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Title: Photocatalytic Applications of TIO2 For Catechol Degradation and α-FE2O3 for Carbon Dioxide Reduction

Abstract: Natural and anthropogenic processes are emitting organic and inorganic pollutants, such as phenolic compounds and carbon dioxide (CO₂), and polluting the atmosphere. In addition, to meet the energy demand of the world’s growing population, the use of nonrenewable fossil fuels is causing their depletion. Heterogenous semiconductor photocatalysis is a clean and low-cost methodology, which can simultaneously contribute to solve the above energy and environmental problems. In this work, photocatalytic degradation of catechol, an organic pollutant, is explored with Degussa P25 (mixed phase of titanium dioxide, TiO₂), and CO₂ reduction is accomplished with potassium doped iron oxide.

Degussa P25 is used to study the degradation of catechol at the air solid interface because of low cost, stability, and abundant sources of TiO₂. Catechol forms a chelate with TiO₂ and shows an absorption band in the visible range through ligand to metal charge transfer transition. The photocatalytic activity of catechol degradation on TiO₂ surface is reported at variable wavelength of irradiation. The generation and quantification of reactive oxygen species and redox pairs has been studied with scavengers. Finally, the apparent quantum efficiency (AQE) for catechol loss and CO₂ and carbon monoxide (CO) growths are determined.

Potassium doped iron oxides of varying composition (100 Fe:x K, 0 £ x £ 5) are synthesized using an incipient wetness impregnation method. The structure, composition, and properties of the catalysts are investigated by diffraction methods, thermal analysis, and multiple spectroscopies. UV-visible light excites the catalysts in the presence of pure CO₂ or air under a saturated water vapor atmosphere. The AQE for the CO(g) production shows maximum for 100 Fe:1 K catalyst.

The study creates a path for the application of semiconductor photocatalysis in air purification, water splitting, and fuel production.

Faculty Advisor: Dr. Marcelo Guzman

Title: Succinylated polyethyleneimine gene delivery agents for enhanced transfection efficacy

Abstract: Gene therapy aims to treat patients by altering or controlling gene expression. Today, most current clinical approaches are viral-based due to their inherent gene delivery activity. However, there is still a significant interest in nonviral alternatives for gene delivery, particularly synthetic lipids and polymers, that do not suffer the immunogenicity, high cost, or mutagenesis concerns of viral vectors. Polymeric vectors are of particular interest due to the ability to further tune the polymer properties through the incorporation of additional functional units such as targeting ligands or shielding domains. Polyethylenimine (PEI), a highly cationic polymer, is often considered a benchmark for polymer-based gene delivery and thus serves as an excellent model for investigating gene delivery mechanisms. One reason PEI, especially branched PEI, is thought to outperform many other cationic polymers is due to the presence of secondary and tertiary amines. These amines are thought to help facilitate escape from endocytic vesicles via a 'proton-sponge' mechanism. Despite its successful use for gene delivery, PEI was initially developed for use in common processes such as water purification. As such, the properties of PEI should not be expected to be optimal for gene delivery. In this dissertation, our research efforts focused on the incorporation of negatively charged succinate groups to the PEI backbone to create succinylated zwitterion-like PEI (zPEIs). Specifically, we focused on the synthesis and characterization of zPEIs as well as the impact of zPEI on DNA condensation and gene expression.

This dissertation will discuss the results of three projects. In project (1), we studied the suitability of minimally modified zPEIs for gene expression. In this work, we reveal that modification of PEI amines as low as 2% was sufficient to provide significant improvements in gene delivery particularly in the presence of serum proteins. In project (2), we investigate the self-assembly of DNA induced by modified and unmodified branched PEIs using small-angle X-ray scattering (SAXS). Modified PEIs included both succinylated zPEI and acetylated PEIs (acPEI) both modified from 0-40%. We demonstrate that changing the degree of modification significantly alters the packing density of the resulting polyplexes. While acPEI shows a continuous decrease in DNA packaging efficiency with increasing degree of modification, zPEI shows a crossover behavior where DNA-DNA interhelical spacings increase at low succinylation but decrease at higher degrees of succinylation. Studies on the pH dependence on the inter-DNA spacing also shows that lowering the pH leads to tighter DNA packaging for all PEIs studied. In project (3), we studied the efficacy of zPEI polyplexes at varying protein concentrations ranging from 0-10 mg/mL of bovine serum albumin (BSA). These high protein concentrations are comparable to in vivo protein concentrations. We show that while PEI/DNA transgene expression decreases with higher protein concentrations, the zPEI studied stayed approximately constant over the protein range studied. To test if these conditions may lead to the formation of a protein corona on the nanoparticles, which was recently shown to enhance serum-free transfection in unmodified bPEI/DNA, we also measured the transgene expression of polyplexes pre-treated to form a protein corona to uncoated polyplexes.

