Four cytotoxic N4‐substituted thiosemicarbazones derived from 2‐hydroxynaphthalene‐1‐carboxaldehyde

The X‐ray crystal structures are reported of four novel and potentially O,N,S‐tridentate donor ligands that demonstrate antitumour activity. These ligands are 1‐[(4‐methyl­thio­semicarbazono)methyl]‐2‐naphthol, C₁₃H₁₃N₃OS, (III), 1‐[(4‐ethylthio­semicarbazono)­methyl]‐2‐naphthol, C₁₄H₁₅N₃OS, (IV), 1‐[(4‐phenyl­thio­semicarbazono)­methyl]‐2‐naphthol, C₁₈H₁₅N₃OS, (V), and 1‐[(4,4‐di­methyl­thio­semicarbazono)­methyl]‐2‐naphthol di­methyl sulfoxide solvate, C₁₄H₁₅N₃OS·C₂H₆OS, (VI). These chelators are N4‐substituted thio­semicarbazones, each based on the same parent aldehyde, namely 2‐­zhydroxynaphthalene‐1‐carboxaldehyde isonicotinoylhydrazone. Conformational variations within this series are discussed in relation to the optimum conformation for metal‐ion binding.     

Structural resolution and mechanistic insight into hydrogen adsorption in flexible ZIF-7

Flexible metal–organic frameworks offer a route towards high useable hydrogen storage capacities with minimal swings in pressure and temperature via step-shaped adsorption and desorption profiles. Yet, the understanding of hydrogen-induced flexibility in candidate storage materials remains incomplete. Here, we investigate the hydrogen storage properties of a quintessential flexible metal–organic framework, ZIF-7. We use high-pressure isothermal hydrogen adsorption measurements to identify the pressure–temperature conditions of the hydrogen-induced structural transition in ZIF-7. The material displays narrow hysteresis and has a shallow adsorption slope between 100 K and 125 K. To gain mechanistic insight into the cause of the phase transition correlating with stepped adsorption and desorption, we conduct powder neutron diffraction measurements of the D₂ gas-dosed structures at conditions across the phase change. Rietveld refinements of the powder neutron diffraction patterns yield the structures of activated ZIF-7 and of the gas-dosed material in the dense and open phases. The structure of the activated phase of ZIF-7 is corroborated by the structure of the activated phase of the Cd congener, CdIF-13, which we report here for the first time based on single crystal X-ray diffraction measurements. Subsequent Rietveld refinements of the powder patterns for the gas-dosed structure reveal that the primary D₂ adsorption sites in the dense phase form D₂–arene interactions between adjacent ligands in a sandwich-like adsorption motif. These sites are prevalent in both the dense and the open structure for ZIF-7, and we hypothesize that they play an important role in templating the structure of the open phase. We discuss the implications of our findings for future approaches to rationally tune step-shaped adsorption in ZIF-7, its congeners, and flexible porous adsorbents in general. Lastly, important to the application of flexible frameworks, we show that pelletization of ZIF-7 produces minimal variation in performance.

Hydrogen induced flexibility in MOFs can be leveraged to increase useable gas storage capacities. Here hydrogen adsorption isothermal and in situ powder neutron diffraction measurements combine to reveal the mechanism driving flexibility in ZIF-7.     

Total Syntheses of Vancomycin and Eremomycin Aglycons

Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations.     

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

Using two ways of functionalizing amiridine—acylation with chloroacetic acid chloride and reaction with thiophosgene—we have synthesized new homobivalent bis-amiridines joined by two different spacers—bis-N-acyl-alkylene (3) and bis-N-thiourea-alkylene (5) —as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). All compounds exhibited high inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity for BChE. These new agents displayed negligible carboxylesterase inhibition, suggesting a probable lack of untoward drug–drug interactions arising from hydrolytic biotransformation. Compounds 3 with bis-N-acyl-alkylene spacers were more potent inhibitors of both cholinesterases compared to compounds 5 and the parent amiridine. The lead compounds 3a–c exhibited an IC₅₀(AChE) = 2.9–1.4 µM, IC₅₀(BChE) = 0.13–0.067 µM, and 14–18% propidium displacement at 20 μM. Kinetic studies of compounds 3a and 5d indicated mixed-type reversible inhibition. Molecular docking revealed favorable poses in both catalytic and peripheral AChE sites. Propidium displacement from the peripheral site by the hybrids suggests their potential to hinder AChE-assisted Aβ₄₂ aggregation. Conjugates 3 had no effect on Aβ₄₂ self-aggregation, whereas compounds 5c–e (m = 4, 5, 6) showed mild (13–17%) inhibition. The greatest difference between conjugates 3 and 5 was their antioxidant activity. Bis-amiridines 3 with N-acylalkylene spacers were nearly inactive in ABTS and FRAP tests, whereas compounds 5 with thiourea in the spacers demonstrated high antioxidant activity, especially in the ABTS test (TEAC = 1.2–2.1), in agreement with their significantly lower HOMO-LUMO gap values. Calculated ADMET parameters for all conjugates predicted favorable blood–brain barrier permeability and intestinal absorption, as well as a low propensity for cardiac toxicity. Thus, it was possible to obtain amiridine derivatives whose potencies against AChE and BChE equaled (5) or exceeded (3) that of the parent compound, amiridine. Overall, based on their expanded and balanced pharmacological profiles, conjugates 5c–e appear promising for future optimization and development as multitarget anti-AD agents.     

