Chemistry Department Seminar
Conjugated polymers have been the cornerstone of organic electronics, with applications in such diverse areas as photovoltaics, field effect transistors, batteries, and bioelectronics. However, a number of challenges are still apparent, including, scalability, sustainability, and applicability under a broad range of real-world conditions. Our efforts have focused on novel, simplified polymer architectures, scalable synthetic methods and applications in solar cells and batteries. In this talk, a primary focus will be on the design of novel semiconducting polymers for intrinsically stretchable solar cells (IS-PSCs). We have designed novel side-chain functionalized conjugated polymers bearing hydrogen-bonding groups, such as thymine. Such units capable of inducing strong intermolecular hydrogen-bonding leading to polymer assembly and highly efficient and mechanically robust PSCs. Importantly, such polymers have enabled IS-PSCs showing an unprecedented combination of PCE (13.7%) and ultrahigh mechanical durability (maintaining 80% of initial PCE after 43% strain). Additionally, efforts toward the development of novel non-conjugated electroactive polymers will be introduced where we focus on elucidating structure-function relationships and synthetic pathways for this promising materials class.
Folding of proteins into their active 3D-structure occurs spontaneously or is assisted with the help of chaperones within a biologically reasonable time, from micro- to milliseconds. It occurs within different compartments of the cell, controlled by the chemical environment. When folding goes wrong in cells, misfolded and/or aggregated proteins may arise, unable to perform their specific biological function. The correlation between structural motifs and their 3D-structure has been established to influence biology. However, less is known about the biological implications of protein topology, i.e., motifs that can act as a structural switch in response to environmental changes. Leptin is the founding member of the Pierced Lasso Topology (PLT), a newly discovered protein family sharing the unique features of a “knot-like” topology. A PLT is formed when the protein backbone pierces through a covalent loop formed by a single disulfide bond. PLTs are found in all kingdoms of life, with 14-different biological functions, found in different cell compartments. Despite the large number found in nature, where more than 600 proteins have been found with a PLT, a connection between topology and biological function has not yet been determined. We investigate three biological systems, the hormone leptin, chemokines, and the oxidoreductase superoxide dismutase (SOD1) and the association between the threaded topology and the biological function. Our results show that a PLT may control conformational dynamics switching biological activity on/off depending on the chemical environment. Thus, we propose that PLTs may act as a molecular switch to control biological activity in vivo.
Abstract: There is a pressing need to develop novel therapeutic agents against new targets for chronic pain. The Tidgewell Lab uses cyanobacterial-derived natural products as the starting point for chronic neuropathic pain drug development by targeting receptors and other targets involved in pain. The Tidgewell lab works in the areas of natural products chemistry conducting isolation and structure elucidation work and combines that with medicinal and organic chemistry for the understanding and enhancement of these leads for physicochemical and biological effect. In this talk, you will hear about the background of natural products for developing our understanding of the brain as well as current work and projects using marine cyanobacterial natural products to understand and treat chronic pain.
Bio: Tidgewell grew up in southern California before heading east to earn his BS in Chemistry with a minor in Mathematics from Mercyhurst College (now University). He then joined the Prisinzano lab at the University of Iowa, where he earned his Ph.D. in 2007, working to develop non-addictive analgesics based on the plant hallucinogen Salvinorin A.
Tidgewell returned to southern California for a Post-Doc in the Gerwick Lab at Scripps Institution of Oceanography and the University of California, San Diego. He spent two years working at SIO on cancer drug discovery from marine cyanobacteria before moving to Panama to work on Dr. Gerwick’s ICBG project at the Smithsonian Tropical Research Institute. Tidgewell spent just over two years working in Panama on neglected tropical diseases drug discovery from marine cyanobacteria before starting a faculty position at Duquesne University in 2012.
The Tidgewell lab moved to Kentucky in July of 2023, and the work focuses on combining marine natural products with synthetic, medicinal chemistry to discover and better understand novel compounds from marine cyanobacteria for CNS disorders.
Exploring the Role of Ring Annulation in Polycyclic Aromatic Hydrocarbons for Organic Electronic Applications
The ability to systematically alter the electronic properties of organic materials is vital for their incorporation into next-generation electronic devices. Polycyclic aromatic hydrocarbons (PAHs) are of significant interest for organic electronics, as relevant properties are highly dependent on their size, structure, and functionalities, and thus can be tuned to fit a wide variety of applications. Due to the enormous number of structural isomers available in larger PAHs, the development of design protocols is necessary to efficiently develop high-performing materials. Linear extension of the aromatic core, such as that seen in the acene series, is an efficient yet underexplored method for tuning the electronic properties of 2-D PAHs. The development of synthetic procedures is necessary to systematically explore the properties of the larger aromatic compounds. This work will explore novel synthetic routes that allow for the systematic exploration of acene-fused PAHs of similar size but vastly different electronic properties. Such work demonstrates that by strategically altering the mode of ring fusion, PAHs can be tuned for applications such as organic field-effect transistors (OFETs) and quantum information science (QIS). The impact of linear ring extension in 2-D PAHs is also explored, demonstrating that the electronic structure of larger PAHs can be systematically tuned with significant implications for their applications and stability. The functionalization of a series of organic dyes, with the goal of tuning their optical properties for implementation into wearable radiation sensors, will also be discussed.
