) (5) C. Douat, C. et al. Angew. Chem Int. Ed 54, 11133 (2015) (6) C. Aisenbrey, B. Bechinger, Langmuir 30, 10374 (2014). (7) R. Macháň, P. Jurkiewicz, T. Steinberger, B. Bechinger, M. Hof, Langmuir 30, 6171 (2014). (8) A. Farrotti, G. Bocchinfuso, A. Palleschi, N. Rosato, E. S. Salnikov, N. Voievoda, B. Bechinger, L. Stella, BBA 1848, 581 (2015).

The histidine-rich designer peptide LAH4-L1 exhibits antimicrobial and potent cell-penetrating activities for a wide variety of cargo including nucleic acids, polypeptides, adeno-associated viruses, and nanodots. The non-covalent complexes formed between the peptide and cargo enter the cell via an endosomal pathway where the pH changes from neutral to acidic. Here, we investigated the membrane interactions of the peptide with phospholipid bilayers and its membrane topology using static solid-state NMR spectroscopy. Oriented 15N solid-state NMR indicates that in membranes composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) 3:1 mol/mole and at neutral pH, the peptide adopts transmembrane topologies. Furthermore, 31P and 2H solid-state NMR spectra show that liquid crystalline 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and POPC/POPS 3:1 liposomes retain a bilayer macroscopic phase even at the highest peptide concentrations investigated, with an oblate orientational distribution of the phospholipids at a peptide/lipid ratio of 1:5. At pH 5, as it occurs in the endosome, the alignment of LAH4-L1 at a peptide/lipid ratio of 1:25 is predominantly parallel to POPC/POPS 3:1 bilayers (prolate deformation) when at the same time it induces a considerable decrease of the deuterium order parameter of POPC/2H31-POPS 3:1. In addition, when studied in mechanically supported lipid membranes, a pronounced disordering of the phospholipid alignment is observed. In the presence of even higher peptide concentrations, lipid spectra are observed that suggest the formation of magnetically oriented or isotropic bicelles. This membrane-disruptive effect is enhanced for gel phase DMPC membranes. By protonation of the four histidines in acidic environments, the overall charge and hydrophobic moment of LAH4-L1 considerably change, and much of the peptide is released from the cargo. Thus, the amphipathic peptide sequences become available to disrupt the endosomal membrane and to assure highly efficient release from this organelle.

Efficient surface functionalization with polydopamine (PDA) films can be easily achieved on virtually any object via single immersion in slightly basic dopamine solutions. In such conditions, however, poor homogeneity, low thickness, and long time of reaction are usually the major limitations. Herein, we report a rational entry to the control of PDA deposition via chemical oxidation under slightly acidic conditions (pH 5.0) ensuring inhibition of uncontrolled autoxidation processes to gain insight about the reaction mechanism and the impact of oxidation conditions on PDA structure. Comparative chemical analysis of dopamine oxidation with three different oxidants (ammonium peroxodisulfate, sodium periodate, and copper sulfate) revealed significant differences in the reaction course and allowed selection of periodate for the fast and homogeneous deposition of PDA films with thickness never before reported. Notably, PDA coatings with unprecedented superhydrophilic/superoleophobic properties were obtained under conditions of high periodate concentration due to degradation of quinone units to yield carboxyl functions. Moreover, these films still present biocompatibility and metal cation reduction properties. Overall, these results provide a novel rational methodology to tailor PDA coatings for technological applications based on periodate control over dopamine polymerization and postsynthetic functional group modification.

"Polydopamine" (PDA) is the oxidation product of dopamine and can be obtained as thin films covering the surface of all kinds of known materials and simultaneously as insoluble and useless precipitates from dopamine solutions in the presence of appropriate oxidants. The valorization of such precipitates to obtain stable suspensions of functional nanomaterials is highly desirable owing to the chemical and optical properties of PDA. We show that a vast repertoire of polyelectrolytes polycations as well as polyanions, allow to control the size of PDA particles in the 10-100 nm size range. Simultaneously to the production of smaller nanoparticles, a progressive inhibition of PDA deposition on the surface of quartz plates (as well as on the surface of the reaction vessel) is found as the concentration of the polyelectrolytes is increased in the dopamine solution. The mechanism of size control-inhibition of film deposition is investigated in the particular case of poly(allylamine) but remains not understood in the case of polyanions.

Recently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the present study, we have tested the hypothesis that KTP-NH2 is an enhancer of the Ib anti-inflammatory action. Moreover, the impact of the IbKTP-NH2 conjugation on microcirculation was also evaluated by a unified approach based on intravital microscopy in the murine cremasteric muscle. Our data show that KTP-NH2 and conjugates do not cause damage on microcirculatory environment and efficiently decrease the number of leukocyte rolling induced by lipopolysaccharide (LPS). Isothermal titration calorimetry showed that the drugs bind to LPS directly thus contributing to LPS aggregation and subsequent elimination. In a parallel study, molecular dynamics simulations and NMR data showed that the IbKTP-NH2 tandem adopts a preferential “stretched” conformation in lipid bilayers and micelles, with the simulations indicating that the Ib moiety is anchored in the hydrophobic core, which explains the improved partition of IbKTP-NH2 to membranes and the permeability of lipid bilayers to this conjugate relative to KTP-NH2. The ability to bind glycolipids concomitant to the anchoring in the lipid membranes through the Ib residue explains the analgesic potency of IbKTP-NH2 given the enriched glycocalyx of the blood–brain barrier cells. Accumulation of IbKTP-NH2 in the membrane favors both direct permeation and local interaction with putative receptors as the location of the KTP-NH2 residue of IbKTP-NH2 and free KTP-NH2 in lipid membranes is the same.

