Aspartate‐Based CXCR4 Chemokine Receptor Binding of Cross‐Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes

The CXCR4 chemokine receptor is implicated in a number of diseases including HIV infection and cancer development and metastasis. Previous studies have demonstrated that configurationally restricted bis‐tetraazamacrocyclic metal complexes are high‐affinity CXCR4 antagonists. Here, we present the synthesis of Cu²⁺ and Zn²⁺ acetate complexes of six cross‐bridged tetraazamacrocycles to mimic their coordination interaction with the aspartate side chains known to bind them to CXCR4. X‐ray crystal structures for three new Cu²⁺ acetate complexes and two new Zn²⁺ acetate complexes demonstrate metal‐ion‐dependent differences in the mode of binding the acetate ligand concomitantly with the requisite cis‐V‐configured cross‐bridged tetraazamacrocyle. Concurrent density functional theory molecular modelling studies produced an energetic rationale for the unexpected [Zn(OAc)(H₂O)]⁺ coordination motif present in all of the Zn²⁺ cross‐bridged tetraazamacrocycle crystal structures, which differs from the chelating acetate [Zn(OAc)]⁺ structures of known unbridged and side‐bridged tetraazamacrocyclic Zn²⁺‐containing CXCR4 antagonists.     

Stack the Bowls: Tailoring the Electronic Structure of Corannulene‐Integrated Crystalline Materials

We report the first examples of purely organic donor–acceptor materials with integrated π‐bowls (πBs) that combine not only crystallinity and high surface areas but also exhibit tunable electronic properties, resulting in a four‐orders‐of‐magnitude conductivity enhancement in comparison with the parent framework. In addition to the first report of alkyne–azide cycloaddition utilized for corannulene immobilization in the solid state, we also probed the charge transfer rate within the Marcus theory as a function of mutual πB orientation for the first time, as well as shed light on the density of states near the Fermi edge. These studies could foreshadow new avenues for πB utilization for the development of optoelectronic devices or a route for highly efficient porous electrodes.     

A Schiff-base cross-linked supramolecular polymer containing diiminophenol compartments and its interaction with copper(II) ions

We report here the preparation of a Schiff-base linked organic polymer 1 based on linkages containing the potent supramolecular aggregator benzene-1,3,5-tricarboxamide, connected through 2,6-diiminophenol metal binding pockets into a cross-linked polymer. The morphological and physical properties of this material are studied using electron microscopy techniques, thermal analysis, NMR, fluorescence spectroscopy and gas adsorption studies. The interaction of the polymer 1 with Cu^II ions is then investigated by soaking the material with methanolic copper acetate solution, and studying the resulting aggregates using EDX microscopy and FTIR spectroscopy. A small-molecule model compound 2 is also prepared and crystallographically characterised to act as a spectroscopic comparison, providing strong evidence that 1 interacts with copper ions through a nucleation/seeding mechanism for the growth of microcrystalline copper acetate deposits, rather than via chemisorption of the copper ions within the diiminophenol binding pockets. Preliminary results suggest a similar mechanism for Co^II adsorption, while Zn^II ions exhibit a separate interaction mode.     

UV-induced immobilization of tethered zirconocenes on H-terminated silicon surfaces

A tethered ethylenebis(indenyl) zirconocene was covalently immobilized on H-terminated Si(111) surfaces using UV-mediated alkene hydrosilylation, thus making possible the development of structured catalytic surfaces with highly controlled properties.     

Reactive uptake of acetic acid on calcite and nitric acid reacted calcite aerosol in an environmental reaction chamber

The heterogeneous chemistry of gas-phase acetic acid with CaCO(3)(calcite) aerosol was studied under varying conditions of relative humidity (RH) in an environmental reaction chamber. Infrared spectroscopy showed the loss of gas-phase reactant and the appearance of a gaseous product species, CO(2). The acetic acid is observed to adsorb onto the calcite aerosol through both a fast and a slow uptake channel. While the fast channel is relatively independent of RH, the slow channel exhibits enhanced uptake and reaction as the RH is increased. In additional experiments, the calcite aerosol was exposed to both nitric and acetic acids in the presence of water vapor. The rapid conversion of the particulate carbonate to nitrate and subsequent deliquescence significantly enhances the uptake and reaction of acetic acid. These results suggest a possible mechanism for observed correlations between particulate nitrate and organic acids in the atmosphere. Calcium rich mineral dust may be an important sink for simple organic acids.     

