Structure‐Driven Selection of Adaptive Transmembrane Na+ Carriers or K+ Channels

Self‐assembled alkyl‐ureido‐benzo‐15‐crown‐5‐ethers are selective ionophores for K⁺ cations, which are preferred to Na⁺ cations. The transport mechanism is determined by the optimal coordination rather than classical dimensional compatibility between the crown ether hole and the cation diameter. Herein, we demonstrate that systematic changes of the structure lead to unexpected modifications in the cation‐transport activity and suffice to produce adaptive selection. We show that the main contribution to performance arises from optimal constraints on the conformational freedom, which are determined by the binding macrocycles, the nature of the hydrogen‐bonding groups, and the hydrophobic tails. Simple changes to the flexible 15‐crown‐5‐ether lead to selective carriers for Na⁺. Hydrophobic stabilization of the channels through mutual interactions between lipids and variable hydrophobic tails appears to be an important cause of increased activity. Oppositely, restricted translocation is achieved when constrained hydrogen‐bonded macrocyclic relays are less dynamic in a pore superstructure.     

Polygermoxanes suitable for biochemical purposes: II Linear trigermoxanes (high-viscosity oils)

Linear trigermoxanes, R¹ RGeOGe(R³)₂OGeRR¹, a new series of organogermanium compounds, were synthesized by reaction of a lithium organogermanolate with a suitable organogermanium dihalide. With alkyl or phenyl substituents, these trigermoxanes are structurally unstable viscous oils, due to redistribution reactions. When R³ substituents are bulky groups, such as mesityl, trigermoxanes are thermally and structurally stable oils; depending on the R¹ and R² substituents their viscosities lie in the range 240 to more than 1500 cPo (mPa s) at 20°C. When both terminal germanium atoms are substituted with two mesityl groups, trigermoxanes are stable glassy solids.     

Synthesis of 2- and 2,7-functionalized pyrene derivatives: an application of selective C-H borylation

An efficient synthetic route to 2- and 2,7-substituted pyrenes is described. The regiospecific direct C-H borylation of pyrene with an iridium-based catalyst, prepared in situ by the reaction of [{Ir(μ-OMe)cod}(2)] (cod = 1,5-cyclooctadiene) with 4,4'-di-tert-butyl-2,2'-bipyridine, gives 2,7-bis(Bpin)pyrene (1) and 2-(Bpin)pyrene (2, pin = OCMe(2)CMe(2)O). From 1, by simple derivatization strategies, we synthesized 2,7-bis(R)-pyrenes with R = BF(3)K (3), Br (4), OH (5), B(OH)(2) (6), and OTf (7). Using these nominally nucleophilic and electrophilic derivatives as coupling partners in Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig cross-coupling reactions, we obtained 2,7-bis(R)-pyrenes with R = (4-CO(2)C(8)H(17))C(6)H(4) (8), Ph (9), C≡CPh (10), C≡C[{4-B(Mes)(2)}C(6)H(4)] (11), C≡CTMS (12), C≡C[(4-NMe(2))C(6)H(4)] (14), C≡CH (15), N(Ph)[(4-OMe)C(6)H(4)] (16), and R = OTf, R' = C≡CTMS (13). Lithiation of 4, followed by reaction with CO(2), yielded pyrene-2,7-dicarboxylic acid (17), whilst borylation of 2-tBu-pyrene gave 2-tBu-7-Bpin-pyrene (18) selectively. By similar routes (including Negishi cross-coupling reactions), monosubstituted 2-R-pyrenes with R = BF(3)K (19), Br (20), OH (21), B(OH)(2) (22), [4-B(Mes)(2)]C(6)H(4) (23), B(Mes)(2) (24), OTf (25), C≡CPh (26), C≡CTMS (27), (4-CO(2)Me)C(6)H(4) (28), C≡CH (29), C(3)H(6)CO(2)Me (30), OC(3)H(6)CO(2)Me (31), C(3)H(6)CO(2)H (32), OC(3)H(6)CO(2)H (33), and O(CH(2))(12)Br (34) were obtained from 2. These derivatives are of synthetic and photophysical interest because they contain donor, acceptor, and conjugated substituents. The crystal structures of compounds 4, 5, 7, 12, 18, 19, 21, 23, 26, and 28-31 have also been obtained from single-crystal X-ray diffraction data, revealing a diversity of packing modes, which are described in the Supporting Information. A detailed discussion of the structures of 1 and 2, their polymorphs, solvates, and co-crystals is reported separately.     