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Faculty Advisor: Dr. Jason DeRouchey

Abstract:

Electron bifurcation is considered as a third fundamental mode of energy conservation mechanism, in which endergonic and exergonic redox reactions are coupled. The newly discovered flavin based electron bifurcation in Electron transfer flavoproteins (ETFs) helps to reduce low potential ferredoxin, which provides electrons to drive biologically demanding reactions such as atmospheric dinitrogen fixation in diazotroph and methane production in methanogens. Current research demonstrates the capacity for electron bifurcation in the Rhodopseudomonas palustris ETF (RpalETF) system. RpalETF contains two chemically identical but functionally different FADs: ET-FAD is bound in highly mobile domain II, which sits in a stable base created by domains I and III. Bf-FAD is buried in between domain I and III. The two flavins execute contrasting, complementary electron transfer reactions. Whereas one mediates single electron transfer (ET-FAD), the other accepts electrons pairwise (Bf-FAD), yet both flavins’ sites include a conserved Arg sidechain. R273 favors the ASQ of ET-FAD, whereas R165 near the Bf-FAD appears not to, possibly due to neutralization of its positive charge by nearby C174. R273 forms a pi- pi stacking interaction with ET-FAD whereas R165 appears to form hydrogen bond interactions with Bf-FAD. To learn whether the active site arginine residues each have different effects on their respective neighboring flavins, we replaced each of the Args in turn with chemically conservative, and divergent substitutions. Our data shows, R273 plays a vital role in BfETF by stabilizing the ASQ of the ET-FAD, whereas R165 favors binding of the Bf-FAD that is essential for electron bifurcation in RpalETF. Along with the electron bifurcation studies, we report an irreversible, pH dependent, site selective, enzyme mediated, anaerobic chemical modification of ET-FAD to a pink amino FAD, which opens a new perspective with which to understand the 726 nm band formed in bifurcating ETF.

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Abstract: Cancer is a worldwide public health crisis that requires new and improved drugs to be developed to extend survival rates and improve the quality of life for the patient. Platinum-based drugs are used in approximately 50% of cancer treatment regimens. These drugs are highly effective in many kinds of cancer; however, cancers can develop platinum resistance and these drugs have troubling side effects that reduced their use and efficacy. To overcome these disadvantages, many other metals have been studied for their anticancer properties. Notably, the anticancer properties of ruthenium-based agents have drawn considerable attention with multiple ruthenium complexes entering clinical trials. Unlike platinum complexes, which are flat (square planar), ruthenium compounds can adapt a multitude of 3D structures, which leads to many possible mechanisms of actions.

One of the most promising applications of ruthenium(II) complexes is their ability to act as photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) agents. Both of these methodologies use light to “turn on” a non-toxic light-sensitive drug to form highly cytotoxic species that can kill cancer cells. These methods are appealing as they present a way to control the cytotoxic species to spatially isolated regions of the body. This control can reduce damage to healthy cells and reduce harmful side effects. Ruthenium(II) polypyridyl complexes are especially well suited for these applications as they have highly tunable excited states that can be tuned with careful ligand modification and selection.

Ruthenium complexes have also shown great promise as non-light-activated anticancer drugs. The coordination of small pharmacologically active molecules to ruthenium(II) polypyridyl complex is one promising method to develop potential ruthenium-based drugs. This strategy aims to create drugs that are greater than the sum of their parts by achieving synergistic mechanisms of action not achievable with either component individually.

Here we report on the synthesis and anticancer properties of Ru(II) complexes designed for PDT, PACT, and light-independent anticancer mechanisms. Highly potent lead compounds are identified and explored for PDT and light-independent anticancer applications. These lead compounds incorporated organometallic ligands with ruthenium(II) polypyridyl scaffolds to modulate their excited-state properties to produce improved PDT agents. The integration of O,O-chelating ligands into various ruthenium(II) scaffolds produced a range of complexes suitable for PDT, PACT, and light-independent mechanisms. Notably, the majority of these complexes possessed low submicromolar potency and low in vivo toxicity. Our results presented here show multiple new strategies for making new ruthenium(II) anticancer agents. These new methods have promising implications for bioinorganic research because they further expand our understanding of how to use ruthenium(II) complexes for biological applications.

