The convex hull of two core capacitated network design problems

The network loading problem (NLP) is a specialized capacitated network design problem in which prescribed point-to-point demand between various pairs of nodes of a network must be met by installing (loading) a capacitated facility. We can load any number of units of the facility on each of the arcs at a specified arc dependent cost. The problem is to determine the number of facilities to be loaded on the arcs that will satisfy the given demand at minimum cost.This paper studies two core subproblems of the NLP. The first problem, motivated by a Lagrangian relaxation approach for solving the problem, considers a multiple commodity, single arc capacitated network design problem. The second problem is a three node network; this specialized network arises in larger networks if we aggregate nodes. In both cases, we develop families of facets and completely characterize the convex hull of feasible solutions to the integer programming formulation of the problems. These results in turn strengthen the formulation of the NLP.Research of this author was supported in part by a Faculty Grant from the Katz Graduate School of Business, University of Pittsburgh.     

Dielectric, thermal and optical study of an unusually shaped liquid crystal

Dielectric measurements have been carried out for the determination of real and imaginary parts of the permittivity of a newly synthesized, unusually shaped liquid crystal. The sample has been investigated in the frequency range from 100 Hz to 10 MHz within a temperature range 80-130 °C. The dielectric measurements in the smectic A phase indicate a Cole-Cole type of dispersion, and the activation energy was found to be 5.5 meV by using the Arrhenius plot of relaxation time. In addition to this, thermal and optical transmittance studies have also been conducted in the above mentioned temperature range, and the temperature dependence of these parameters has been discussed in detail. The phase transition temperature obtained from a differential scanning calorimetry (DSC) study matches within 2 °C that was obtained from an optical transmittance study. The dielectric and optical behavior of the unusually shaped liquid crystal has been explained on the basis of a proposed theoretical model in which a sample possesses two different conformers having induced polarizations in opposite directions.     

Facile Chan‐Lam coupling using ferrocene tethered N‐heterocyclic carbene‐copper complex anchored on graphene

Ferrocene tethered N‐heterocyclic carbene‐copper complex anchored on graphene ([GrFemImi]NHC@Cu complex) has been synthesized by covalent grafting of ferrocenyl ionic liquid in the matrix of graphene followed by metallation with copper (I) iodide. The [GrFemImi]NHC@Cu complex has been characterized by fourier transform infrared (FT‐IR), fourier transform Raman (FT‐Raman), CP‐MAS ¹³C NMR spectroscopy, transmission electron microscopy (TEM), thermogravimetric analysis (TGA), energy dispersive X‐ray (EDX) analysis, X‐ray photoelectron spectroscopy (XPS), Brunauer–Emmett–Teller (BET) surface area analysis and X‐ray diffractometer (XRD) analysis. This novel complex served as a robust heterogeneous catalyst for the synthesis of bioactive N‐aryl sulfonamides from variety of aryl boronic acids and sulfonyl azides in ethanol by Chan‐Lam coupling. Recyclability experiments were executed successfully for six consecutive runs.     

Discovery of Cell‐Permeable Inhibitors That Target the BRCT Domain of BRCA1 Protein by Using a Small‐Molecule Microarray

BRCTs are phosphoserine‐binding domains found in proteins involved in DNA repair, DNA damage response and cell cycle regulation. BRCA1 is a BRCT domain‐containing, tumor‐suppressing protein expressed in the cells of breast and other human tissues. Mutations in BRCA1 have been found in ca. 50 % of hereditary breast cancers. Cell‐permeable, small‐molecule BRCA1 inhibitors are promising anticancer agents, but are not available currently. Herein, with the assist of microarray‐based platforms, we have discovered the first cell‐permeable protein–protein interaction (PPI) inhibitors against BRCA1. By targeting the (BRCT)₂ domain, we showed compound 15 a and its prodrug 15 b inhibited BRCA1 activities in tumor cells, sensitized these cells to ionizing radiation‐induced apoptosis, and showed synergistic inhibitory effect when used in combination with Olaparib (a small‐molecule inhibitor of poly‐ADP‐ribose polymerase) and Etoposide (a small‐molecule inhibitor of topoisomerase II). Unlike previously reported peptide‐based PPI inhibitors of BRCA1, our compounds are small‐molecule‐like and could be directly administered to tumor cells, thus making them useful for future studies of BRCA1/PARP‐related pathways in DNA damage and repair response, and in cancer therapy.     

LC–MS/MS and NMR characterization of forced degradation products of mirabegron

A rapid, precise, and reliable liquid chromatography tandem mass spectrometry (LC–MS/MS) method has been developed for the characterization of stressed degradation products of mirabegron. It is used in the treatment of overactive bladder and administered to treat urinary symptoms such as urgency or frequency and incontinence. It also works by relaxing the muscles around bladder.