Incorporating solvation effects into density functional theory: Calculation of absolute acidities

An approach to the calculation of molecular electronic structures, solvation energies, and pK_a values in condensed phases is described. The electronic structure of the solute is described by density functional quantum mechanics, and electrostatic features of environmental effects are modeled through external charge distributions and continuum dielectrics. The reaction potential produced by a mode of the molecular charge distribution is computed via finite-difference solutions to the Poisson-Boltzmann equation and incorporated into the self-consistent field procedure. Here we report results on three sets of organic acids, whose pK_a values range over 16 pH units. The first set provides models for ionizable side chains in proteins; the second set considers the effects of substituting one to three chlorine atoms for hydrogens in acetic acid; and the final set consists of 4-substituted-bicyclo-[2.2.2]-octanecarboxylic acids. Successful prediction of “absolute” pK_a values places stringent requirements on the computation of gas-phase proton affinities and on the response to solvation. In some cases the current model shows substantial errors, but overall the results and trends are in good agreement with experiment. Prospects for extending this approach to more complex systems such as proteins are briefly discussed. © 1997 John Wiley & Sons, Inc.     

The role of non-coordinating anions in homogeneous olefin polymerization

We present an overview of homogeneous olefin polymerization catalysts in which chain initiation and propagation involves a metallocenium ion (e.g. Cp₂ZrMe⁺) that can be produced by equilibrium or irreversible CH₃⁻ transfer. The Kaminsky catalyst is an example of the former. Complexes of (C₆F₅)₃B with water, alcohols, mercaptans, silanols and oximes are strong acids which can protonate dialkylmetallocenes to produce weakly-coordinated metallocenium salts that are hydrocarbon soluble and which produce high molecular weight poly-1-olefins. Polymer molecular weight is correlated with the steric and electronic effects of the ligands attached to the metal.     

Scintillating-Glass-Fiber Neutron Sensors, their Application and Performance for Plutonium Detection and Monitoring

Most neutron detection sensors presently employ ³He gas-filled detectors. Despite their excellent performance and widespread use, there are significant limitations to this technology. A significant alternative neutron sensor utilizing neutron-active material incorporated into a glass scintillator is presented that offers novel commercial sensors not possible or practical with gas tube technology. The scintillating optical fiber permits sensors with a multitude of sizes ranging from devices of a single fiber of 150µm to sensors with tens of thousands of fibers with areas as large as 5 m² depending on the neutron flux to be measured. A second significant advantage is the use of high-speed electronics that allow a greater dynamic range, not possible with gas detectors. These sensors are flexible, conformable and less sensitive to vibration that optimizes the source-to-detector geometry and provides robust performance in field applications. The glass-fibers are sensitive to both gamma-rays and neutrons. However, the coincidence electronics are optimized for neutron to gamma-ray discrimination allowing very sensitive measurements with a low false-alarm rate. Applications include SNM surveillance, material control and accountability (MC&A), safeguard inspections, Pu health physics/bioassay and environmental characterization.     

Subcategories of Filter Tower Spaces

The concept of a convergence tower space, or equivalently, a convergence approach space is formulated here in the context of a Cauchy setting in order to include a completion theory. Subcategories of filter tower spaces are defined in terms of axioms involving a general t-norm, T, in order to include a broad range of spaces. A T-regular sequence for a filter tower space is defined and, moreover, it is shown that the category of T-regular objects is a bireflective subcategory of all filter tower spaces. A completion theory for subcategories of filter tower spaces is given.