Synthesis, structure and conformation of partially-modified retro- and retro-inverso psi[NHCH(CF3)]Gly peptides

Partially modified retro- (PMR) and retro-inverso (PMRI) psi[NHCH(CF(3))]Gly peptides, a conceptually new class of peptidomimetics, have been synthesized in wide structural diversity and variable length by aza-Michael reaction of enantiomerically pure alpha-amino esters and peptides with enantiomerically and geometrically pure N-4,4,4-trifluorocrotonoyl-oxazolidin-2-ones. The factors underlying the observed moderate to good diastereocontrol have been investigated. The conformations of model PMR-psi[NHCH(CF(3))]Gly tripeptides have been studied in solution by (1)H NMR spectroscopy supported by MD calculations, as well as in the solid-state by X-ray diffraction. Remarkable stability of turn-like conformations, comparable to that of parent malonyl-based retropeptides, was evidenced, as a likely consequence of two main factors: 1) severe torsional restrictions about sp(3) bonds in the [CO-CH(2)-CH(CF(3))-NH-CH(R)-CO] module, which is biased by the stereoelectronically demanding CF(3) group and the R side chain; 2) formation of nine-membered intramolecularly hydrogen-bonded rings, which have been clearly detected both in CHCl(3) solution and in some crystal structures. The former factor seems to be more important, as turn-like conformations were found in the solid-state even in the absence of intramolecular hydrogen bonding. The relative configuration of the -C*H(CF(3))NHC*H(R)- stereogenic centers has a major effect on the stability of the turn-like conformation, which seems to require a syn stereochemistry. X-ray diffraction and ab initio computational studies showed that the [-CH(CF(3))NH-] group can be seen as a sort of hybrid between a peptide bond mimic and a proteolytic transition state analogue, as it combines some of the properties of a peptidyl -CONH- group (low NH basicity, CH(CF(3))-NH-CH backbone angle close to 120 degrees, C-CF(3) bond substantially isopolar with the C=O) with some others of the tetrahedral intermediate [-C(OX)(O(-))NH-] involved in the protease-mediated hydrolysis reaction of a peptide bond (high electron density on the CF(3) group, tetrahedral backbone carbon).     

Synthesis of 4H-3,1-benzoxazines, quinazolin-2-ones, and quinoline-4-ones by palladium-catalyzed oxidative carbonylation of 2-ethynylaniline derivatives

An effective and straightforward approach to the synthesis of 4H-3,1-benzoxazines 3 and 4, quinazolin-2-ones 5, and quinoline-4-one derivatives 6 and 7 is provided by palladium-catalyzed cyclization-alkoxycarbonylation of variously substituted 2-(trimethylsilanyl)ethynylaniline amide or urea derivatives 2. Reactions are carried out in 7:1 MeCN/MeOH at 65 or 75 degrees C in the presence of catalytic amounts of 10% Pd/C in conjunction with Bu(4)NI and KF and under 2.4 MPa of a 3:1 mixture of CO and air. Anti and syn 6-exo-dig cyclization modes account for the formation of the two stereoisomers. Isomerization of the vinylpalladium intermediate may occur as well. Formation of a double carbonylation product 7r and of a gem-dimethoxycarbonylation product 6s, whose structures have been determined by X-ray diffraction analysis, is justified through an unusual type of rearrangement.     

Synthesis of stereo-defined α-trifluoromethyl (Tfm)-malic units

Aldol reactions of titanium enolates of N-acyl-1,3-oxazolidin-2-ones with ethyl trifluoropyruvate occurred with low to good stereoselectivity depending on the steric properties of the N-acyl group. Attempts to transform the resulting aldols into peptidomimetics incorporating stereo-defined α-trifluoromethyl (Tfm)-malic units are described.     

Structural basis for recognition of bacterial cell wall teichoic acid by pseudo-symmetric SH3b-like repeats of a viral peptidoglycan hydrolase

Endolysins are bacteriophage-encoded peptidoglycan hydrolases targeting the cell wall of host bacteria via their cell wall-binding domains (CBDs). The molecular basis for selective recognition of surface carbohydrate ligands by CBDs remains elusive. Here, we describe, in atomic detail, the interaction between the Listeria phage endolysin domain CBD500 and its cell wall teichoic acid (WTA) ligands. We show that 3′O-acetylated GlcNAc residues integrated into the WTA polymer chain are the key epitope recognized by a CBD binding cavity located at the interface of tandem copies of beta-barrel, pseudo-symmetric SH3b-like repeats. This cavity consists of multiple aromatic residues making extensive interactions with two GlcNAc acetyl groups via hydrogen bonds and van der Waals contacts, while permitting the docking of the diastereomorphic ligands. Our multidisciplinary approach tackled an extremely challenging protein–glycopolymer complex and delineated a previously unknown recognition mechanism by which a phage endolysin specifically recognizes and targets WTA, suggesting an adaptable model for regulation of endolysin specificity.

Combining genetic, biochemical and computational approaches, we elucidated the molecular mechanisms underlying the recognition of Listeria wall teichoic acid by bacteriophage-encoded SH3b repeats.     