A slowly relaxing rigid biradical for efficient dynamic nuclear polarization surface-enhanced NMR spectroscopy: expeditious characterization of functional group manipulation in hybrid materials

A new nitroxide-based biradical having a long electron spin-lattice relaxation time (T(1e)) has been developed as an exogenous polarization source for DNP solid-state NMR experiments. The performance of this new biradical is demonstrated on hybrid silica-based mesostructured materials impregnated with 1,1,2,2-tetrachloroethane radical containing solutions, as well as in frozen bulk solutions, yielding DNP enhancement factors (ε) of over 100 at a magnetic field of 9.4 T and sample temperatures of ~100 K. The effects of radical concentration on the DNP enhancement factors and on the overall sensitivity enhancements (Σ(?)) are reported. The relatively high DNP efficiency of the biradical is attributed to an increased T(1e), which enables more effective saturation of the electron resonance. This new biradical is shown to outperform the polarizing agents used so far in DNP surface-enhanced NMR spectroscopy of materials, yielding a 113-fold increase in overall sensitivity for silicon-29 CPMAS spectra as compared to conventional NMR experiments at room temperature. This results in a reduction in experimental times by a factor >12,700, making the acquisition of (13)C and (15)N one- and two-dimensional NMR spectra at natural isotopic abundance rapid (hours). It has been used here to monitor a series of chemical reactions carried out on the surface functionalities of a hybrid organic-silica material.     

Synthesis of a new family of acyclic nucleoside phosphonates, analogues of TPases transition states

A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2-hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase.     

New transesterification reaction between acetylated wood and tetramethoxysilane: A feasibility study

Novel transesterification of acetylated maritime pine sapwood (Pinus pinaster Soland) reaction was performed with tetramethoxysilane (TMOS) in presence of dibutyltin oxide as a catalyst. Transesterification was confirmed by weight percent gain calculations (WPG), infrared spectroscopy (FTIR) as well as ¹³C and ²⁹Si NMR CP-MAS analysis. The results showed that transesterification indeed occurs via exchange of acetate groups from acetylated wood and methoxysilane groups from TMOS. The effect of temperatures and reaction time upon transesterification efficiency was also investigated.     

The low energy tautomers and conformers of the dipeptides HisGly and GlyHis and of their sodium ion complexes in the gas phase

The low-lying conformers of the dipeptides HisGly and GlyHis, and of their sodium cation complexes, have been studied with a combination of Monte Carlo search with the Amber force field and local geometry optimization at the ab initio HF/6-31G(d) level, completed with MP2(full)/6-311+G(2d,2p) energetics at the HF/6-31G(d) geometries. For each dipeptide, both the N(delta)-H and N(epsilon)-H tautomers of the imidazole side chain of His were considered. For each of the four isomeric dipeptides, 20-30 conformers were fully characterized at the ab initio level. All low energy structures are found to involve H-bonding at the N(delta) position of imidazole, either as a N-H donor or a N acceptor, depending upon the tautomer. In three out of the four species, the most stable conformer involves a C-terminus carboxylic acid in its less favorable trans conformation, in order to maximize intramolecular H bonding. It turns out that the lowest energy tautomer of HisGly is N(epsilon)-H, while that of GlyHis is N(delta)-H. This result argues in favor of the diversity of His tautomeric states in peptides and proteins. The sodium cation complexes of both GlyHis and HisGly have been studied as well, again considering both tautomers in each case. In three out of the four species, the most stable structure involves chelation of sodium by the two carbonyl oxygens and the imidazole ring. On the contrary, the sodium complex of the N(delta)-H tautomer of HisGly favors chelation to the peptidic carbonyl oxygen, the imidazole ring and the amino terminus. In the N(epsilon)-H tautomers of both peptides, the most favorable binding site of imidazole is the N(delta) nitrogen, while in the N(delta)-H tautomers, it is the pi cloud which provides side chain interaction. As a result, both GlyHisNa+ and HisGlyNa+ favor the N(epsilon)-H tautomer of His, in contrast to what was found for the free peptides.     

Identification and functional characterization of a novel α-conotoxin (EIIA) from Conus ermineus

Nicotinic acetylcholine receptors (nAChRs) are one of the most important families in the ligand-gated ion channel superfamily due to their involvement in primordial brain functions and in several neurodegenerative pathologies. The discovery of new ligands which can bind with high affinity and selectivity to nAChR subtypes is of prime interest in order to study these receptors and to potentially discover new drugs for treating various pathologies. Predatory cone snails of the genus Conus hunt their prey using venoms containing a large number of small, highly structured peptides called conotoxins. Conotoxins are classified in different structural families and target a large panel of receptors and ion channels. Interestingly, nAChRs represent the only subgroup for which Conus has developed seven distinct families of conotoxins. Conus venoms have thus received much attention as they could represent a potential source of selective ligands of nAChR subtypes. We describe the mass spectrometric-based approaches which led to the discovery of a novel α-conotoxin targeting muscular nAChR from the venom of Conus ermineus. The presence of several posttranslational modifications complicated the N-terminal sequencing. To discriminate between the different possible sequences, analogs with variable N-terminus were synthesized and fragmented by MS/MS. Understanding the fragmentation pathways in the low m/z range appeared crucial to determine the right sequence. The biological activity of this novel α-conotoxin (α-EIIA) that belongs to the unusual α4/4 subfamily was determined by binding experiments. The results revealed not only its selectivity for the muscular nAChR, but also a clear discrimination between the two binding sites described for this receptor.