Silver(I) and thallium(I) complexes of a PNP ligand and their utility as PNP transfer reagents

Silver(I) and thallium(I) complexes of a diarylamido-based PNP pincer ligand have been prepared and characterized. The silver complex [(PNP)Ag]2 exists as a dimer both in solution and in the solid state and is stable under an ambient atmosphere. Thallium complex (PNP)Tl is, however, monomeric and acutely sensitive to moisture and air. Both reagents serve to transfer PNP into the coordination sphere of divalent nickel, palladium, and platinum. [(PNP)Ag]2 is able to effect PNP transfer in air, but the transfer to nickel(II) is less efficient than that with the thallium(I) analogue.     

Understanding the role of an easy-to-prepare aldimine-alkyne carboamination catalyst, [Ti(NMe2)3(NHMe2)][B(C6F5)4]

A series of reactivity studies of the carboamination pre-catalyst [Ti(NMe₂)₃(NHMe₂)][B(C₆F₅)₄] as well as the preparation of other catalysts are reported in this work. Treatment of [Ti(NMe₂)₃(NHMe₂)][B(C₆F₅)₄] with the aldimines Ar′NCHtol (Ar′ = 2,6-Me₂C₆H₃, tol = 4-MeC₆H₄), and depending on the reaction conditions, results in isolation of [Me₂NCHR′][B(C₆F₅)₄] (1) or (Me₂N)₂CHtol, as well as the asymmetric titanium dimer [(Me₂N)₂(HNMe₂)Ti(μ₂-N[2,6-Me₂C₆H₃])₂Ti(NHMe₂)(NMe₂)][B(C₆F₅)₄] (2). Protonation of CpTi(NMe₂)₃ and Cp^∗Ti(NMe₂)₃ results in isolation of the salts, [CpTi(NMe₂)₂(NHMe₂)][B(C₆F₅)₄] (3) and [Cp^∗Ti(NMe₂)₂(NHMe₂)][B(C₆F₅)₄] (4), respectively. Treatment of compounds 3 or 4 with H₂N[2,6-ⁱPr₂C₆H₃] results in formation of the imido salts [CpTi(N[2,6-ⁱPr₂C₆H₃])(NHMe₂)₂][B(C₆F₅)₄] (5) (58% yield) or [Cp^∗Ti(N[2,6-ⁱPr₂C₆H₃])(NHMe₂)₂][B(C₆F₅)₄] (6). When Ti(NMe₂)₄ is treated with [Et₃Si][B(C₆F₅)₄], the salt [Ti(NMe₂)₃(N[SiEt₃]Me₂)][B(C₆F₅)₄] (7) is obtained, and treatment of the latter with [2,6-ⁱPr₂C₆H₃]NCHtol produces the imine adduct [Ti(NMe₂)₃(κ¹-[2,6-ⁱPr₂C₆H₃]NCHtol)][B(C₆F₅)₄] (8). The carboamination catalytic activity of complexes 2-7 was investigated and compared to [Ti(NMe₂)₃(NHMe₂)][B(C₆F₅)₄]. Likewise, a proposed mechanism to the active carboamination catalyst stemming from [Ti(NMe₂)₃(NHMe₂)][B(C₆F₅)₄] is described.     

Current trends in virtual high throughput screening using ligand-based and structure-based methods

High throughput in silico methods have offered the tantalizing potential to drastically accelerate the drug discovery process. Yet despite significant efforts expended by academia, national labs and industry over the years, many of these methods have not lived up to their initial promise of reducing the time and costs associated with the drug discovery enterprise, a process that can typically take over a decade and cost hundreds of millions of dollars from conception to final approval and marketing of a drug. Nevertheless structure-based modeling has become a mainstay of computational biology and medicinal chemistry, helping to leverage our knowledge of the biological target and the chemistry of protein-ligand interactions. While ligand-based methods utilize the chemistry of molecules that are known to bind to the biological target, structure-based drug design methods rely on knowledge of the three-dimensional structure of the target, as obtained through crystallographic, spectroscopic or bioinformatics techniques. Here we review recent developments in the methodology and applications of structure-based and ligand-based methods and target-based chemogenomics in Virtual High Throughput Screening (VHTS), highlighting some case studies of recent applications, as well as current research in further development of these methods. The limitations of these approaches will also be discussed, to give the reader an indication of what might be expected in years to come.     

Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays

Glucose transporters play an essential role in cancer cell proliferation and survival and have been pursued as promising cancer drug targets. Using microarrays of a library of new macrocycles known as rapafucins, which were inspired by the natural product rapamycin, we screened for new inhibitors of GLUT1. We identified multiple hits from the rapafucin 3D microarray and confirmed one hit as a bona fide GLUT1 ligand, which we named rapaglutin A (RgA). We demonstrate that RgA is a potent inhibitor of GLUT1 as well as GLUT3 and GLUT4, with an IC₅₀ value of low nanomolar for GLUT1. RgA was found to inhibit glucose uptake, leading to a decrease in cellular ATP synthesis, activation of AMP‐dependent kinase, inhibition of mTOR signaling, and induction of cell‐cycle arrest and apoptosis in cancer cells. Moreover, RgA was capable of inhibiting tumor xenografts in vivo without obvious side effects. RgA could thus be a new chemical tool to study GLUT function and a promising lead for developing anticancer drugs.     

An Alternative Approach to Predicting Reservoir Performance in a Coalbed Methane (CBM) Well Flowing Under Dominant Matrix Shrinkage Effect

Coalbed methane (CBM) reservoirs contain gas molecules in adsorbed state into the solid matrix of coal. The pressure depletion in CBM reservoir causes the matrix gas to desorb into the cleat system which leads to matrix shrinkage. The pore volume of the cleat network changes as coal matrix shrinks. Consequently, cleat porosity and permeability of reservoir change as reservoir pressure depletes. The change in cleat porosity and permeability due to shrinkage of coal matrix with depletion of reservoir pressure invalidates the underlying assumptions made in the derivation of diffusivity equation. Under the conditions of changing porosity and permeability, the utility of the standard method of inflow performance relationship (IPR), paired with \(\frac{P}{Z^{*}}\) method suggested by King (in: SPE Annual Technical Conference and Exhibition, New Orleans, 1990), for performance prediction diminishes. In this paper, an effort has been made to predict reservoir performance of such CBM reservoirs with an alternative approach. The method suggested by Upadhyay and Laik (Transp Porous Media, 2017. doi: 10.1007/s11242-016-0816-6) has been leveraged to describe pseudo-steady-state flow in the form of a new equation that relates stress-dependent pseudo-pressure function with time. The analytical equation derived in this paper is useful in predicting reservoir pressure and flowing bottom hole pressure of a CBM well under the situation when coal matrix shrinks below desorption pressure. The paper aims to predict production performance of CBM reservoirs producing under the influence of matrix shrinkage effect with an approach alternative to conventional IPR approach paired with \(\frac{P}{Z^{*}}\) method. The results of this analytical solution have been validated with the help of numerical simulator CMG–GEM as well as in-field production data. The equations and workflow suggested in this paper can be easily implemented in spreadsheet applications like Microsoft Excel tools.     

Modeling quasi-static crack growth with the extended finite element method Part I: Computer implementation

The extended finite element method (X-FEM) is a numerical method for modeling strong (displacement) as well as weak (strain) discontinuities within a standard finite element framework. In the X-FEM, special functions are added to the finite element approximation using the framework of partition of unity. For crack modeling in isotropic linear elasticity, a discontinuous function and the two-dimensional asymptotic crack-tip displacement fields are used to account for the crack. This enables the domain to be modeled by finite elements without explicitly meshing the crack surfaces, and hence quasi-static crack propagation simulations can be carried out without remeshing. In this paper, we discuss some of the key issues in the X-FEM and describe its implementation within a general-purpose finite element code. The finite element program Dynaflow™ is considered in this study and the implementation for modeling 2-d cracks in isotropic and bimaterial media is described. In particular, the array-allocation for enriched degrees of freedom, use of geometric-based queries for carrying out nodal enrichment and mesh partitioning, and the assembly procedure for the discrete equations are presented. We place particular emphasis on the design of a computer code to enable the modeling of discontinuous phenomena within a finite element framework.     

Biological reference materials and analysis of toxic elements

Summary Biological monitoring of toxic metal pollution in the environment requires quality control analysis with use of standard reference materials. A variety of biological tissues are increasingly used for analysis of element bioaccumulation, but the available Certified Reference Materials (CRMs) are insufficient. An attempt is made to review the studies made using biological reference materials for animal and human tissues. The need to have inter-laboratory studies and CRM in the field of biological monitoring of toxic metals is also discussed.

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Biologische Referenzmaterialien und Analyse toxischer Elemente

     

Path integral methods for inelastic scattering

Corrections to the primitive semi-classical amplitude for multiple inelastic scattering are obtained from a path integral formulation of scattering theory. The path integrals are calculated by making an expansion about a classical orbit describing elastic scattering. Terms are collected to give a series in inverse powers of the reduced mass m of relative motion of the target and projectile. The leading term is the primitive semi-classical amplitude for multiple excitation and explicit formulae are given for the corrections of order $\text{1}\text{m}$. These are calculated in detail for a one-dimensional model. It is shown that some, but not all, of the corrections can be included by evaluating the primitive amplitude with a symmetrized orbit.