Mirabegron was subjected to hydrolysis (acidic, alkaline, and neutral) and peroxidation, as per ICH-specified conditions. The drug showed degradation under stress conditions. However, it was stable to neutral conditions. A total of seven degradation products were observed and the chromatographic separation of the drug and its degradation products was achieved on X-TerraRP-8 (250 mm × 4.6 mm, i.d., 5 µm) column using 0.01 M ammonium acetate as mobile phase-A and 60:40 ratio of acetonitrile (ACN):water as mobile phase-B. The degradation products were characterized by LC–MS/MS and its fragmentation pathways were proposed. Probable possible structures were drawn based on parent and daughter molecular ions. One peroxide degradant impurity was isolated using preparative LC and characterized using liquid chromatography–mass spectrometry and NMR data.     

Ab Initio and DFT Studies on CO2 Interacting with Znq+–Imidazole (q=0, 1, 2) Complexes: Prediction of Charge Transfer through σ‐ or π‐Type Models

Using first‐principles methodologies, the equilibrium structures and the relative stability of CO₂@[Zn^q+Im] (where q=0, 1, 2; Im=imidazole) complexes are studied to understand the nature of the interactions between the CO₂ and Zn^q+–imidazole entities. These complexes are considered as prototype models mimicking the interactions of CO₂ with these subunits of zeolitic imidazolate frameworks or Zn enzymes. These computations are performed using both ab initio calculations and density functional theory. Dispersion effects accounting for long‐range interactions are considered. Solvent (water) effects were also considered using a polarizable continuum model approach. Natural bond orbital, charge, frontier orbital and vibrational analyses clearly reveal the occurrence of charge transfer through covalent and noncovalent interactions. Moreover, it is found that CO₂ can adsorb through more favorable π‐type stacking as well as σ‐type hydrogen‐bonding interactions. The inter‐monomer interaction potentials show a significant anisotropy that might induce CO₂ orientation and site‐selectivity effects in porous materials and in active sites of Zn enzymes. Hence, this study provides valuable information about how CO₂ adsorption takes place at the microscopic level within zeolitic imidazolate frameworks and biomolecules. These findings might help in understanding the role of such complexes in chemistry, biology and material science for further development of new materials and industrial applications.     

Selective recognition of alkyl pyranosides in protic and aprotic solvents

The design and synthesis of receptors capable of selective, noncovalent recognition of carbohydrates continues to be a signature challenge in bioorganic chemistry. We report a new generation of tripodal receptors incorporating three pyridine (compound 2) or quinoline (compound 3) rings around a central cyclohexane core for use in molecular recognition of monosaccharides in apolar and polar protic solvents. These tripodal receptors were investigated using (1)H NMR, UV, and fluorescence titrations in order to determine their binding abilities toward a set of octyl glycosides. Receptor 2 displayed the highest binding affinity reported to date for noncovalent 1:1 binding of an alpha-glucopyranoside in chloroform (Ka = 212,000 +/- 27,000 M(-1)) and an approximately 8-fold selectivity for the alpha anomer over the beta anomer of the glucopyranoside. Most importantly, 2 retained its micromolar range of affinities toward monosaccharides in a polar and highly competitive solvent (methanol). The quinoline variant 3 also displayed micromolar binding affinities for selected monosaccharides in methanol (as measured by fluorescence) that were generally smaller than those of 2. Compound 3 was found to follow a selectivity pattern similar to that of 2, displaying higher affinities for glucopyranosides than for other monosaccharides. The binding stoichiometry was estimated to be 1:1 for the complexes formed by both 2 and 3 with glucopyranosides, as determined by Job plots. Nuclear Overhauser effect spectroscopy allowed for the derivation of a binding model consistent with the observed selectivities.     

Isolation, structure, and antibacterial activity of philipimycin, a thiazolyl peptide discovered from Actinoplanes philippinensis MA7347

Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 microg/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED50 value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro23, Pro22, and Pro26 of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described.     

Catalytic cycles for the reduction of [UO2]2+ by cytochrome c7 proteins proposed from DFT calculations

The mechanism of the reduction of the hydrated uranyl cation, [UO2](2+), by the cytochromes G. sulfurreducens and D. acetoxidans has been studied using density functional theory calculations. We propose that the initial electron transfer step from the heme is to a cation-cation complex in the case of D. acetoxidans, but for G. sulfurreducens, it is to a single uranyl cation, which then forms a U(V)-U(VI) complex with a second uranyl cation. For both enzymes, the subsequent catalytic pathways are very similar. A U(V)-U(V) complex is formed, which then undergoes disproportionation via two successive protonation steps of one uranyl group, to give a U(VI)-U(IV) complex which dissociates to individual U(VI) and U(IV) species, the former being bound at the enzyme active site. Intermediate structures along the catalytic pathway are consistent with EXAFS data.