Micellization of Alkyltriphenylphosphonium Bromides in Ethylene Glycol and Diethylene Glycol + Water Mixtures: Thermodynamic and Kinetic Investigation

The thermodynamics of micellization and other micellar properties of alkyl- (C₁₀-, C₁₂-, C₁₄- and C₁₆-) triphenylphosphonium bromides in water + ethylene glycol (EG) (0 to 30% v/v) mixtures over a temperature range of 298 to 318 K and cetyltriphenylphosphonium bromide in water + diethylene glycol (DEG) mixtures (0 to 30% v/v) at 298 K have been studied conductometrically. In all cases, an increase in the percentage of co-solvent results in an increase in the cmc values. On the basis of these results, the thermodynamic parameters, the Gibbs energy (ΔG _m^o), enthalpy (ΔH _m^o) and entropy (ΔS _m^o) of micellization have been evaluated. In addition to the conductivity measurements, kinetic experiments have also been done to determine the dependence of observed rate constant for the nucleophilic substitution reaction of p-nitrophenyl acetate and benzohydroxamate ions in the presence of the surfactant cetyltriphenylphosphonium bromide with a varying concentration of EG and DEG ranging from 0 to 50% v/v at pH=7.9 and 300 K. All of the reactions followed pseudo-first-order kinetics. An increase in the surfactant concentration results in an increase in the reaction rate and for a given surfactant concentration, the rate constant decreases as the concentration of co-solvent in the mixture increases. The kinetic micellar effects have been explained by using the pseudophase model. The thermodynamic and structural changes originating from the presence of solvents control the micellar kinetic effects.     

Synthesis of epi-oxetin via a serine-derived 2-methyleneoxetane

The unique reactivity of 2-methyleneoxetanes and 1,5-dioxaspiro[3.2]hexanes has been exploited for the synthesis of epi-oxetin (26), an oxetane-containing beta-amino acid. While the preparation of the natural product oxetin (1) was the original goal, the unexpected diastereoselectivity of an precedented reduction provided the epi-oxetin framework. The methodology described herein should be amenable for the preparation of oxetin with a change in nitrogen protection.     

Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase

Candida glabrata is a lethal fungal pathogen resistant to many antifungal agents and has emerged as a critical target for drug discovery. Over the past several years, we have been developing a class of propargyl-linked antifolates as antimicrobials and hypothesized that these compounds could be effective inhibitors of dihydrofolate reductase (DHFR) from C. glabrata. We initially screened a small collection of these inhibitors and found modest levels of potency. Subsequently, we determined the crystal structure of C. glabrata DHFR bound to a representative inhibitor with data to 1.6 A resolution. Using this structure, we designed and synthesized second-generation inhibitors. These inhibitors bind the C. glabrata DHFR enzyme with subnanomolar potency, display greater than 2000-fold levels of selectivity over the human enzyme, and inhibit the growth of C. glabrata at levels observed with clinically employed therapeutics.     

Dynamics of hyperthermal collisions of O(3P) with CO

The dynamics of O(3P) + CO collisions at a hyperthermal collision energy near 80 kcal mol-1 have been studied with a crossed molecular beams experiment and with quasi-classical trajectory calculations on computed potential energy surfaces. In the experiment, a rotatable mass spectrometer detector was used to monitor inelastically and reactively scattered products as a function of velocity and scattering angle. From these data, center-of-mass (c.m.) translational energy and angular distributions were derived for the inelastic and reactive channels. Isotopically labeled C18O was used to distinguish the reactive channel (16O + C18O 16OC + 18O) from the inelastic channel (16O + C18O 16O + C18O). The reactive 16OC molecules scattered predominantly in the forward direction, i.e., in the same direction as the velocity vector of the reagent O atoms in the c.m. frame. The c.m. translational energy distribution of the reactively scattered 16OC and 18O was very broad, indicating that 16OC is formed with a wide range of internal energies, with an average internal excitation of approximately 40% of the available energy. The c.m. translational energy distribution of the inelastically scattered C18O and 16O products indicated that an average of 15% of the collision energy went into internal excitation of C18O, although a small fraction of the collisions transferred nearly all the collision energy into internal excitation of C18O. The theoretical calculations, which extend previously published results on this system, predict c.m. translational energy and angular distributions that are in near quantitative agreement with the experimentally derived distributions. The theoretical calculations, thus validated by the experimental results, have been used to derive internal state distributions of scattered CO products and to probe in detail the interactions that lead to the observed dynamical behavior.     

Quantification of real-time Salmonella effector type III secretion kinetics reveals differential secretion rates for SopE2 and SptP

Gram-negative pathogenic bacteria such as Salmonella utilize the type III secretion system to inject bacterial effector proteins into a host cell. Upon entry, these effectors bind mammalian cell proteins, hijack cellular signaling pathways, and redirect cellular function, thus enabling bacterial infection. In this study we use the FlAsH/tetracysteine labeling system to fluorescently tag specific effectors in Salmonella to observe real-time secretion of these proteins into a mammalian host cell. The tetracysteine tag is genomically incorporated, thus preserving endogenous control of bacterial effectors. We demonstrate that two effectors, SopE2 and SptP, exhibit different secretion kinetics, as well as different rates of degradation within the host cell. These proteins respectively activate and suppress GTPase Cdc42, suggesting that there is a temporal hierarchy for effector delivery and persistence within the cell that is directly related to effector function.