Abstract: Protein-protein interactions (PPIs) are vital to many biological processes, including gene expression, and immune reactions to pathogens. There are approximately 650,000 PPIs in humans with pertinent physiological functions. Aberrant expression of PPIs leads to improper function and contributes to a plethora of disease conditions including cancer. Thus, PPIs represent an enormous target space for drug discovery and chemical probes. Direct targeting of clinically relevant PPIs with small molecules remains an unmet medical need. The development of small-molecule inhibitors of PPIs is a challenging enterprise and, in most cases, considered undruggable due to large protein surfaces, lack of deep binding pockets, and enzymatic activities. Despite these limitations, significant progress has been made in the area of compound development that selectively targets oncogenic PPIs and those underlying inflammation. This talk will focus on the identification and rational design of small-molecule inhibitors of PPIs, as applied to distinct protein targets, including the proto-oncogene product c-MYC, which dimerizes with MAX; the immunotherapeutic target programmed death receptor (PD-1) and programmed death ligand-receptor (PD-L1), and the epigenetic target AT-rich interacting domain 4B (ARID4B). The fundamentals of the small-molecule drug discovery process will be covered. More so, the use of in silico methods and synthetic chemistry to discover gold-based small-molecule covalent inhibitors of the intrinsically disordered protein, MYC, as well as the first-in-class small molecule inhibitors of ARID4B will be presented. This talk will also shed light on the medicinal chemistry of the recently identified dual-action small molecule inhibitors that perturb both Poly(ADP-ribose) polymerase (PARP) and PD-1/PD-L1 pathways.

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Abstract: Development of stable gold-based complexes has been a rapidly advancing field due to the popularity of gold complexes, particularly for use in biomedical applications and catalytic transformations. Given that auranofin, a gold(I) complex having FDA approval for the treatment of rheumatoid arthritis has been the only clinically relevant gold-based agent, the need for stable gold-based molecules is at an all-time high. Herein are reported synthetic strategies used for the development of new classes of gold(I) and gold(III) complexes for advancement in mitochondrial modulation for use as chemotherapeutics as well as application to gold catalysis due to the unique geometry of complexes presented within. Mitochondrial structure and function are integral to maintaining mitochondrial homeostasis and are an emerging biological targets in aging, inflammation, neurodegeneration, and cancer. Meanwhile, targeting cellular metabolism has emerged as a key cancer hallmark that has led to the therapeutic targeting of glycolysis. The study of mitochondrial structure and its functional implications remain challenging partially because of the lack of available tools for direct engagement, particularly in a disease setting. Furthermore, agents that target dysfunctional mitochondrial respiration for targeted therapy remain underexplored. Both the synthesis and characterization of highly potent organometallic gold(III) complexes supported by dithiocarbamate ligands as selective inhibitors of mitochondrial respiration and a gold-based approach using tricoordinate gold(I) complexes to perturb mitochondrial structure and function for selective inhibition cancer cells have been elucidated. Mitochondrial targeting and inhibitory effects are characterized using a plethora of both in vitro and in vivo experiments. While developing the tricoordinate framework, the unique geometry led to the pursuit of identifying other applications for these unique gold(I) complexes. The development of oxidant-free, gold-catalyzed, cross-coupling reactions involving aryl halides have been hampered by the lack of gold catalysts capable of performing oxidative addition at Au(I) centers under mild conditions or without some external oxidant. The catalytic method developed is insensitive to air or moisture. The asymmetrical character of the air-stable gold(I) complex is critical to facilitating this necessary orthogonal transformation. Taken everything together, rational design of novel gold complexes with unique binding motifs and geometry provide a building block for future applications with a diverse array of applications.

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Abstract: Secondary metabolites are organic compounds produced by an organism for reasons other than growth and development. In plants, secondary metabolites generally act as defense agents produced to deter predators and inhibit other competitive species. For humans, these compounds can often have a beneficial effect and are pursued and utilized as natural pharmaceuticals. The development of sensitive, high-throughput analytical screening methods for plant derived metabolites is crucial for natural pharmaceutical product discovery and plant metabolomic profiling. Here, metabolomic profiling methods were developed using a microfluidic capillary zone electrophoresis device and evaluated against traditional separation approaches. An alkaloid screening assay was constructed to analyze transgenic mutant plant extracts for novel metabolites. Putatively identified novel features were detected, elucidated, and then isolated and purified for pharmaceutical evaluation. Additionally, methods for the analysis of polyphenolic plant-derived secondary metabolites, such as cannabinoids, were also developed and evaluated. In this case, the occurrence of cross-instrumental variation was addressed, given the tight legal restrictions regarding commercialization the products in question. Lastly, the microfluidic CZE-MS methods were further applied for both primary and secondary metabolite profiling in a DMPK assay. This assay was developed to inclusively monitor metabolic changes as a response to varying concentrations of a therapeutic in circulation. The metabolomic methods developed and evaluated in this work displayed high sensitivity, efficiency, and accuracy and can be utilized across a wide variety of applications.

