Oxo-Rhenium-Mediated Allylation of Furanoside Derivatives: A Computational Study on the Mechanism and the Stereoselectivity.

Properly substituted tetrahydrofuran (THF) rings are important building blocks in the synthesis of many natural metabolites. Having reliable procedures to control the stereoselectivity at the THF core while decorating it with different substituents is a fundamental requirement to achieve and fulfill the complexity of nature. We recently reported a new chemical approach to control the stereochemistry in the alkylation and arylation of furanoside derivatives by using a rhenium(V) complex to form an intermediate oxo-carbenium species able to react with proper soft nucleophiles.

Chiroptical sensing of perrhenate in aqueous media by a chiral organic cage.

A chiral cage is proposed as an effective chiroptical sensor for perrhenate (surrogate for TcO) in water, fruit juice and artificial urine media. The key mechanism for the chiroptical sensing resides in the change of dihedral angle of the binaphthyl unit and H-bonds with the guest, resulting in ample changes of the CD signal as a consequence of the binding event.

2,3-Carbamate mannosamine glycosyl donors in glycosylation reactions of diacetone-d-glucose. An experimental and theoretical study.

The role of the cyclic 2,3-N,O-carbamate protecting group in directing the selectivity of mannosylation reactions of diacetone-d-glucose, promoted by BSP/TfO via α-triflate intermediates, has been investigated through a combined computational and experimental approach. DFT calculations were used to locate the transition states leading to the α or β anomers. These data indicate the preferential formation of the β-adduct with mannosyl donors either equipped with the 4,6-O-benzylidene protection or without it.

An In-Depth Computational Study of Alkene Cyclopropanation Catalyzed by Fe(porphyrin)(OCH) Complexes. The Environmental Effects on the Energy Barriers.

Iron porphyrin methoxy complexes, of the general formula [Fe(porphyrin)(OCH)], are able to catalyze the reaction of diazo compounds with alkenes to give cyclopropane products with very high efficiency and selectivity. The overall mechanism of these reactions was thoroughly investigated with the aid of a computational approach based on density functional theory calculations. The energy profile for the processes catalyzed by the oxidized [Fe(Por)(OCH)] (Por = porphine) as well as the reduced [Fe(Por)(OCH)] forms of the iron porphyrin was determined.

Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands.

In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)--piperidin-1-yl-4,5-dihydrobenzo-1-6-oxa-cyclohepta[1,2-]pyrazole-3-carboxamide and its deaza cyclohexyl analogue has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of ,, derivatives -, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays.

Halide-Controlled Extending-Shrinking Motion of a Covalent Cage.

Herein, we present an example of covalent cages, whose flexible framework undergoes extending-shrinking motion under halide control. In the absence of halide anions, the free cage assumes a flattened conformation: the cavity is compressed along the C axis passing through the tertiary amines, and the two tribenzylamine platforms are eclipsed. Halide encapsulation promotes a large conformational rearrangement of the cage, involving an extension of the cavity along the C axis and shrinkage along the equatorial plane.

Self-Assembly of Pseudorotaxane Structures from a Dicopper(II) Molecular Cage and Dicarboxylate Axles.

In this work, we employed for the first time a dinuclear bis[tris(2-aminoethyl)amine] cryptate to obtain the self-assembly of pseudorotaxane structures in an aqueous solution. The goal was achieved by exploiting the well-known affinity of the dicopper azacryptate with diphenyl spacers for the terephthalate anion. In particular, a series of molecular threads were synthesized by appending either alkyl or polyoxyethylene chains on both sides of the terephthalate benzene ring.

Synthesis and conformational analysis of a simplified inositol-model of the Streptococcus pneumoniae 19F capsular polysaccharide repeating unit.

Carbohydrate mimics have been studied for a long time as useful sugar substitutes, both in the investigation of biological events and in the treatment of sugar-related diseases. Here we report further evaluation of the capabilities of inositols as carbohydrate substitutes. The conformational features of an inositol-model of a simplified repeating unit corresponding to the capsular polysaccharide of Streptococcus pneumoniae 19F has been evaluated by computational analysis, and compared to the native repeating unit.