Single-ion magnetism in the extended solid-state: insights from X-ray absorption and emission spectroscopy

Large single-ion magnetic anisotropy is observed in lithium nitride doped with iron. The iron sites are two-coordinate, putting iron doped lithium nitride amongst a growing number of two coordinate transition metal single-ion magnets (SIMs). Uniquely, the relaxation times to magnetisation reversal are over two orders of magnitude longer in iron doped lithium nitride than other 3d-metal SIMs, and comparable with high-performance lanthanide-based SIMs. To understand the origin of these enhanced magnetic properties a detailed characterisation of electronic structure is presented. Access to dopant electronic structure calls for atomic specific techniques, hence a combination of detailed single-crystal X-ray absorption and emission spectroscopies are applied. Together K-edge, L_2,3-edge and Kβ X-ray spectroscopies probe local geometry and electronic structure, identifying iron doped lithium nitride to be a prototype, solid-state SIM, clean of stoichiometric vacancies where Fe lattice sites are geometrically equivalent. Extended X-ray absorption fine structure and angular dependent single-crystal X-ray absorption near edge spectroscopy measurements determine Fe^I dopant ions to be linearly coordinated, occupying a D_6h symmetry pocket. The dopant engages in strong 3dπ-bonding, resulting in an exceptionally short Fe–N bond length (1.873(7) Å) and rigorous linearity. It is proposed that this structure protects dopant sites from Renner–Teller vibronic coupling and pseudo Jahn–Teller distortions, enhancing magnetic properties with respect to molecular-based linear complexes. The Fe ligand field is quantified by L_2,3-edge XAS from which the energy reduction of 3d_z² due to strong 4s mixing is deduced. Quantification of magnetic anisotropy barriers in low concentration dopant sites is inhibited by many established methods, including far-infrared and neutron scattering. We deduce variable temperature L₃-edge XAS can be applied to quantify the J = 7/2 magnetic anisotropy barrier, 34.80 meV (∼280 cm⁻¹), that corresponds with Orbach relaxation via the first excited, M_J = ±5/2 doublet. The results demonstrate that dopant sites within solid-state host lattices could offer a viable alternative to rare-earth bulk magnets and high-performance SIMs, where the host matrix can be tailored to impose high symmetry and control lattice induced relaxation effects.

Taking advantage of synchrotron light source methods, we present the geometric and electronic structure of iron doped in lithium nitride.     

Synthesis and evaluation of stereopure α-trifluoromethyl-malic hydroxamates as inhibitors of matrix metalloproteinases

The total synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloproteinases (MMPs) inhibitors has been performed. The synthetic protocol is based on a moderately stereoselective aldol reaction of trifluoropyruvate with an N-acyl-oxazolidin-2-thione for the construction of the core α-Tfm-malic unit. Both the diastereomeric forms of the target α-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, with a substantial drop with respect to the parent unfluorinated compounds.     

Establishing the synthetic origin of amphetamines by 2H NMR spectroscopy

Nine samples of N-acetyl-3,4-methylenedioxyamphetamine (N-acetyl-MDA), prepared according to the most common synthetic procedures, are submitted to (2)H NMR spectroscopy. The relative deuterium content at the various sites of the molecule is shown to depend on its synthetic history. The technique provides a chemical fingerprint of N-acetyl-MDAs and it can be used to trace back the precursor materials and the synthetic pathways employed in the preparation of the samples.     

Determination of metal concentration in fat supplements for swine nutrition by atomic absorption spectroscopy

The presence of some essential and toxic metals in fat supplements for swine diet was investigated. Collected samples represented a relevant production of the Italian industry. In particular, some samples were enriched with antioxidants or waste cooking oils. The method for the determination of Ca, Cu, Cd, Fe, Mg, Mn, Ni, Pb, and Zn in fat samples was developed by means of a certified reference material (CRM 186) and a representative fatty sample (RFS). All samples were digested in closed vessels in a microwave oven and then analyzed by flame atomic absorption or graphite furnace atomic absorption spectrometry. The entire analytical method provided a satisfactory repeatability and reproducibility confirmed by agreement between the experimental recovery data obtained for the CRM 186 sample and, with the method of standard additions, for the RFS material. The samples generally showed a small amount of metals compared with the recommended daily intake for the essential elements. On the other hand, some samples contained a significant concentration, from an analytical point of view, of Cd, Ni, and Pb. Principal component analysis (PCA) was applied to inspect the experimental data obtained from samples analysis. Basically no differences were detected in terms of metal concentration among the fat supplements analyzed.     

Electrochromic devices based on binuclear mixed valence compounds adsorbed on nanocrystalline semiconductors

A series of cyano-bridged binuclear mixed valence complexes of the general formula M-Ru(III)(NH(3))(4)pyCOOH [pyCOOH = isonicotinic acid; M = cis-Ru(bpy)(2)(CN)(2), 1 (bpy = 2,2' bipyridine); trans-Ru(py)(4)(CN)(2), 2 (py = pyridine); [Ru(CN)(6)](4)(-), 3; [Fe(CN)(6)](4)(-), 4] have been prepared and anchored through the carboxylic function to nanocrystalline TiO(2) or SnO(2) electrodes. The complexes display a reversible electrochromic behavior in the range of applied potential from -0.5 to +0.5 V, versus SCE. Tuning of the electronic transitions in the visible and near-infrared spectral regions is achieved through changes of the solvent and of the cyano-bridged metal moiety M.     

Can simple enones be useful partners for the catalytic stereoselective alkylation of indoles?

A new catalytic system for the first example of enantioselective Friedel-Crafts-type (FC) addition of indoles to simple enones is described. The use of an equimolar amount of chiral [Al(salen)Cl] and 2,6-lutidine (10 mol %) was found to be effective in promoting the conjugate addition of indoles to (E)-arylcrotyl ketones, furnishing the corresponding beta-indolyl ketones in excellent yield and high enantioselectivity (ee up to 89%). The role of the base was investigated through spectroscopic as well as computational analyses, which suggested that in situ formation of a new chiral (base.[Al(salen)]) complex was operating under our reaction conditions. In particular, a stable cationic [Al(salen)] hexacoordinate trans complex with the additive base and the enone is suggested as being responsible for the stereocontrolled reaction. Finally, detailed monitoring of the reaction course was carried out showing that a conventional FC pathway induced by [Al(salen)Cl] acting as a Lewis acid is operating.