Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross-Linking Activity of a Transpeptidase of l,d Specificity

The carbapenem class of β-lactams has been optimized against Gram-negative bacteria producing extended-spectrum β-lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d -transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β-lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido-carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems.     

Syntheses of 3-Chloro-7-[(Chlorocarbonyl)Methoxy]-4-Methylcoumarin

Two efficient syntheses of 3-chloro-7-[(chlorocarbonyl)methoxy]-4-methylcoumarin are described, one utilizing traditional chemistry starting from 3-chloro-7-hydroxy-4-methylcoumarin, while the other uses a novel reagent, sulfuryl chloride/thionyl chloride, in a one-pot reaction starting from 7-(carboxymethoxy)-4-methylcoumarin.     

One-Step Generalized Estimating Equations With Large Cluster Sizes

Medical studies increasingly involve a large sample of independent clusters, where the cluster sizes are also large. Our motivating example from the 2010 Nationwide Inpatient Sample (NIS) has 8,001,068 patients and 1049 clusters, with average cluster size of 7627. Consistent parameter estimates can be obtained naively assuming independence, which are inefficient when the intra-cluster correlation (ICC) is high. Efficient generalized estimating equations (GEE) incorporate the ICC and sum all pairs of observations within a cluster when estimating the ICC. For the 2010 NIS, there are 92.6 billion pairs of observations, making summation of pairs computationally prohibitive. We propose a one-step GEE estimator that (1) matches the asymptotic efficiency of the fully iterated GEE; (2) uses a simpler formula to estimate the ICC that avoids summing over all pairs; and (3) completely avoids matrix multiplications and inversions. These three features make the proposed estimator much less computationally intensive, especially with large cluster sizes. A unique contribution of this article is that it expresses the GEE estimating equations incorporating the ICC as a simple sum of vectors and scalars.     

Back to the future: A retrospective assessment of model‐based scenarios for the management of the shrimp fishery in French Guiana facing global change

While the number of models dedicated to predicting the consequences of alternative resource management strategies has increased, instances in which authors look back at past predictions to learn from discrepancies between these and observed developments are scarce. In the past decades, the French Guiana shrimp fishery has experienced shrimp market globalization and decreasing levels of shrimp recruitment due to environmental changes. In 2006, a bio‐economic model of this fishery was developed to simulate its possible responses to economic and environmental scenarios up to 2016. Here, we compare here these predictions to the observed trajectories. While the number of active vessels corresponds to that which was predicted, the estimated shrimp stock does not. Important driving factors had not been anticipated, including a general strike, natural disasters, and the end of the global financial crisis. These results show the importance of participative approaches involving stakeholders in the co‐construction and shared representation of scenarios. Recommendations for resource managers

• Effective fisheries resources management and a fortiori, the capacity of the fisheries to adapt to global change, requires understanding of both ecological and economics dynamics.
• The temporal trajectory of the trawling shrimp fisheries has been well monitored, and the decline of both stock and fleet is understood regarding ecological and economic changes: Changes in the environmental conditions of shrimp recruitment, and oil price increase and selling price decrease.
• However, our bio‐economic modeling work showed that, even with a good understanding of the dynamics explaining past trajectories, unpredictable events (strike, natural disasters…) have acted as other key driving factors altering the capacity of the model to represent possible futures.
• These results led us to recommend a better integration of the expertise of social and political scientists in developing models of bio‐economic systems to increase the quality of scenario predictions, and to argue for more participative approaches involving the stakeholders.

     

Molecular Design Principles for Near‐Infrared Absorbing and Emitting Indolizine Dyes

Desirable components for dye‐sensitzed solar cell (DSC) sensitizers and fluorescent imaging dyes include strong donating building blocks coupled with well‐balanced acceptor functionalities for absorption beyond the visible range. We have evaluated the effects of increasing acceptor strengths and incorporation of dye morphology controlling groups on molar absorptivity and absorption breadth with indolizine donor‐based dyes. Indolizine‐based D –A and D –π–A sensitizers incorporating bis‐rhodanine, tricyanofuran (TCF), and cyanoacrylic acid functionalities were analyzed for performance in DSC devices. The TCF derivatives were also evaluated as near‐infrared (NIR)‐emissive materials with the AH25 emissions extending past 1000 nm.     

Construction of the 17-Thiasteroid Ring System by the Diene-Sulfur Dioxide Cycloaddition Reaction

Abstract

We recently showed² that the steroid ring system can be constructed with a phosphorus atom replacing a carbon in the D-ring by the cycloaddition of a phosphorus (III) halide with a diene that is a vinyl dihydrophenanthrene derivative, such as (1). The phosphine oxide (3) resulting from the hydrolysis of the initial cycloadduct (2) has some resemblance to the hormone equilenin, which also has rings A and B in naphthalene form.     

THERMAL DEGRADATION OF DIMERS OF PHOSPHOLES

Abstract

The pathway followed by dimers of P-methylphospholes in their thermal degradation in solution is strongly dependent on the concentration. At low concentrations (around 0.04 M) in n-decane or toluene as solvent, decomposition is extensive after 17 h in the range 120–130°C. The major product is the P-methylphosphole from de-dimerization. At concentrations above 1.0 M, decomposition is faster and intermolecular interactions are more important. These interactions dominate over de-dimerization and lead to the loss of the bridging P in the 7-phosphanorbornene moiety to yield the cis-3a,7a-dihydrophosphindole system. From the dimer of 1,3-dimethylphosphole, isomeric dihydrophosphindoles are formed, which differ in location of the methyl group on the 6-membered ring and in configuration at phosphorus. These seem to result from attack by a phosphine group as a nucleophile on the bridging P, followed by bond rearrangements in the resulting phosphoranide ion. Decomposition was faster in the presence of tri-n-butylphosphine, which apparently acted as a catalyst through a similar mechanism. By using appropriate conditions each dihydrophosphindole isomer (1,3,5- or 1,3,7-trimethyl) could be made to predominate and this allowed their isolation. Characterization of the isomers and of some derivatives by ³¹P, ¹H, and ¹³C NMR techniques was performed. Most of the thermolysis products were highly complex mixtures and many minor products remain unidentified. The dimer of 1-phenyl-3-methyl-phosphole did not decompose to the phosphole, but the product composition was dependent on concentration.     

Modeling of rod-structures in nonlinear elasticity

This Note deals with the modeling of a structure made of straight elastic rods whose thickness tends to 0. We show that, upon an adequate scaling, the infimum of the total elastic energy tends to the minimum of a functional which depends on fields defined on the centerlines of the rods.