Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity

The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of aromatase inhibitory pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed SN2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC50 3.5 nM), comparable with that of Anastrozole (IC50 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition.Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase.     

The gamma-core and coalition formation

This paper reinterprets the γ-core (Chander and Tulkens in Int Tax Pub Financ 2:279–293, 1995; in Int J Game Theory 26:379–401, 1997) and justifies it as well as its prediction that the efficient coalition structure is stable in terms of the coalition formation theory. The problem of coalition formation is formulated as an infinitely repeated game in which the players must choose whether to cooperate or not. It is shown that a certain equilibrium of this game corresponds to the γ-core assumption that when a coalition forms the remaining players form singletons, and that the grand coalition is an equilibrium coalition structure. An earlier version of this paper was presented at the conference on Game Theory and Its Applications held in Mumbai in 2003 and was subsequently circulated as CORE Discussion Paper 2003/46.     

Single, binary, and multicomponent sorption of iron and manganese on lignite

Acid mine drainage (AMD) has long been a significant environmental problem resulting from the microbial oxidation of iron pyrite in the presence of water and air, affording an acidic solution that contains toxic metal ions. The main objective of this study was to remove metal ions [Fe(II), Fe(III), Mn(II), Zn(II)] from AMD using lignite, a low-cost adsorbent. The lignite sorbent was utilized for the sorption of ferrous, ferric, manganese, zinc, and calcium ions in aqueous solutions. Studies were performed at different pH to find optimum pH. Equilibrium isotherms were determined to assess the maximum adsorption capacity of lignite for different metal ions. Sorption capacities were compared in single, binary, ternary, and multicomponent systems. The sorption data are correlated with Freundlich and Langmuir isotherms in each system. Both Freundlich and Langmuir isotherms fit the data reasonably well in terms of regression coefficients. Sorption studies were also performed at different temperatures to obtain the thermodynamic parameters of the process. The maximum lignite adsorption capacities at 25 degrees C were 34.22, 25.84, and 11.90 mg/g for Fe(II), Mn(II), and Fe(III), respectively. Adsorption of Fe(2+) (24.70 mg/g at 10 degrees C and 46.46 mg/g at 40 degrees C) increased with increased temperature, while Mn(2+) adsorption (28.11 mg/g at 10 degrees C and 7.70 mg/g at 40 degrees C) decreased with increased temperature.     

Photoconductivity studies of Te-substituted Sn-Sb-Se semiconducting films

Amorphous thin films of chalcogenide Sn₁₀Sb₂₀Se_70?X Te _X (0≤X≤8) composition were deposited using the thermal evaporation technique. The dark conductivity measurement showed a thermally activated conduction process with single activation energy in a studied temperature regime. Photoconductivity showed no maxima in the measured temperature regime revealing that the material belongs to the type II photoconductor. The observed small difference between activation energy for photoconduction ΔE _ph and dark conduction ΔE accounts for low photosensitivity of the material. The intensity variation of the photocurrent obeys the power law with the exponent γ～0.56–0.64 revealing the dominant bimolecular recombination mechanism in the studied compositions. Transient photoconductivity revealed that initial rise of the photocurrent becomes slow with tellurium content in the sample. The change in the shape of the transient photocurrent with composition is qualitatively explained based upon change in defect statistics introduced by the tellurium content in the sample. The decay process after the initial decay was found to be nonexponential and is described with a differential life time of charge carrier that showed a decreasing trend with the tellurium content in the sample.     

4,5‐Pyrenocyanine—Just Another Phthalocyanine? A STM and 2D WAXS Study

Pyrene‐fused tetraazaporphyrins were synthesized from pyrene‐4,5‐dicarbonitrile precursors using a recently reported procedure as the key step for the asymmetric substitution of pyrene. Metal‐free, zinc‐ and lead‐centered pyrenocyanines were obtained and their optical properties as well as their molecular assembly in the solution and bulk phases and at the liquid/solid interface were studied. The characteristic Q‐band appears broadened, most likely owing to distortion of the molecule introduced by the steric demand of the angularly extended aromatic residue. The angular annulation does not bathochromically shift the Q‐band as far as would have been expected for the linear case. Peripheral substitution with linear and branched alkoxy chains affords solubility of the compounds in organic solvents. The influence of the distinct steric demand of the substituents on aggregation was investigated for metal‐centered pyrenocyanines by using temperature‐dependent ¹H NMR and UV/Vis spectroscopy. The self‐assembly at the liquid/solid interface was studied using scanning tunneling microscopy. The alkoxy substituents facilitate the anchoring of these slightly non‐planar molecules on the surface of graphite. Pyrenocyanine molecules form well‐ordered 2D arrays in which the molecules are arranged in rows. The angular annulation of the pyrenocyanine residue leads to characteristic adsorption behavior at the liquid/solid interface, in which the molecules adsorb in two different adsorption geometries. The alkoxy side‐chains give rise to a discotic columnar superstructure and induce distinct thermotropic behavior. Dependent on the steric demand of the branched chains and the central metal atom, the molecules are rotated with respect to each other to form helical organization.     