Abstract: Traumatic brain injury (TBI) continues to be a significant cause of morbidity and mortality worldwide. Despite significant progress in understanding the complex pathophysiology of TBI, the underlying mechanisms remain poorly understood. The primary brain damage is acute and irreversible. However, secondary brain injuries often develop gradually over months to years, creating an opportunity for critical therapeutic interventions. In the past decade, research on TBI biomarkers has seen significant progress. This progress has been driven by the diverse nature of TBI pathologies and the challenges they present for evaluation, management, and prognosis. TBI biomarker proteins resulting from axonal, neuronal, or glial cell injuries have been extensively studied and widely used. However, their detection in peripheral blood specimens may be limited due to difficulties in crossing the blood-brain barrier in sufficient quantities. Even with the advances made in TBI research, there remains a clinical need to develop and identify novel TBI biomarkers that can address these limitations and provide more accurate and accessible diagnostic tools.
Applications of Mass Spectrometry for the Characterization of Synthetic Oligomers and Natural Lignin
As part of the ongoing effort to substitute finite fuel and chemical resources with renewable ones, biomass is emerging as one of the most promising sources. Biomass consists of three main components of cellulose, hemicellulose, and lignin. Traditionally, cellulose has been used extensively in pulping industry, while lignin has been considered waste and is burned to generate heat. Lignin, a complex aromatic polymer component of biomass, has the potential to be used as a source of aromatic chemicals and pharmaceutical synthons. The recalcitrant nature of lignin, the lack of effective lignin breakdown methods and analytical techniques to analyze it are the main obstacles to obtaining high-yield chemicals from lignin. Mass spectrometry has proven to be one of the most promising analytical techniques and it is widely used in the pharmaceutical and chemical industries. The goal of this work is to develop analytical methods using mass spectrometry and lignin model compounds. Additionally, this work focused on the development and application of quantitative Derivatization Followed by Reductive Cleavage(q-DFRC) for the evaluation of various biomass pretreatment methods.
Since most commercially available lignin model compounds fail to mimic the structure of native lignin, it is necessary to develop compounds that more closely reflect the functionality of native lignin. The first project of this dissertation is focused on developing precursors for synthesizing b-O-4 model compounds and modifying their functional groups. The precursors have been synthesized and analyzed using gas chromatography-mass spectrometry. These precursors were used to synthesize b-O-4 model compounds that exhibit all characteristics of the native lignin.
The second project involved the synthesis and mass spectral analysis of a mixed linkage trimer containing both b-O-4 and b-5 bond types. A detailed analysis of the mass spectral fragmentation of lignin trimer with lithium adduct ionization is presented. The developed analysis of the lignin trimer facilitates the structural elucidation of lignin breakdown products.
The third project involved the application of q-DFRC as one of the lignin breakdown techniques to evaluate different biomass pretreatment methods. Ethanosolv, dioxosolv, co-solvent enhanced lignocellulosic fractionation (CELF), hydrotropic, and acetic acid/formic acid pretreatments were evaluated by q-DFRC with deuterium-labeled acylated monolignols internal standard. An evaluation and comparison of the quality of lignin obtained from each of these pretreatments was conducted. This dissertation provides valuable information for the advancement of mass spectrometric analysis of lignin, and it can be applied to lignin oligomer analysis. Furthermore, the q-DFRC results provide insight into how various pretreatments are related to the extent of condensation in extracted lignin.
Organic semiconductors have gained attention recently due to their potential applications in flexible, low-cost, lightweight electronics and solar cells. However, developing new organic semiconductors with improved performance remains a significant challenge due to the vast space of possible molecular structures. Furthermore, the high cost and time-consuming nature of experimental synthesis and characterization hinder the rapid discovery of new materials. To overcome these challenges, this dissertation presents a novel data-driven approach. The primary focus of this work is the development of data-driven tools, namely machine learning models, to predict critical electronic and structural properties of molecular organic semiconductors. These models are trained on a large dataset of quantum chemical calculations, enabling the efficient screening of thousands of candidate molecules. In addition to developing the predictive models, this work includes creating a user-friendly web platform. The platform enables scientists and engineers to access the models and rapidly explore the chemical space to design new materials. The platform also includes visualization and analysis tools to guide the design process and facilitate collaboration between researchers. The data-driven tools developed in this research have the potential to significantly accelerate the discovery and development of new molecular organic semiconductors, paving the way for the next generation of flexible electronics and renewable energy technologies. Overall, this dissertation offers a practical and innovative framework for designing organic semiconductors, leveraging data-driven approaches to overcome the challenges of the traditional experimental trial-and-error process.
