Chemistry, Department of

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Free Radical Reactivity of a Phosphaalkene Explored Through Studies of Radical Isotopologues

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-11-18
Abstract: 

Muonium (Mu), an H atom analogue, is employed to probe the addition of free radicals to the P=C bond of a phosphaalkene. Specifically, two unprecedented muoniated free radicals, MesP•-CMu(Me)2 (1a, minor product) and MesPMu-C•Me2 (1b, major product), were detected by muon spin spectroscopy (µSR) when a solution of MesP=CMe2 (1: Mes = 2,4,6-trimethylphenyl) was exposed to a beam of positive muons (µ+). The µ+ serves as a source of Mu (i.e. Mu = µ+ + e–). To confirm the identity of the major product 1b, its spectral features were compared to its isotopologue, MesPH-C•(Me)CH2Mu (2a). Conveniently, 2a is the sole product of the reaction of MesPH(CMe=CH2) (2) with Mu. For all observed radicals, muon, proton and phosphorus hyperfine coupling constants were determined by µSR and compared to DFT-calculated values.

Document type: 
Article

Chemotaxis by Pseudomonas putida (ATCC 17453) Towards Camphor Involves Cytochrome P450cam (CYP101A1)

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-10-30
Abstract: 

The camphor-degrading microorganism, Pseudomonas putida strain ATCC 17453, is an aerobic, gram-negative soil bacterium that uses camphor as its sole carbon and energy source. The genes responsible for the catabolic degradation of camphor are encoded on the extra-chromosomal CAM plasmid. A monooxygenase, cytochrome P450cam, mediates hydroxylation of camphor to 5-exo-hydroxycamphor as the first and committed step in the camphor degradation pathway, requiring a dioxygen molecule (O2) from air. Under low O2 levels, P450cam catalyzes the production of borneol via an unusual reduction reaction. We have previously shown that borneol downregulates the expression of P450cam. To understand the function of P450cam and the consequences of down-regulation by borneol under low O2 conditions, we have studied chemotaxis of camphor induced and non-induced P. putida strain ATCC 17453. We have tested camphor, borneol, oxidized camphor metabolites and known bacterial attractants (D)-glucose, (D) - and (L)-glutamic acid for their elicitation chemotactic behavior. In addition, we have used 1-phenylimidazole, a P450cam inhibitor, to investigate if P450cam plays a role in the chemotactic ability of P. putida in the presence of camphor. We found that camphor, a chemoattractant, became toxic and chemorepellent when P450cam was inhibited. We have also evaluated the effect of borneol on chemotaxis and found that the bacteria chemotaxed away from camphor in the presence of borneol. This is the first report of the chemotactic behaviour of P. putida ATCC 17453 and the essential role of P450cam in this process.

Document type: 
Article

Revealing the Mechanism for Covalent Inhibition of Glycoside Hydrolases by Carbasugars at an Atomic Level

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-08-13
Abstract: 

Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate’s structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.

Document type: 
Article
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Designs for Donor-Acceptor Copolymer Based Double Heterojunction Solar Cells

Author: 
Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2017-07-10
Abstract: 

Self-consistent field calculations were used to examine a design motif for organic double heterojunction solar cell materials. They are a specific type of cascade heterojunction designed to increase cell voltage without sacrificing current and consist of fully conjugated block polymers. The design employs three sections; a p-type section, an n-type section and a third section called the bridge. The energy alignment between sections is important to optimal device function and a motif based on electron donating and electron accepting subunits was evaluated. If the energetic offset between p-type and n-type sections is greater than the exciton binding energy and if the bridge is formed using the scheme presented, a nearly ideal energetic alignment is obtained. In addition, calculations on the excited states of the system were performed to illustrate the relationship between bridge length and the magnitude of charge carrier recombination currents. An order of magnitude decrease relative to the corresponding diblock polymer can be expected for bridge lengths of > 6 repeat units. Taken in sum, these results offer concrete guidelines for the development of synthetic targets in this promising class of materials.

Document type: 
Article
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Synthesis and Characterization of a Photoaffinity Labelling Probe Based on the Structure of the Cystic Fibrosis Drug Ivacaftor

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-06-15
Abstract: 

Cystic Fibrosis (CF) is a genetic disorder caused by loss-of-function mutations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Ivacaftor (1) was the first therapeutic approved for the treatment of CF that is able to restore gating activity to certain CFTR variants although the mechanism of action is poorly understood. Herein we describe the synthesis of a photoaffinity labelling (PAL) probe (2) based on the structure of ivacaftor incorporating a photoreactive diazirine moiety for use in labelling studies designed to identify the binding site for ivacaftor on mutant CFTR. The PAL probe 2 retained potentiation activity, with a potency similar to 1, using a Fluorescent Imaging Plate Reader (FLIPR®) assay measuring ion conductance potentiation of wild type (Wt)-CFTR. Photolabelling experiments with human serum albumin (HSA) as a model protein have shown that probe 2 can label HAS in a manner consistent with observed and predicted binding.