Thickness dependence of thermally induced changes in surface and bulk properties of Nafion® nanofilms

Thermally induced changes in surface wettability, dewetting behavior, and proton transport of “self‐assembled” nanothin Nafion^® films (4–300 nm) on SiO₂ substrate is reported. Thermal annealing induces switching of the surface wettability of 55 nm and thinner films from hydrophilic to super‐hydrophobic. Thickness dependence of this behavior is observed with higher annealing temperature required for lower thickness films, indicating highly restrictive mobility of Nafion^® ionomer as film thickness decreases. Dewetting is only observed for 4‐nm thin film. Significant suppression in proton conductivity upon thermal annealing was noted. Similarly, two other bulk properties, water uptake and swelling, were found to decrease upon annealing. This work reports a systematic examination of the thickness dependence of thermally induced changes in both surface and bulk properties of ultra‐thin Nafion^®. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 1267–1277     

Multicomponent Self‐Assembly with a Shape‐Persistent N‐Heterotriangulene Macrocycle on Au(111)

Multicomponent network formation by using a shape‐persistent macrocycle ( MC6 ) at the interface between an organic liquid and Au(111) surface is demonstrated. MC6 serves as a versatile building block that can be coadsorbed with a variety of organic molecules based on different types of noncovalent interactions at the liquid–solid interface. Scanning tunneling microscopy (STM) reveals the formation of crystalline bicomponent networks upon codeposition of MC6 with aromatic molecules, such as fullerene (C₆₀) and coronene. Tetracyanoquinodimethane, on the other hand, was found to induce disorder into the MC6 networks by adsorbing on the rim of the macrocycle. Immobilization of MC6 itself was studied in two different noncovalently assembled host networks. MC6 assumed a rather passive role as a guest and simply occupied the host cavities in one network, whereas it induced a structural transition in the other. Finally, the central cavity of MC6 was used to capture C₆₀ in a complex three‐component system. Precise immobilization of organic molecules at discrete locations within multicomponent networks, as demonstrated here, constitutes an important step towards bottom‐up fabrication of functional surface‐based nanostructures.     

Biochemical evidence for the tyrosine involvement in cationic intermediate stabilization in mouse β-carotene 15, 15'-monooxygenase

Background  

β-carotene 15,15'-monooxygenase (BCMO1) catalyzes the crucial first step in vitamin A biosynthesis in animals. We wished to explore the possibility that a carbocation intermediate is formed during the cleavage reaction of BCMO1, as is seen for many isoprenoid biosynthesis enzymes, and to determine which residues in the substrate binding cleft are necessary for catalytic and substrate binding activity. To test this hypothesis, we replaced substrate cleft aromatic and acidic residues by site-directed mutagenesis. Enzymatic activity was measured in vitro using His-tag purified proteins and in vivo in a β-carotene-accumulating E. coli system.     

Squeezing,Then Stacking: From Breathing Pores to Three‐Dimensional Ionic Self‐Assembly under Electrochemical Control

We demonstrate the spontaneous and reversible transition between the two‐ and three‐dimensional self‐assembly of a supramolecular system at the solid–liquid interface under electrochemical conditions, using in situ scanning tunneling microscopy. By tuning the interfacial potential, we can selectively organize our target molecules in an open porous pattern, fill these pores to form an auto‐host–guest structure, or stack the building blocks in a stratified bilayer. Using a simple electrostatic model, we rationalize which charge density is required to enable bilayer formation, and conversely, which molecular size/charge ratio is necessary in the design of new building blocks. Our results may lead to a new class of electrochemically controlled dynamic host–guest systems, artificial receptors, and smart materials.