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.

Attend the seminar here.

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.

Attend the seminar here. Password 618011.

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: 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.

Bio: Curtis P. Berlinguette is a Professor of Chemistry and Chemical & Biological Engineering at the University of British Columbia. He is also a CIFAR Program Co-Director and a Principal Investigator at the Stewart Blusson Quantum Matter Institute (SBQMI), and the CEO of Miru Smart Technologies.

Prof. Berlinguette leads a large, interdisciplinary team seeking ways to discover and scale disruptive clean energy materials. His academic group has advanced a range of clean energy applications including CO₂ utilization, next-generation solar cells, and self-driving labs. Prof. Berlinguette also likes to work on high-risk, high-impact clean energy projects like cold fusion. He has authored more than 100 scientific articles and 20 patent applications, and has participated in over 190 invited lectures at leading universities and international conferences. Prof. Berlinguette has been recognized with several awards, including an Alfred P. Sloan Research Fellowship and an NSERC E.W.R. Steacie Memorial Fellowship.

Abstract: The electrochemical conversion of CO₂ by the CO₂ reduction reaction (CO₂RR) is a promising strategy that enables renewable energy to be stored in carbon chemicals and fuels using atmospheric or emitted CO₂. Pilot-scale electrolyzers utilizing gaseous CO₂ feedstocks can mediate high rates of CO₂RR, however, this approach relies on several complex and energy-intensive steps required to produce purified, high-pressure CO₂ from carbon capture. This presentation will focus on the direct conversion of aqueous carbon capture solutions (i.e., those rich in bicarbonate anions) into useful chemicals (i.e., CO) over extended periods of time. I will show how to design an electrolyzer that converts liquid bicarbonate feedstocks into carbon products at comparable rates and greater efficiencies than reactors relying on pressurized CO₂. Our work demonstrates bicarbonate electrolysis as a practical strategy for storing renewable energy in carbon chemicals while bypassing CO₂ separation and pressurization processes in upstream CO₂ capture.

Abstract:

Materials are chemicals that we use every day for tools, tasks, and technology. For most of history, making a material required trial-and-error, synthesizing and testing, a costly endeavor in time and money. With modern computing, not only can the trial-and-error be hastened, but sometimes avoided altogether. The application of a material depends on its properties, which arise from its structure, thus by exploring chemical structure we can predict properties and design materials to suit. One tool to accomplish this is the genetic algorithm (GA), which can build and test chemical structures for a desired property, and then produce new chemical structures through reproduction. Genetic algorithms have been applied to chemistry for 30 years in solving X-ray diffraction patterns, protein folding, and predicting surface structures. Here a GA is applied to solve the structure of Li-Al layered double hydroxide (LDH), given an experimental X-ray diffraction pattern and debate in the literature. The resulting GA can build a wide variety of LDH structures by stacking layers of crystal and molecule together, eventually providing a set of structures that can be used for further quantum mechanical calculations. The GA was then generalized to a wider variety of layered structures, resulting in the development of the Genetic Algorithm for Layered Structures (GALS). GALS is able to generate LDH structures with multiple elements and molecules, structures with different coordinating groups, molecular crystals, and perovskites. Initial results are promising, with testing under a small number of generations showing significant improvements in fitness, and room for generalization down the road.

Abstract: Process analytical technology (PAT) plays an essential role in understanding and optimization chemical manufacturing routes by furnishing data-dense reaction profiles. However, each PAT tool presents certain limitations with respect to chemical component resolution, reaction compatibility or useful operational domain. High-pressure liquid chromatography (HPLC) represents one of the most versatile analytical tools available for providing detailed reaction progress analysis. Yet this technology introduces a new set of challenges relating to sample acquisition and preparation, especially when trying to utilize HPLC as a real time analytical technology.

Our lab has developed a comprehensive set of automated tools, which allow nearly any chemical process to be visualized in real time by HPLC. This includes reactions performed under inert atmosphere, systems with heterogenous reagents, and complex competition reactions with many components. The combination of excellent resolving power of UHPLC, coupled to the high dynamic range of standard UV/Vis and MSD detectors has allowed this tool to be broadly deployed. This has allowed complex reactions to be visualized in exceptional details with unprecedented ease. This presentation will discuss several case studies to demonstrate the flexibility and fidelity of this new online HPLC technology. Examples will include studying reaction mechanisms, measuring crystallization processes and deployment as an in-process control for reaction automation.