The synthetic LAH4 peptides were designed to investigate the interactions that determine the membrane topology of helical peptides (1). Their core consist of alanines, leucine and four histidines arranged to form an amphipathic helix, as well as two lysines at each terminus. Through protonation of its histidines (pKs between 5.4 and 6.0) the alignment of the helices is transmembrane at neutral pH and in-plane at pH <5.5 (1). The LAH4 peptides exhibit membrane pore-formation and antimicrobial action at both neutral and at acidic pH including against clinical isolates where the low pH configuration is more active (2). The LAH4 peptides have been found to also exhibit potent DNA and siRNA transfection activities (3). LAH4 can therefore act as a non-viral vector and has indeed been used for the delivery of quantum dots or protein-based vaccines. Furthermore, transduction by adeno-associated viruses or lentiviruses is enhanced by LAH4 peptides (4). Ongoing biophysical and structural investigations will be reported which aim to understand these activities at atomic resolution (5-8). 1. B. Bechinger, J.Mol.Biol. 263, 768 (1996). 2. A. J. Mason, et al., J. Biol. Chem. 284, 119 (2009). 3. B. Bechinger, V. Vidovic, P. Bertani, A. Kichler, J Pept Sci 17, 88 (2011). 4. D. Fenard, D. Ingrao, A. Seye, J. Buisset, S. Genries, S. Martin, A. Kichler, A. Galy, Molecular Therapy-Nucleic Acids 2, doi:10.1038/mtna.2013.17 (2013). 5. C. Aisenbrey, B. Bechinger, Langmuir 30, 10374 (2014). 6. R. Macháň, P. Jurkiewicz, T. Steinberger, B. Bechinger, M. Hof, Langmuir 30, 6171 (2014). 7. B. Perrone, A. J. Miles, E. Salnikov, B. Wallace, B. Bechinger, Eur. Biophys. J. epub. Sep. 3, (2014). 8. A. Farrotti, G. Bocchinfuso, A. Palleschi, N. Rosato, E. Salnikov, N. Voievoda, B. Bechinger, L. Stella, (2014, submitted).

Anionic and cationic surfactants such as sodium dodecylsulfate (SDS) and hexadecyltrimethylammonium bromide (HTAB) are able to control the size of "polydopamine" particles produced from dopamine solutions and to simultaneously strongly inhibit the deposition of "polydopamine" on surfaces. Indeed, dynamic light scattering experiments allowed to show that the hydrodynamic radius of polydopamine progressively decreases from about 1 μm to a few nanometer upon an increase in the SDS and CTAB concentration. At the highest surfactant concentration used (50 mM) the size of the aggregates is only slightly larger than the size of the surfactant micelles. On the other hand, the non-ionic Triton X-100 surfactant has no significant influence on both phenomena. It is suggested that the observed effect originates from the anionic and cationic surfactants acting as a template in which the growth of "polydopamine" is confined.

The one-step synthesis of a mesoporous silica of SBA type, functionalized with a 1-(2,6-diisopropylphenyl)-3-propyl-imidazolium (iPr2Ar-NHC-propyl) cation located in the pore channels, is described. This material was obtained by the direct hydrolysis and co-condensation of tetraethylorthosilicate (TEOS) and 1-(2,6-diisopropylphenyl)-3-[3-(triethoxysilyl)propyl]-imidazolium iodide in the presence of Pluronic P123 as a non-ionic structure-directing agent and aqueous HCl (37%) as an acid catalyst. Small-angle X-ray diffraction measurements, scanning and transmission electron microscopies, as well as dinitrogen sorption analyses revealed that the synthesized material is highly mesoporous with a 2D hexagonal arrangement of the porous network. (13)C and (29)Si CP-MAS NMR spectroscopy confirmed that the material contains intact iPr2Ar-NHC-propyl cations, which are covalently anchored via silicon atoms fused into the silica matrix. Moreover, comparison of the latter data with those of an analogous post-synthetic grafted SBA-NHC material allowed us to establish that, as expected, (i) it is most probably more homogeneous and (ii) it shows a more robust anchoring of the organic units. Finally, elemental mapping by energy dispersive X-ray spectroscopy in the scanning electron microscope demonstrated a very homogeneous distribution of the imidazolium units within the one-pot material, moreover with a high content. This study thus demonstrates that a relatively bulky and hydrophilic imidazolium unit can be directly co-condensed with TEOS in the presence of a structure-directing agent to provide in a single step a highly ordered and homogeneous mesoporous hybrid SBA-NHC material, possessing a significant number of cationic NHC sites.

Solid-state NMR spectroscopy has much advanced during the last decade and provides a multitude of data that can be used for high-resolution structure determination of biomolecules, polymers, inorganic compounds or macromolecules. In some cases the chemical shift referencing has become a limiting factor to the precision of the structure calculations and we have therefore evaluated a number of methods used in proton-decoupled (15)N solid-state NMR spectroscopy. For (13)C solid-state NMR spectroscopy adamantane is generally accepted as an external standard, but to calibrate the (15)N chemical shift scale several standards are in use. As a consequence the published chemical shift values exhibit considerable differences (up to 22 ppm). In this paper we report the (15)N chemical shift of several commonly used references compounds in order to allow for comparison and recalibration of published data and future work. We show that (15)NH4Cl in its powdered form (at 39.3 ppm with respect to liquid NH3) is a suitable external reference as it produces narrow lines when compared to other reference compounds and at the same time allows for the set-up of cross-polarization NMR experiments. The compound is suitable to calibrate magic angle spinning and static NMR experiments. Finally the temperature variation of (15)NH4Cl chemical shift is reported.