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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

Abstract: The Resistant Nodulation Division (RND) super family member, tripartite AcrA-AcrB-TolC efflux pump is a major contributor in conferring multidrug-resistance in Escherichia coli. The structure of the pump complex, drug translocation by functional rotation mechanism has been widely studied through crosslinking studies, crystallography, and Cryo-EM efforts. Furthermore, the ClpXP system has been identified as important in degrading ssrA tagged AcrB. Despite all this data, the dynamics of assembly process of the pump and AcrB during functional rotation in the process of drug efflux, the proteases in degrading AcrB remains poorly understood. The focus of my thesis is understanding pump assembly process, dynamics of AcrB in functional rotation mechanism, and identifying the proteases that degrade ssrA tagged AcrB. First, I used disulfide bond crosslinking, minimum inhibitory concentration (MIC) and EtBr efflux assay in studying the importance of the relative flexibility at the inter-subunit interface by introducing 6 inter-subunit disulfide bonds into the periplasmic domain of AcrB using site directed mutagenesis. Based on MIC the double Cys mutants tested led to equal or higher susceptibility to AcrB substrates compared to their corresponding single mutants. EtBr accumulation assays was conducted utilizing DTT as the reducing agent. In two cases, the activities of the double Cys-mutants were partially restored by DTT reduction, confirming the importance of relative movement in the respective location for function. In the second project, I tested the effect of over-expressing functionally defective pump components in wild type E. coli cells to probe the pump assembly process. Incorporation of defective component is expected to reduce the efflux efficiency of the complex and leading to the so called “dominant negative” effect. We examined two groups of mutants defective in different aspects and found that none of them demonstrated the expected dominant negative effect, even at concentrations many folds higher than their genomic counterpart. Based on the data the assembly of the AcrAB-TolC complex appears to have a proof-read mechanism that effectively eliminated the formation of futile pump complex. Moreover, I utilized a novel tool- transposons library creation in studying the possible other proteases contribute to degradation of the AcrB-ssrA. The next generation sequencing identified already known ClpXP gene and MIC and western blot analysis confirmed the results. These, findings provide new insights to the dynamics of the AcrAB-TolC efflux pump in E. coli.  Key words: multidrug efflux pump, AcrB, assembly, disulfide, conformational changes, ssrA.

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Abstract:: Plasmonic nanostructures have been extensively studied for their potential application in numerous fields such as nanophotonics, biosensors, and bioimaging. One of the key properties of nanostructures that can be manipulated for practical applications is their capabilities to modulate the optical and photophysical properties of fluorophores residing nearby. Surface plasmons (SP), which can be defined as the collective oscillation of the delocalized electrons, are the fundamental characteristic of nanostructures that are primarily responsible for altering those properties. Elucidating fluorophores at the single-molecule level has received significant attention since more specific information can be extracted from single molecule-based studies, which otherwise, could be obscured in ensemble studies. However, single-molecule studies are inherently challenging because the signal from a single molecule is usually deem, which makes it difficult to detect. The situation is even worse in the case of a crowded environment due to higher background noise, such as cellular autofluorescences in the case of cell-based studies. Thus, one of the possible ways out of this single-molecule detection problem is to couple the fluorophore with a plasmonic nanostructure which can potentially enhance the fluorescence intensity of the single fluorophore leading to the improvement in signal to noise ratio. Throughout the projects presented here, I studied the fluorescence characteristics of single fluorophore molecules coupled in a plasmonic nano-aperture which is termed as Zero Mode Waveguides (ZMWs). I utilized single fluorophores of different origins, such as organic dyes and quantum dots (QDs), in ZMWs of different metallic compositions. By probing ZMWs made from the mixture of Aluminum and gold, with a range of ATTO dyes emitting across the visible wavelength, we found that the surface plasmon resonance of ZMWs is tunable by optimizing the metal ratio. Apart from the ATTO dyes, I investigated the photoluminescence (PL) behavior of single QDs in ZMWs and observed a significant enhancement in PL intensity and a substantial improvement in the blinking characteristics of the QDs, which are beneficial for the utility of QDs as a bio-imaging agent or a single-photon source. Single QDs in ZMWs exhibited a significant enhancement in biexciton quantum yield, which is crucial for their potential application in lasing where materials with a high optical gain are desired. I also examined the fluorescence properties of the single fluorophores in gold ZMWs in the presence of a gold nanoparticle (AuNP) and observed a more significant enhancement in fluorescence intensity in the gap between AuZMW and AuNP compared to the case of only AuZMW or only AuNP. The experimental design and the resulting findings throughout the three projects presented here should be a valuable resource for the future development of plasmon-mediated single-molecule studies.

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Abstract: Plastic semiconductors incorporated into transistors have shown enormous potential for flexible, printable electronics as well as bioelectronics that communicate with the body. In my talk I will discuss the background and potential applications of these exotic transistors, as well as novel, state-of-the-art materials systems I have developed to overcome their intrinsic bottlenecks. I will show how these simple, low-cost solutions to organic transistor problems work towards the realization of a broad suite of organic electronic technologies.