Document type: 
Article

Multifunctional Quinoline-Triazole Derivatives as Potential Modulators of Amyloid-b Peptide Aggregation

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2016-05
Abstract: 

Metal ion dyshomeostasis is hypothesized to play a role in the toxicity and aggregation of the amyloid beta (Aβ) peptide, contributing to Alzheimer's disease (AD) pathology. We report on the synthesis andmetal complexation ability of three bidentate quinoline-triazole derivatives 3-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)propan-1-ol (QOH), 4-(2-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)morpholine (QMorph), and 4-(2-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)thiomorpholine (QTMorph). We further study the utility of these ligands tomodulate Aβ peptide aggregation processes in the presence and absence of Cu2+ions. Ligand-peptide interactions were first investigated using both 2-D 1H-15N band-selective optimized flip angle short transient heteronuclear multiple quantumcorrelation (SOFAST-HMQC) NMR spectroscopy and molecular modeling techniques, indicating interactionswith glutamic acid (E3) and several residues in the hydrophobic region of Aβ. Native gel electrophoresiswith western blotting along with transmission electron microscopy provided information on the ability of each ligand to modulate Aβ aggregation.While the ligands alone did not modify Aβ peptide aggregation at the 24 h timepoint, signifying relatively weak ligand-peptide interactions, the ligands did modify the aggregation profile of the peptide in the presence of stoichiometric and suprastoichiometric Cu. Interestingly, the thioether derivative QTMorph exhibited the most pronounced effect on peptide aggregation in the presence of Cu. Overall, the quinoline-triazole ligand series were shown to interact with the hydrophobic region of the Aβ peptide, and modulate the Cu-Aβ aggregation process.

Document type: 
Article
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Double layer of Platinum Electrodes: Non-Monotonic Surface Charging Phenomena and Negative Double Layer Capacitance

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-01
Abstract: 

In this study, the refined double layer model of platinum electrodes accounts for chemisorbed oxygen species, oriented interfacial water molecules and ion size effects in solution. It results in a non-monotonic surface charging relation and a peculiar capacitance vs. potential curve with a maximum and maybe negative-defined values in the potential regime of oxide-formation.

 

Document type: 
Article
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Unifying Theoretical Framework for Deciphering the Oxygen Reduction Reaction on Platinum

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2018-04-05
Abstract: 

Rapid conversion of oxygen into water is crucial to the operation of polymer electrolyte fuel cells and other emerging electrochemical energy technologies. Chemisorbed oxygen species play double-edged roles in this reaction, acting as vital intermediates on one hand and site-blockers on the other. Any attempt to decipher the oxygen reduction reaction (ORR) must first relate the formation of oxygen intermediates to basic electronic and electrostatic properties of the catalytic surface, and then link it to parameters of catalyst activity. An approach that accomplishes this feat will be of great utility for catalyst materials development and predictive model formulation of electrode operation. Here, we present a theoretical framework for the multiple interrelated surface phenomena and processes involved, particularly, by incorporating the double-layer effects. It sheds light on the roles of oxygen intermediates and gives out the Tafel slope and exchange current density as continuous functions of electrode potential. Moreover, it develops the concept of a rate determining term which should replace the concept of a rate determining step for multi-electron reactions, and offers a new perspective on the volcano relation of the ORR.

 

Document type: 
Article

Chemisorbed Oxygen at Pt(111): a DFT Study of Structural and Electronic Surface Properties

Peer reviewed: 
Yes, item is peer reviewed.
Date created: 
2017-11-26
Abstract: 

Simulations based on density functional theory are used to study the electronic and electrostatic properties of a Pt(111) surface covered by a layer of chemisorbed atomic oxygen. The impact of the oxygen surface coverage and orientationally ordered interfacial water layers is explored. The oxygen adsorption energy decreases as a function of oxygen coverage due to the lateral adsorbate repulsion. The surficial dipole moment density induced by the layer of chemisorbed oxygen causes a positive shift of the work function. In simulations with interfacial water layers, ordering and orientation of water molecules strongly affect the work function. It is found that the surficial dipole moment density and charge density are roughly linearly dependent on the oxygen surface coverage. Moreover, we found that water layers exert only a small impact on the surface charging behavior of the surface.

Document type: 
Article

Targeting Therapeutics to Bone by Conjugation with Bisphosphonates

Peer reviewed: 
No, item is not peer reviewed.
Date created: 
2018-04-04
Abstract: 

Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively  to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily.

Document type: 
Article