Synthesis of High‐Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?

Terminal “high‐mannose oligosaccharides” are involved in a broad range of biological and pathological processes, from sperm‐egg fusion to influenza and human immunodeficiency virus infections. In spite of many efforts, their synthesis continues to be very challenging and actually represents a major bottleneck in the field. Whereas multivalent presentation of mannopyranosyl motifs onto a variety of scaffolds has proven to be a successful way to interfere in recognition processes involving high‐mannose oligosaccharides, such constructs fail at reproducing the subtle differences in affinity towards the variety of protein receptors (lectins) and antibodies susceptible to binding to the natural ligands. Here we report a family of functional high‐mannose oligosaccharide mimics that reproduce not only the terminal mannopyranosyl display, but also the core structure and the branching pattern, by replacing some inner mannopyranosyl units with triazole rings. Such molecular design can be implemented by exploiting “click” ligation strategies, resulting in a substantial reduction of synthetic cost. The binding affinities of the new “click” high‐mannose oligosaccharide mimics towards two mannose specific lectins, namely the plant lectin concanavalin A (ConA) and the human macrophage mannose receptor (rhMMR), have been studied by enzyme‐linked lectin assays and found to follow identical trends to those observed for the natural oligosaccharide counterparts. Calorimetric determinations against ConA, and X‐ray structural data support the conclusion that these compounds are not just another family of multivalent mannosides, but real “structural mimics” of the high‐mannose oligosaccharides.     

Efficient Synthesis of Differentiated syn‐1,2‐Diol Derivatives by Asymmetric Transfer Hydrogenation–Dynamic Kinetic Resolution of α‐Alkoxy‐Substituted β‐Ketoesters

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α‐alkoxy‐β‐ketoesters in the presence of well‐defined, commercially available, chiral catalyst Ru^II–(N‐p‐toluenesulfonyl‐1,2‐diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α‐alkoxy‐β‐hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru^II‐ and Rh^III‐tethered precatalysts extended this process to more‐challenging substrates that bore alkenyl‐, alkynyl‐, and alkyl substituents to provide the corresponding syn α‐alkoxy‐β‐hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)‐2‐ethoxy‐3‐(4‐hydroxyphenyl)‐propanoate, which is an important pharmacophore in a number of peroxisome proliferator‐activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type‐II diabetes.     

Comparison of two solid-phase microextraction methods for the quantitative analysis of VOCs in indoor air

Competitive adsorption on adsorptive solid-phase microextraction (SPME) fibres implies careful determination of operating conditions for reliable quantitative analysis of VOCs in indoor air. With this objective, two analytical approaches, involving non-equilibrium and equilibrium extraction, were compared. The average detection limit obtained for GC-MS analysis of nine VOCs by the equilibrium method is 0.2 μg m⁻³, compared with 1.9 μg m⁻³ with the non-equilibrium method. The effect of the relative humidity of the air on the calibration plots was studied, and shown to affect acetone adsorption only. Hence, the concentrations that can be accurately determined are up to 9 μmol m⁻³. The methods were then applied to indoor air containing different concentrations of VOCs. The non-equilibrium method, involving short extraction time, can be used for detection of pollution peaks whereas equilibrium extraction is preferable for measurement of sub-μg m⁻³ ground concentration levels.      

Comparative Analysis of Conjugated Alkynyl Chromophore–Triazacyclononane Ligands for Sensitized Emission of Europium and Terbium

A series of europium and terbium complexes based on a functionalized triazacyclononane carboxylate or phosphinate macrocyclic ligand is described. The influence of the anionic group, that is, carboxylate, methylphosphinate, or phenylphosphinate, on the photophysical properties was studied and rationalized on the basis of DFT calculated structures. The nature, number, and position of electron‐donating or electron‐withdrawing aryl substituents were varied systematically within the same phenylethynyl scaffold in order to optimize the brightness of the corresponding europium complexes and investigate their two‐photon absorption properties. Finally, the europium complexes were examined in cell‐imaging applications, and selected terbium complexes were studied as potential oxygen sensors.     

Tuning the Guest‐Binding Ability of a Helically Folded Capsule by In Situ Modification of the Aromatic Oligoamide Backbone