Molecular Architecture and Symmetry Properties of 1,3-Alternate Calix[4]arenes with Orientable Groups at the Para Position of the Phenolic Rings.

Two glycoclusters constituted by four fully acetylated β-acetylmannosamine residues linked through trimethylenethioureido spacers to a calix[4]arene core and differing for the presence of methoxy or propoxy groups at the lower rim were synthesized. One of the two compounds is fixed in the 1,3-alternate geometry by the presence of the propoxy groups, while the other is potentially free to assume one of the different geometries allowed in calix[4]arene. Their similar NMR spectra in chloroform clearly suggest the same 1,3-alternate geometry.

GM-3 Lactone Mimetic Interacts with CD4 and HIV-1 Env Proteins, Hampering HIV-1 Infection without Inducing a Histopathological Alteration.

Glycosphingolipids (GSLs) are involved in HIV-1 entry. GM-3 ganglioside, a widespread GSL, affects HIV entry and infection in different ways, depending on the concentration, through its anchoring activity in lipid rafts. This explains why the induction of an altered GSLs metabolism was a tempting approach to reducing HIV-1 cell infection.

Cone Calix[4]arenes with Orientable Glycosylthioureido Groups at the Upper Rim: An In-Depth Analysis of Their Symmetry Properties.

The two glycoclusters α- and β-d-mannosylthioureidocalix[4]arenes 1 and 2 in the cone geometry have been submitted to a conformational investigation with the DFT approach at the standard B3LYP/6-31G(d) level and using a water continuum solvent model. After a reasoned choice of the level of calculation and the evaluation of the properties of the monomeric components of 1 and 2, the intrinsic conformational properties of cone calix[4]arenes with orientable groups at the upper rim were thoroughly analyzed. From the possible combinations of the directions that the groups may assume, 10 different geometries derive, all chiral.

Computational mechanistic study of the Julia-Kocieński reaction.

This paper describes the first detailed computational mechanistic study of the Julia-Kocieński olefination between acetaldehyde (1) and ethyl 1-phenyl-1H-tetrazol-5-yl sulfone (2), considered a paradigmatic example of the reaction between unsubstituted alkyl PT sulfones and linear aliphatic aldehydes. The theoretical study was performed within the density functional approach through calculations at the B3LYP/6-311+G(d,p) level for all atoms except sulfur for which the 6-311+G(2df,p) basis set was used. All the different intermediates and transition states encountered along the reaction pathways leading to final E and Z olefins have been located and the relative energies calculated, both for the reactions with potassium- and lithium-metalated sulfones, in THF and toluene, respectively.

Crystallographic, spectroscopic, and theoretical investigation of the efficiently separated 21R and 21S-diastereoisomers of argatroban.

Argatroban (I), a potent noncovalent reversible thrombin inhibitor, is used as an anticoagulant for the parenteral treatment of heparin-induced thrombocytopenia (HIT) patients. By virtue of its pharmacological properties and the well-balanced risks and benefits, argatroban is now emerging as a clinically relevant antithrombotic agent. The availability of this drug as a mixture of 21R and 21S-diastereoisomers, in a ratio of roughly 64:36, prompted us to design an efficient separation setup of the two epimers.

Multivalent presentation of a hydrolytically stable GM(3) lactone mimetic as modulator of melanoma cells motility and adhesion.

A hydrolytically stable mimetic of the tumour antigen GM(3) lactone is used to decorate multivalent scaffolds. Two of them positively interfere on melanoma cell adhesion, migration and resistance to apoptosis (anoikis). Notably, their ability to hamper melanoma-cells adhesion and reduce the metastatic potential is enhanced when the two scaffolds, presenting a different shape, are used in combination.

Mechanism of falcipain-2 inhibition by α,β-unsaturated benzo[1,4]diazepin-2-one methyl ester.

Falcipain-2 (FP-2) is a papain-family cysteine protease of Plasmodium falciparum whose primary function is to degrade the host red cell hemoglobin, within the food vacuole, in order to provide free amino acids for parasite protein synthesis. Additionally it promotes host cell rupture by cleaving the skeletal proteins of the erythrocyte membrane. Therefore, the inhibition of FP-2 represents a promising target in the search of novel anti-malarial drugs.