Computational studies on molecular mechanisms for dysregulation of monoamine transporters by HIV-1 Tat and drug discovery of novel phosphodiesterase-2 inhibitors
HIV is among the world’s most deadly infectious diseases. Recent therapeutic advancements have begun to increase the life expectancy of people living with this virus. The mechanisms that lead to neurobiological complications in HIV cases are not well understood. HIV infection in macrophages results in HIV-1 Tat proteins being released and impairing the function of monoamine transporters. HIV-infected patients have displayed unusual synaptic levels of neurotransmitters and led to reduced binding and function of monoamine transporters such as the norepinephrine transporter, vesicular monoamine transporter, and serotonin transporter. Here we use different approaches to develop an accurate three-dimensional model of the HIV-1 Tat and NET binding complex which would help reveal how HIV-1 Tat causes toxicity in the neurons by affecting uptake. The modeling results show that HIV-1 Tat-hNET binding is highly dynamic and HIV-1 Tat preferentially binds to hNET in an outward-open state. VMAT2 is related to NET as it transports a wide range of substrates including dopamine, norepinephrine, and serotonin. HIV-1 Tat affects VMAT2 similarly to NET, binding and inhibiting its function. VMAT2 is also inhibited by a number of small molecules and the binding modes are explored. The neurobiological mechanisms underlying HIV-associated depression are not well understood. Depression severity in HIV cases has been linked to acute and chronic markers of systemic inflammation and relates to serotonin levels. HIV-1 Tat affects the serotonin reuptake mechanism by inhibiting the serotonin transporter. Here we explore the possible binding modes of HIV-1 Tat and SERT. There are also a number of substrates that inhibit SERT normal function and the binding of HIV-1 Tat-SERT complex. The binding modes of these complexes are also explored here. There is a significant need for new therapeutic compounds for the treatment of cognitive dysfunction. Current therapies provide minimal symptomatic relief, without curing or halting cognitive impairment. Preclinical data have shown that inhibitors of cyclic nucleotide phosphodiesterase 2 improve memory in Alzheimer’s disease mouse models and reverse some markers of neuropathology. Family members of PDE, notably PDE4 and PDE5, have been shown to be druggable targets and suggest the same can apply to PDE2. PDE2A is the most prevalent of the family and is expressed in the hippocampus and frontal/temporal cortex regions. PDE2 is a dual specific enzyme that hydrolyzes cGMP and cAMP, and is involved in memory and cognition and is susceptible to Alzheimer’s disease associated neuropathology. Clinical studies have not produced improved candidates due in part to suboptimal selectivity, poor metabolic stability, or limited brain penetrance. Currently there are no PDE2A inhibitors that are approved for clinical use. Here we utilize state-of-the-art drug discovery tools and techniques to discover, design, and optimize novel and drug-like inhibitors for PDE2A. The discovery schema for novel, potent and selective PDE2A inhibitors will use a proven, iterative process where outcomes of in vitro and in vivo testing informs and guides modeling and medicinal chemistry.
Pt(II)-based agents are used in approximately 50% of all cancers that are treated with chemotherapy. Unfortunately, the dose-limiting toxicity of these agents remains problematic for patients undergoing treatment. Additionally, Pt(II) therapeutics suffer from transporter-dependent uptake, limited chemical functionalization, and high susceptibility to inactivation by free thiols within the cytosol. Developing small molecules with non-canonical mechanisms of action is one strategy that can be employed to circumvent these limitations. Utilization of coordination complexes with Ru(II) metal centers is one attractive strategy. Ru(II) compounds are often octahedral, facilitating greater accessibility for chemical diversity; Ru(II) complexes use passive transport and transferrin-mediated transport for cellular uptake; Ru(II) is a harder Lewis acid than Pt(II), facilitating reduced thiol coordination, which results in reduced inactivation. Herein, we investigate several Ru(II) scaffolds that display non-canonical mechanisms. They are able to preferentially induce ribosome biogenesis stress and mitochondrial membrane uncoupling. Complementary to this work, we investigated the mechanism of action for photoactive chemotherapeutics (PACTs) and photodynamic therapeutics (PDTs). Despite the fact that reactive oxygen species (ROS) generated by PDTs can oxidize nucleobases, cellular bioenergetic pathways are effectively shut down before DNA damage could be recognized by DNA damage repair (DDR) machinery, suggesting that, unlike Pt(II) therapeutics, DNA damage is not the cause of cell death for these compounds.