Partially Saturated Bicyclic Heteroaromatics as an sp3‐Enriched Fragment Collection

Fragment‐based lead generation has proven to be an effective means of identifying high‐quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp²‐rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp³ character. Subsequent derivatization led to a fragment collection featuring regio‐ and stereo‐controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.     

Nanowire Chemical/Biological Sensors: Status and a Roadmap for the Future

Chemiresistive sensors are becoming increasingly important as they offer an inexpensive option to conventional analytical instrumentation, they can be readily integrated into electronic devices, and they have low power requirements. Nanowires (NWs) are a major theme in chemosensor development. High surface area, interwire junctions, and restricted conduction pathways give intrinsically high sensitivity and new mechanisms to transduce the binding or action of analytes. This Review details the status of NW chemosensors with selected examples from the literature. We begin by proposing a principle for understanding electrical transport and transduction mechanisms in NW sensors. Next, we offer the reader a review of device performance parameters. Then, we consider the different NW types followed by a summary of NW assembly and different device platform architectures. Subsequently, we discuss NW functionalization strategies. Finally, we propose future developments in NW sensing to address selectivity, sensor drift, sensitivity, response analysis, and emerging applications.     

Relativistic electron transport and confinement within charge-insulated, mass-limited targets

We present experimental results on the interaction of short-pulse ultra-high-intensity laser beams with small size (“mass-limited”) targets. Several diagnostics (X-ray spectroscopy, K_α and optical imaging of target rear side) have been simultaneously used in order to characterize the laser-generated fast electron transport and energy deposition into the target material. Our results show that fast electrons are effectively confined inside the target by the induced space charge. This electrostatic confinement opens new opportunities to create “Warm Dense Matter” states characterized by solid-state density and temperatures of the order of a few tens of eV.     

Quantitation of Cu+‐catalyzed Decomposition of S‐Nitrosoglutathione Using Saville and Electrochemical Detection: a Pronounced Effect of Glutathione and Copper Concentrations

S‐nitrosothiols (RSNOs) are composed of nitric oxide (NO) bound to the sulfhydryl group of amino acids of peptides or proteins. There is a great interest for their quantitation in biological fluids as they have a crucial impact on physiological and pathophysiological events. Most analytical methodologies for quantitation of RSNOs are based on their decomposition followed by the detection of the released NO. In order to obtain the optimal sensitivity for each detection method, the total decomposition of RSNOs is highly desired. The decomposition of RSNOs can be obtained by using catalytically active metal ions, such as Cu⁺, obtained from CuSO₄ in presence of a reducing agent such as glutathione (GSH) that is naturally present in biological environment. In this work, we have re‐investigated the decomposition of S‐nitrosoglutathione (GSNO) which is the most abundant in vivo low molecular weight RSNO, with a special emphasis on the effect of CuSO₄, GSH, and GSNO concentrations and of their ratio. To this aim, GSNO decomposition optimization was performed by both indirect (Griess assay) and direct (real time electrochemical detection of NO at NO‐microsensor) quantitation methods. Our results show that the ratio between CuSO₄, GSH and GSNO should be adjusted to tune the highest decomposition rate of GSNO and the most efficient electrochemical detection of released NO; also it shows the deleterious effect of very high GSH concentration on the detection of GSNO.     

Nanoscale Platelet Formation by Monounsaturated and Saturated Sophorolipids under Basic pH Conditions

The self‐assembly behavior of the yeast‐derived bolaamphiphile sophorolipid (SL) is generally studied under acidic/neutral pH conditions, at which micellar and fibrillar aggregates are commonly found, according to the (un)saturation of the aliphatic chain: the cis form, which corresponds to the oleic acid form of SL, spontaneously forms micelles, whereas the saturated form, which corresponds to the stearic acid form of SL, preferentially forms chiral fibers. By using small‐angle light and X‐ray scattering (SLS, SAXS) combined with high‐sensitivity transmission electron microscopy imaging under cryogenic conditions (cryo‐TEM), the nature of the self‐assembled structures formed by these two compounds above pH 10, which is the pH at which they are negatively charged due to the presence of a carboxylate group, has been explored. Under these conditions, these compounds self‐assemble into nanoscale platelets, despite the different molecular structures. This work shows that the electrostatic repulsion forces generated by COO^? mainly drive the self‐assembly process at basic pH, in contrast with that found at pH below neutrality, at which self‐assembly is driven by van der Waals forces and hydrogen bonding, and thus, is in agreement with previous findings on carbohydrate‐based gemini surfactants.     