Molecular dynamics simulations of the Salmonella typhi Vi antigenic polysaccharide and effects of the introduction of a zwitterionic motif.

A series of hexasaccharides corresponding to the Vi capsular polysaccharide, a polymer of α-(1→4)-galacturonic acid, and analogs containing a zwitterionic motif with various degrees of acetylation at positions 3 have been modeled. When submitted to molecular dynamics simulations in a water box, all the structures visited only two quite restricted regions of the φ/ψ conformational space both corresponding to extended geometries without any tendency towards supercoiling. The most stable conformation showed a clockwise helix arrangement of substituents on the molecular surface whereas the opposite arrangement was observed for the other conformation.

Stable GM3 lactone mimetic raises antibodies specific for the antigens expressed on melanoma cells.

Immunotherapy of tumors and of melanoma in particular has a long history, and recently this therapeutic approach found a reliable scientific rationale. This biological therapy aims to teach the patient's immune system to recognize the antigens expressed on tumor cells and destroy them, leaving normal cells intact. The success of this therapy highly depends on the selection of target antigens that are essential for tumors growth and progression.

Synthesis, molecular dynamics simulations, and biology of a carba-analogue of the trisaccharide repeating unit of Streptococcus pneumoniae 19F capsular polysaccharide.

The synthesis of a carba-analogue corresponding to the trisaccharide repeating unit of Streptococcus pneumoniae type 19F capsular polysaccharide, where a residue of carba-L-rhamnose has been inserted into the natural trisaccharide in place of L-rhamnose, is described. The conformational properties of the analogue were investigated with the aid of molecular dynamics simulations and were strictly analogous to those of the natural compound. The biological activity of the carba-analogue was comparable to that of the corresponding natural repeating unit, thus suggesting that this compound, more stable to hydrolysis, is a good mimic of the natural structure.

Enantioselective synthesis and olfactory evaluation of bicyclic alpha- and gamma-ionone derivatives: the 3D arrangement of key molecular features relevant to the violet odor of ionones.

Violet smelling ionones 1-3, occurring in the headspace of different flowers, are well-known perfumery raw materials. With the goal to recognize the still ill-defined spatial arrangement of structural features relevant to the binding of ionones to olfactory G-protein coupled receptors, through B3LYP/6-31G(d) modeling studies we identified bicyclic compounds 7-9 as conformationally constrained 13-alkyl-substituted analogues of monocyclic alpha- and gamma-ionones. They were thus synthesized to evaluate the olfactory properties.

Modeling of synthetic phosphono and carba analogues of N-acetyl-alpha-D-mannosamine 1-phosphate, the repeating unit of the capsular polysaccharide from Neisseria meningitidis serovar A.

The conformational behavior of methyl (2-acetamido-2-deoxy-alpha-d-mannopyranosyl)phosphate 1, and its analogues, methyl C-(2-acetamido-2-deoxy-alpha-d-mannopyranosyl)methanephosphonate 2 and methyl O-(2-acetamido-2-deoxy-5a-carba-alpha-d-mannopyranosyl)phosphate , where a methylene group replaces, respectively, the anomeric and the pyranose oxygen atom, was investigated at the B3LYP/6-311+G(d,p) level [6-311+G(2df,p) for the phosphorus atom]. The energy of the optimized structures was recalculated using the continuum solvent model C-PCM choosing water as the solvent. The compounds exhibited several populated conformations, but they all showed a marked preference for the (4)C(1) geometry of the pyranose ring; this preference was almost complete for 1, very large for the phosphono analogue 2, and large for the carba analogue 3.

Cyclic glycopeptidomimetics through a versatile sugar-based scaffold.

Cyclic peptidomimetics are attracting structures to obtain a distinct, bioactive conformation. Even more attractive are sugar-containing cyclic peptidomimetics which present turn structures induced by the pyranose ring when incorporated in cyclic peptides. The use of a new and versatile saccharidic scaffold to achieve sugar-based peptidomimetics is here reported together with the successful synthesis of diastereomerically pure cyclic SAA peptidomimetics 15 and 16.

Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors.

Alpha series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards alpha4beta2 and alpha7 nAChR subtypes were evaluated.