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.

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:

 

 ClpXP is an Escherichia coli protease that carryout energy-dependent intracellular proteolysis. In recent years, this system has been widely studied due to its importance as a protein regulatory machinery and a virulence factor.  Protein substrates of ClpXP contain degrons with a specific protein sequence. SsrA tag is one of the five degrons known to subject proteins for ClpXP degradation. SsrA is an 11 amino acid peptide added to the C-terminus of nascent polypeptide chains translated from aberrant messenger RNAs lacking stop codons via a process called trans-translation.

ClpXP was known to targets only cytosolic proteins with degrons until recently, AcrB, an E. coli membrane protein was found to be degraded by ClpXP when it is tagged by ssrA peptide, which leads to the speculation that ClpXP is capable of degrading membrane proteins.   However, this speculation was challenged with the finding that ssrA tagging of ProW1−182, a different inner-membrane protein resulted in degradation by AAA+ membrane protease FtSH. We report that the membrane substrates of ClpXP bear long c-terminal cytoplasmic domains while metastable proteins lacking cytoplasmic domains are degraded by FtsH. For instance, ssrA tagged Aquaporin-Z (AqpZ), a stable tetrameric membrane protein lacking a c-terminal cytoplasmic domain is subjected to degradation by neither ClpXP nor FtsH. Nevertheless, when the c-terminus of AqpZ is fused with ssrA tagged Cyan fluorescent protein ClpXP degrades the resulted fusion protein while truncated metastable version, AqpZ 1-155 is degraded by FtSH.

This presentation also emphasizes our attempt to unravel the possible effect of proton motive force on the activity of ClpXP. We used Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to disrupt the proton motive force. Our results suggest that degradation of soluble protein substrates such as GFP-ssrA, MurA-ssrA, Chloramphenicol acetyltransferase ssrA are not affected by CCCP. However, degradation of membrane protein substrates by ClpXP is diminished in the presence of CCCP. We speculate that either the proton motive force or ATP provided from oxidative phosphorylation is essential, or both are important for ClpXP to degrade membrane proteins. 

It has been shown that the TolC is not a good target for inhibition of multidrug efflux of antibiotic-resistant bacteria as the bacterial susceptibility to antibiotics was not affected even when a significant amount of TolC is depleted.  TolC is a membrane protein channel that functions in conjunction with transporters and membrane fusion proteins and provides a pathway to expel antibiotics across the E. coli outer membrane.  AcrAB-TolC multidrug efflux pump is one such example where TolC cooperates with AcrB transporter and AcrA membrane fusion protein.   We report that the depletion of the number of copies of AcrB makes bacteria highly susceptible to antibiotics. We utilized ClpXP degradation system to regulate the copy number of AcrB in the cell. Our results show that AcrB is an excellent target for inhibiting multidrug efflux, and ClpXP is an excellent tool to regulate antibiotic target proteins for research purposes.

Find details of the event and registration here.

To view a copy of the 2019 abstract booklet, click here.

Note to UK students: Students in CHE 395 planning to graduate or otherwise conclude their research are required to participate in the Poster Session if they have not done so in the past. 

Schedule of Events:
10:00am - Zoom Check-In and Set Up
10:30 - 12:00pm - Group A Presents
1:00pm - 2:30pm - Group B Presents
3:30pm - Awards Presented

Recent winners include students from:

Abstract: Application of organic electronics have increased significantly over the past two decades. Organic materials can be used in flexible devices with cheaper cost of fabrication, yet in most cases the devices suffer from poor performance and stability. Investigating doping mechanism, charge transport and charge transfer in such materials can help us to understand the origin of these issues and later resolve them. In this dissertation, organic materials are used in three different device structures to investigate charge transport and charge transfer. Chemically doped pi-conjugated polymers are promising materials to be used in thermoelectric (TE) devices, yet their application is limited by their low performance. Blending two polymers is a simple way to change the properties of the TE devices. Here we used a simple analytical model to calculate TE properties of polymer blend by taking into account for energetic disorder, energetic offset between two polymers and localization length which proposed TE performance of polymer blend can exceed the individual ones at specific blends of two polymers. We showed these improvements are achievable by experimentally testing TE properties of selected polymer blends. Further, to investigate the doping mechanism in polymers, we used organic electrochemical transistors to investigate the effect of anion size on polaron delocalization and the thermoelectric properties of single polymers. This device structure allowed us to control the charge carrier concentration with minimizing the effects on the film morphology.

In organic photovoltaics (OPVs), upon fluorination of donor molecules the performance of device increases in most cases. So, we investigated the charge transfer state energy between the electron donor anthradithiophene (ADT) and the electron acceptor C60 upon halogenation of the ADT molecule. Interfacial energetics and charge transfer state energies between donor and acceptor are crucial to performance of these devices. We probe interfacial energetics of donor/acceptor interfaces with Ultraviolet photoelectron spectroscopy (UPS) charge transfer state energies with sensitive External Quantum Efficiency (EQE) setup both in bilayer and bulk heterojunction device structure. These measurements coupled with DFT calculations allowed us to explain the effects of halogenation on the OPV devices characteristics. Investigating charge transfer states energies, charge transport and doping mechanism in organic materials allow us to improve the performance of organic based electronics and also propose new applications for these family of materials.

We present examples from our group where biophysical chemistry impacts unsolved problems in infectious diseases and auto-immune diseases. We start with bacterial biofilms, which are structured multi-cellular communities that are fundamental to the biology and ecology of bacteria. By using population tracking algorithms, we dissect bacterial social behavior at the single cell level.  We will also discuss how we can learn from innate immunity peptides to renovate antibiotic design, and make precision antibiotics and antibiotics against persister bacterial populations. Finally, we examine the pathological role of antimicrobial peptides in a range of autoimmune disorders.