Synthesis of freestanding HfO<Subscript>2</Subscript> nanostructures

Two new methods for synthesizing nanostructured HfO₂ have been developed. The first method entails exposing HfTe₂ powders to air. This simple process resulted in the formation of nanometer scale crystallites of HfO₂. The second method involved a two-step heating process by which macroscopic, freestanding nanosheets of HfO₂ were formed as a byproduct during the synthesis of HfTe₂. These highly two-dimensional sheets had side lengths measuring up to several millimeters and were stable enough to be manipulated with tweezers and other instruments. The thickness of the sheets ranged from a few to a few hundred nanometers. The thinnest sheets appeared transparent when viewed in a scanning electron microscope. It was found that the presence of Mn enhanced the formation of HfO₂ by exposure to ambient conditions and was necessary for the formation of the large scale nanosheets. These results present new routes to create freestanding nanostructured hafnium dioxide.     

A Light‐Controlled TLR4 Agonist and Selectable Activation of Cell Subpopulations

The spatial and temporal aspects of immune cell signaling are key parameters in defining the magnitude of an immune response. Toll‐like receptors (TLRs) on innate immune cells are important in the early detection of pathogens and initiation of an immune response. Controlling the spatial and temporal signaling of TLRs would enable further study of immune synergies and assist in the development of new vaccines. Here, we show a light‐based method for the spatial control of TLR4 signaling. A TLR4 agonist, pyrimido[5,4‐b]indole, was protected with a cage at a position critical for receptor binding. This afforded a photocontrollable agonist that was inactive while caged, yet effected NF‐κB activity in cells following UV photocontrolled deprotection. We demonstrated spatial control of NF‐κB activation within a population of cells by treating all cells with the caged TLR4 agonist and constraining light exposure and consequent activation to a region of interest.     

Synthesis and Biological Evaluation of N‐Substituted Noscapine Analogues

Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule‐modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6′‐substituted noscapine derivatives. To underpin this structure–activity study, an efficient synthesis of N‐nornoscapine and its subsequent reduction to the cyclic ether derivative of N‐nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N‐alkyl, N‐acyl, N‐carbamoyl, N‐thiocarbamoyl, and N‐carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell‐cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF‐7), and colon cancer (Caco‐2) cell lines. Compounds that showed activity in the cell‐cycle assay were further evaluated in cell viability assays using PC3 and MCF‐7 cells.     

Ubiquitin C-Terminal Hydrolase L1: Biochemical and Cellular Characterization of a Covalent Cyanopyrrolidine-Based Inhibitor

The deubiquitinase (DUB) ubiquitin C-terminal hydrolase L1 (UCHL1) is expressed primarily in the central nervous system under normal physiological conditions. However, UCHL1 is overexpressed in various aggressive forms of cancer with strong evidence supporting UCHL1 as an oncogene in lung, glioma, and blood cancers. In particular, the level of UCHL1 expression in these cancers correlates with increased invasiveness and metastatic behavior, as well as poor patient prognosis. Although UCHL1 is considered an oncogene with potential as a therapeutic target, there remains a significant lack of useful small-molecule probes to pharmacologically validate in vivo targeting of the enzyme. Herein, we describe the characterization of a new covalent cyanopyrrolidine-based UCHL1 inhibitory scaffold in biochemical and cellular studies to better understand the utility of this inhibitor in elucidating the role of UCHL1 in cancer biology.     

Microwave-specific heating of crystalline species in nuclear waste glass

The microwave heating of a crystal-free and a partially trevorite-crystallized nuclear waste glass simulant was evaluated. Our results show that a 500-mg monolith of partially crystallized waste glass can be heated from room temperature to above 1600°C within 2 minutes using a single-mode, highly focused, 2.45-GHz microwave, operating at 300 W. Using X-ray diffraction measurements, we show that trevorite is no longer detectable after irradiation and thermal quenching. When a crystal-free analog of the same waste glass simulant composition was exposed to the same microwave radiation, it could not be heated above 450°C regardless of the heating time. The reduction in crystalline content achieved by selectively heating spinels in the presence of glass suggests that microwave-specific heating should be further explored as a technique for remediating crystal accumulation in a glass melt.     

Phospholipid Cyclosporine Prodrugs Targeted at Inflammatory Bowel Disease (IBD) Treatment: Design,Synthesis, and in Vitro Validation

Novel phospholipid (PL)-cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A₂ (PLA₂), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Surprisingly, despite previous work indicating that conjugates with six methylene linkers between the lipid and drug would suffer rapid enzymatic hydrolysis, with cyclosporine this was not observed. However, compounds with longer linkers (n=10, 12 methylene units) display complete release of the drug by PLA₂-catalyzed hydrolysis, thus demonstrating the importance and profound impact of structural fine-tuning. This study represents a proof-of-concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract.     

Kinetic study of crude oil-to-chemicals via steam-enhanced catalytic cracking in a fixed-bed reactor

This study presents new experimental results on the direct conversion of crude oil to chemicals via steam-enhanced catalytic cracking. We have organized the experimental results with a kinetics model using crude oil and steam co-feed in a fixed-bed flow reactor at reaction temperatures of 625, 650, and 675°C over the Ce-Fe/ZSM-5 catalyst. The model let us find optimum conditions for crude oil conversion, and the order of the steam cracking reaction was 2.0 for heavy oil fractions and 1.0 for light oil fractions. The estimated activation energies for the steam cracking reactions ranged between 20 and 200 kJ/mol. Interestingly, the results from kinetic modelling helped in identifying a maximum yield of light olefins at an optimized residence time in the reactor at each temperature level. An equal propylene and ethylene yield was observed between 650 and 670°C, indicating a transition from dominating catalytic cracking at a lower temperature to a dominating thermal cracking at a higher temperature. The results illustrate that steam-enhanced catalytic cracking can be utilized to effectively convert crude oil into basic chemicals (52.1% C2-C4 light olefins and naphtha) at a moderate severity (650°C) as compared to the conventional high-temperature steam cracking process.     

An Aqueous Phase Equilibrium Calculation Algorithm

A multiphase chemical equilibrium algorithm is developed which can be used with aqueous systems. The algorithm uses an average chemical potential for each species as a reference chemical potential. Incipient phases can be identified and their proximity to appearance can be determined through their tangent plane distance. Illustrative examples include the calculation of CaSO₄ solubility and the calculation of vapour pressures above an SO₂‐NaCl‐H₂O system, including the prediction of a three‐phase equilibrium. The algorithm proved robust and versatile. The appearance of incipient phases was easily tracked. Future work needs to be done to optimize damping/acceleration coefficients in the calculations.