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Abstract: Small-molecule organic materials are of increasing interest for electronic and photonic devices due to their solution processability and tunability, allowing devices to be fabricated at low temperature on flexible substrates and offering utility in specialized applications. This tunability is the result of functionalization through careful synthetic strategy to influence both material properties and solid-state arrangement, both crucial variables in device applications. Functionalization of a core molecule with various substituents allows the fine-tuning of optical and electronic properties, and functionalization with solubilizing groups allows some degree of control over the solid-state order, or crystal packing. These combinations of core chromophores with varying substituents are systematically evaluated to develop structure-function relationships that can be applied to numerous applications. In this work, heteroacenes are investigated for singlet fission and triplet harvesting, with known crystal engineering strategies applied to optimize crystal packing and maximize relevant solid-state interactions. Further, a class of antiaromatic compounds are investigated using the same approaches to build up structure-function relationships and provide insight into the properties of a relatively understudied core molecule.

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Professor Andrew Gewirth

The University of Illinois at Urbana-Champaign

Understanding and Controlling Electrochemistry for Electrolyzers and Batteries

Abstract:

This talk addresses the electrochemical reactivity associated with electrolyzers and batteries.  Relevant to electrolyzers we show that electrodeposition of CuAg or CuSn alloy films under suitable conditions yields high surface area catalysts for the active and selective electroreduction of CO₂ to multi-carbon hydrocarbons and oxygenates.  Alloy films containing Sn exhibit greater efficiency for CO production relative to either Cu along or CuAg at low overpotentials.   In-situ Raman and electroanalysis studies suggest the origin of the high selectivity towards C₂ products to be a combined effect of the diminished stabilization of the Cu₂O overlayer and the optimal availability of the CO intermediate due to the Ag or Sn incorporated in the alloy.  Sn-containing films exhibit less Cu₂O relative to either the Ag-containing or neat Cu films, likely due to the increased oxophilicity of the admixed Sn.  Incorporation of a polymer into the Cu electrodeposit leads to very active CO₂ reduction electrocatalysis due to pH changes at the electrified interface.  Vibrational spectroscopy is used to evaluate the pH at the interface during electrolyzer operation.

Relevant to batteries, we discuss solid electrolytes (SEs) which have become a practical option for lithium ion and lithium metal batteries due to their improved safety over commercially available ionic liquids. The most promising of the SEs are the thiophosphates whose excellent ionic conductivities at room temperature approach those of commercially-utilized electrolytes. Hybrid solid-liquid electrolytes exhibit higher ionic conductivities than their bare solid electrolyte counterparts due to decreased grain boundary resistance, enhanced interfacial contact with electrodes, and decreased degradation at the interface. Spectroscopic and structural studies on these latter materials lead to new formulations and artificial SEI materials exhibiting advantageous properties.

Host: ECS UK chapter

Professor Marc T. M. Koper

Leiden University, Netherlands

Advances and challenges in understanding the electrocatalytic conversion of carbon dioxide to fuels

Abstract:

The electrocatalytic reduction of carbon dioxide is a promising approach for storing (excess) renewable electricity as chemicalenergy in fuels. Here, I will discuss recent advances and challenges in the understanding of electrochemical CO2 reduction. I will summarize existing models for the initial activation of CO2 on the electrocatalyst and their importance for understanding selectivity. Carbon–carbon bond formation is also a key mechanistic step in CO2 electroreduction to high-density and high-value fuels. I will show that both the initial CO2 activation and C–C bond formation are influenced by an intricate interplay between surface structure (both on the nano- and on the mesoscale), electrolyte effects (pH, buffer strength, ion effects) and mass transport conditions. This complex interplay is currently still far from being completely understood.

Y.Y.Birdja, E.Perez-Gallent, M.C.Figueiredo, A.J.Göttle, F.Calle-Vallejo, M.T.M.Koper, Nature Energy 4 (2019) 732-745

Host: ECS UK chapter