Starting from a previously described aromatic oligoamide helically folded capsule that binds tartaric acid with high affinity and diastereoselectivity, we demonstrate the feasibility of the direct in situ modification of the helix backbone, which results in a conformational change that reduces its affinity for guests by two orders of magnitude. Specifically, ring contraction of the central pyridazine unit into a pyrrole in the full helical sequence was investigated by using electrochemical and chemical processes. The sequence containing the pyrrole was synthesized independently in a convergent manner to ascertain its structure. The conformation of the pyrrolic folded capsule was elucidated in the solid state by X‐ray crystallography and in solution by using ¹H and ¹³C NMR spectroscopy. Solution studies revealed an unanticipated solvent‐dependent equilibrium between the anti–anti and syn–syn conformations of the pyrrole ring with respect to its two adjacent pyridine units. Titrations of the pyrrole‐containing sequence monitored by ¹H NMR spectroscopy confirmed the expected drop in affinity for tartaric acid and malic acid that arises from the conformation change in the backbone that follows the replacement of the pyridazine by a pyrrole. The reduction of the pyridazine to a pyrrole was characterized by cyclic voltammetry both on the entire sequence and on a shorter precursor. The lower cathodic potential of the precursor made its preparative‐scale electroreduction possible. Direct in situ modification of the pyridazine within the entire capsule sequence was achieved chemically by using zinc in acetic acid.     

Circulatory bubble dynamics: From physical to biological aspects

Bubbles can form in the body during or after decompression from pressure exposures such as those undergone by scuba divers, astronauts, caisson and tunnel workers. Bubble growth and detachment physics then becomes significant in predicting and controlling the probability of these bubbles causing mechanical problems by blocking vessels, displacing tissues, or inducing an inflammatory cascade if they persist for too long in the body before being dissolved. By contrast to decompression induced bubbles whose site of initial formation and exact composition are debated, there are other instances of bubbles in the bloodstream which are well-defined. Gas emboli unwillingly introduced during surgical procedures and ultrasound microbubbles injected for use as contrast or drug delivery agents are therefore also discussed. After presenting the different ways that bubbles can end up in the human bloodstream, the general mathematical formalism related to the physics of bubble growth and detachment from decompression is reviewed. Bubble behavior in the bloodstream is then discussed, including bubble dissolution in blood, bubble rheology and biological interactions for the different cases of bubble and blood composition considered.     

A comparative study of microemulsion electrokinetic capillary chromatography and micellar electrokinetic capillary chromatography for the analysis of UV-absorbing compounds in human urine

Separations of human urine by microemulsion electrokinetic chromatography (MEEKC) and micellar electrokinetic capillary chromatography (MEKC) with respect to resolution, migration times and efficiencies were optimized and compared. The optimised MEEKC and MEKC methods were simple and fast, both of which are excellent characteristics for the complex separations required in clinical and biomedical studies. However, resolution in MEKC was significantly greater than in MEEKC although migration times were 30% faster for the optimised MEEKC method. In addition, a faster analysis method (short-end injection) specifically for routine screening purposes was also investigated. With both MEEKC and MEKC modes, this provided short separations (less than 4 min for urine) with no major compromise in resolution. In conclusion, we found that MEEKC offered no real advantage over MEKC for urine analysis.     

Raman Spectroscopic Study of the Conformation and Melting of Poly(dG) · Poly(dC) and Poly(dG-dC) · Poly(dG-dC) in Aqueous Solution

Raman spectroscopic measurements on aqueous solutions of poly(dG) · poly(dC)indicate that the conformation of the polynucleotides in this double helicalcomplex are distributed between the A and B types at room temperature, the Aform being predominant at –15°C and decreasing progressively upon raising thetemperature to 65°C. A reversible pretransition has been found in this complexnear 70°C. Modifications in the spectra at this temperature indicate no majorconformational changes, but rather suggest altered base pairing and hydration ofthe carbonyl groups, accompanied by a slight distortion of the double helix,resulting in a slightly reduced stacking of the cytosine bases. Measurements inself-pressurized solutions of the complex at high temperature show that it meltsat 103°C in 0.1M NaCl solution (107°C in 0.5M NaCl). These values are somewhatlower than those we have determined in the same manner for the complexpoly(dG-dC) · poly(dG-dC): 117°C in 0.1M MgCl₂ and 113°C or higher in 0.1MNaCl solution.     

Pre-study and in-study validation of a SPE-LC-MS-MS method for the determination of 5-S-cysteinyldopa, a melanoma biomarker, in human plasma

The incidence of malignant melanona has increased over the past decades, particularly in Caucasian population. This disease presents defavourable prognosis in terms of survey, especially when detection occurs at the metastatic phase. Reliable analytical methods for biomarker determination are thus an interesting tool in pathology detection and follow-up. In this context, a method using SPE-LC-ESI-MS-MS for the determination of 5-S-cysteinyldopa (5-SCD) in human plasma was optimized. The presence of matrix effect was investigated in details while 5-SCD stability was studied according to FDA requirements for the validation of bioanalytical methods. Pre-study and in-study validations of the entire method were then successfully performed by applying the approach based on total measurement error and accuracy profiles over a concentration ranges from 1.6 to 200 ng/ml. Good results with respect to accuracy, trueness and precision were obtained. The maximum risk of observing future measurements falling outside the acceptance limits during routine analysis was also estimated.