La dynamique des tremblements de terre vue à travers le séisme de Landers du 28 juin 1992

We study the influence of initial conditions and of friction laws on the propagation of dynamic rupture during the earthquake of 28 June 1992 in Landers, California. We model this earthquake solving the elastodynamic wave equation by a finite difference method and we model observed accelerograms in order to get a better knowledge of the dynamic rupture process of this earthquake. In our model rupture propagates spontaneously under the simultaneous control of the initial stress field and friction. We model friction by a simple slip-weakening law. Finally, we inverted the initial stress field and the friction law from the radiation produced by 1992 Landers earthquake using a trial-and-error method. The dynamic model obtained by trial-and-error inversion provides a very satisfactory fit between synthetics and strong motion data. Rupture history and duration of the Landers earthquake are in good agreement with previous kinematic inversion results, without introducing major changes in final slip distribution on the fault. The solution of the dynamic inverse problem is non-unique because this problem is intrinsically ill-posed. Two complementary mechanical models were inverted in order to model the Landers earthquake, and to reproduce the seismic data. The first model corresponds to the asperity model in which only initial stress distribution is heterogeneous. The second model is a barrier model in which the initial stress was perfectly uniform while rupture resistance was heterogeneous. To cite this article: S. Peyrat et al., C. R. Mecanique 330 (2002) 235–248.     

Chlortetracycline,a Novel Arf Inhibitor That Decreases the Arf6-Dependent Invasive Properties of Breast Cancer Cells

Breast cancer is a major disease for women worldwide, where mortality is associated with tumour cell dissemination to distant organs. While the number of efficient anticancer therapies increased in the past 20 years, treatments targeting the invasive properties of metastatic tumour cells are still awaited. Various studies analysing invasive breast cancer cell lines have demonstrated that Arf6 is an important player of the migratory and invasive processes. These observations make Arf6 and its regulators potential therapeutic targets. As of today, no drug effective against Arf6 has been identified, with one explanation being that the activation of Arf6 is dependent on the presence of lipid membranes that are rarely included in drug screening. To overcome this issue we have set up a fluorescence-based high throughput screening that follows overtime the activation of Arf6 at the surface of lipid membranes. Using this unique screening assay, we isolated several compounds that affect Arf6 activation, among which the antibiotic chlortetracycline (CTC) appeared to be the most promising. In this report, we describe CTC in vitro biochemical characterization and show that it blocks both the Arf6-stimulated collective migration and cell invasion in a 3D collagen I gel of the invasive breast cancer cell line MDA-MB-231. Thus, CTC appears as a promising hit to target deadly metastatic dissemination and a powerful tool to unravel the molecular mechanisms of Arf6-mediated invasive processes.     

Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed Annulations with Donor–Acceptor Cyclopropanes

Efficient methods for the convergent synthesis of (poly)cyclic scaffolds are urgently needed in synthetic and medicinal chemistry. Herein, we describe new annulation reactions of thioalkynes with phthalimide‐substituted donor–acceptor cyclopropanes, which gave access to highly substituted cyclopentenes and polycyclic ring systems. With silyl‐thioalkynes, the Lewis acid catalyzed [3+2] annulation reaction with donor–acceptor cyclopropanes took place to afford 1‐thio‐cyclopenten‐3‐amines. On the other hand, an unprecedented polycyclic compound was formed with alkyl‐thioalkynes through a reaction pathway directly involving the phthalimide group. The two transformations proceeded in good yields and tolerated a large variety of functional groups.     

Original Preparation of PEKK Dispersion for Coating by Transfer from a Chloroform Stable Dispersion to an Aqueous Stable Dispersion,by Emulsion/Solvent Evaporation

In this work, aqueous dispersions of PolyEtherKetoneKetone (PEKK) oligomers were obtained by an emulsion/dispersion solvent evaporation technique. The PEKK oligomers were synthesized by a Friedel–Crafts acylation with a number average degree of polymerization of 4. The synthesized PEKK oligomers had very good thermal stability and spontaneously formed a stable dispersion of swollen micrometric fibers in chloroform. After sonication of the chloroform dispersion in water in the presence of sodium dodecyl sulfate (SDS) and evaporation, we obtained aggregated particles with a mean diameter between 120 and 160 nm, decreasing linearly with the PEKK concentration. The most stable dispersions were obtained with 0.5% wt of surfactant and, at a fixed concentration of SDS, the stability decreased when the PEKK concentration was increased. The different dispersions of PEKK in water were very stable and, after water evaporation, formed homogeneous films for high-performance coating.     

An assessment of a days off decomposition approach to personnel shift scheduling

This paper studies a two-phase decomposition approach to solving the personnel scheduling problem. The first phase creates a days-off-schedule, indicating working days and days off for each employee. The second phase assigns shifts to the working days in the days-off-schedule. This decomposition is motivated by the fact that personnel scheduling constraints are often divided into two categories: one specifies constraints on working days and days off, while the other specifies constraints on shift assignments. To assess the consequences of the decomposition approach, we apply it to public benchmark instances, and compare this to solving the personnel scheduling problem directly. In all steps we use mathematical programming. We also study the extension that includes night shifts in the first phase of the decomposition. We present a detailed results analysis, and analyze the effect of various instance parameters on the decompositions’ results. In general, we observe that the decompositions significantly reduce the computation time, but the quality, though often good, depends strongly on the instance at hand. Our analysis identifies which aspects in the instance can jeopardize the quality.