Seminars Archive

Approaches to the Treatment of Alzheimer’s Disease: Two Targets; Two Modalities

Professor Richard Olson | Bristol-Myers Squibb

Professor Ken Hsu

ABSTRACT

Alzheimer’s disease remains a major unmet medical need representing a huge societal burden and a difficult event in the lives of patients and families. Current treatments do not offer hope for disease altering outcomes and recent attempts to bring forward new therapies have proven largely unsuccessful. This presentation will review two programs at Bristol-Myers Squibb spanning two therapeutic targets and two drug structural classes, or modalities: Small molecules and antisense oligonucleotides (ASOs). Efforts to improve the stereospecific synthesis of an important class of ASOs will be described.

Proton-Coupled Electron Transfer by Copper-Oxygen Species Relevant to Enzyme Intermediates

Professor William Tolman | Washington University in St. Louis

Professor Charlie Machan

Characterization of copper intermediates in enzymes and other catalysts that attack strong C-H bonds is important for unraveling oxidation catalysis mechanisms and, ultimately, designing new, more efficient catalytic systems. New insights into the nature of such intermediates may be obtained through the design, synthesis, and characterization of copper-oxygen complexes. Two key proposed examples contain [CuO2]+ and [CuOH]2+ cores, which have been suggested as possible reactive intermediates in monocopper enzymes such as lytic polysaccharide monooxygenase. Recent progress toward the characterization of the structures and properties of complexes with these cores that feature the same supporting ligand will be described, and detailed comparisons of their kinetics in reactions with C-H and O-H bonds will be discussed. Notable differences in their PCET reaction pathways with para-substituted phenols has been discovered that shed new light on the fundamental chemistry of these important core structures.

Magnesium(I) Dimers: Universal Reductants for the Synthetic/Catalytic Chemist?

Professor Cameron Jones | Monash University: Director, Monash Centre for Catalysis

Professor Robert Gilliard

ABSTRACT

The renaissance that has occurred in main group chemistry over the last several decades has been largely driven by the realization that very low oxidation state p-block compounds can be stable species at ambient temperature, given the right ligand environment. Increasingly, such compounds are being shown to possess "transition metal-like" reactivity patterns in small molecule activations, and associated catalytic synthetic transformations.[1] In late 2007 we extended this field to the s-block with the preparation of the first room temperature stable molecular compounds containing magnesium-magnesium covalent bonds, viz. LMgMgL (L = bulky guanidinate or b-diketiminate, e.g. 1).[2] We have subsequently shown that the unique properties these species possess lend them to use as versatile reducing agents in both organic and inorganic synthetic protocols.[3] The products of such reactions are often inaccessible using more classical reducing agents. In this lecture an overview of what has been achieved with these remarkable reagents will be given, with an emphasis placed on the preparation of unprecedented examples of low oxidation state/low coordination number metal-metal bonded complexes involving metals from the s-, p- and d-blocks, e.g. 2-4.[4] The further chemistry of these highly reactive systems will also be discussed, as will our efforts to incorporate magnesium(I) dimers into catalytic cycles.[5]

REFERENCES

[1] Power, P. P. Nature 2010, 463, 171.

[2] Green, S. P.; Jones, C.; Stasch, A. Science 2007, 305, 1136.

[3] Jones, C. Nature Rev. Chem. 2017, 1, 0059.

[4] Bonyhady, S.J.; Collis, D.; Holzmann, N.; Edwards, A.J.; Piltz, R.O.; Frenking, G.; Stasch, A.; Jones, C. Nature Comm., 2018, 9, 3079.

[5] (a) Boutland, A. J.; Carroll, A.; Lamsfus, C. A.; Stasch, A.; Maron, L.; Jones, C. J. Am. Chem. Soc. 2017, 139, 18190; (b) Yuvaraj, K.; Douair, I.; Paparo, A.; Maron, L.; Jones, C. J. Am. Chem. Soc., 2019, 141, 8764.

Graham Lecture: Increasing Access to Global Healthcare through Process Intensification

Dr. Frank Gupton | Virginia Commonwealth University

Professor Brooks Pate

Abstract:   Access to global public healthcare is impacted by many technical, economic, and social factors. It is widely recognized that the resources required to deliver and improve global public health are currently constrained.  A powerful way to increase access is to lower the cost of products and services that have already proven to be effective.  Currently, the cost of producing a wide range of pharmaceutical products is higher than it needs to be. The mission of Medicines for All (M4All) is to transform active pharmaceutical ingredient (API) processes in order to reduce medication cost and improve patient access.  To fulfil this objective, M4ALL has developed a set of core principles for API process development, which are derived from fundamental elements of process intensification that are commonly known but often neglected. These principles have been applied to several global health drugs yielding dramatic improvements in chemical efficiency. The development of novel and highly efficient heterogeneous catalysts for cross-coupling reactions that support this effort will also be presented.

Why does O-GlcNAc Transferase Matter?

Professor Suzanne Walker | Harvard University

Professor Ken Hsu

ABSTRACT

O-GlcNAc transferase (OGT) is essential for viability of all mammalian cells but no one knows why. OGT has two catalytic activities that take place in the same active site. In one, OGT attaches N-acetyl glucosamine to serine and threonine side chains of at least a thousand nuclear and cytoplasmic proteins. In the other, OGT cleaves a transcriptional co-activator involved in cell-cycle regulation. Because OGT is found in several stable protein-complexes, it is also proposed to act as a scaffolding protein. How do you dissect the cellular functions of an essential protein that has multiple biochemical activities and a thousand different substrates? I will argue that you need to start by understanding the chemistry –  mechanisms of catalysis and substrate recognition – so you can develop variants with some activities and not others. I will describe how we have done so and how we have used our knowledge to answer a fundamental question: What is the essential biochemical function of OGT for cell survival? I will also describe how we have developed and used a specific small molecule inhibitor of OGT to uncover an unexpected role in controlling RNA splicing.  

Engineering Adaptive (bio) Materials from Functional Polymers and Peptide Stereocomplexes

Dr. Rachel Letteri | University of Virginia (Department of Chemical Engineering)

Professor Rebecca Pompano

ABSTRACT

Advancing highly tunable synthetic materials to operate in an increasingly cooperative fashion with biological systems and the environment provides a compelling opportunity to expand the repertoire and enhance the performance of critically needed technologies.  To this end, we are developing new building blocks for polymer biomaterials so as to access to a breadth of thermomechanical properties and promote productive interactions with biological systems.  The first part of this talk will describe our research on mirror image peptide complexes, or ‘stereocomplexes’, as tunable, transient junctions in synthetic polymer biomaterials.  Varying the primary structure of the peptides and solvent conditions were found to markedly impact the secondary structure, which in turn determined the macroscale properties of polymer-peptide conjugates.  These junctions are envisioned as molecular ‘VELCRO®’ strips and are anticipated to impart a myriad of adaptive properties, including self-healing and shear thinning, useful for 3D printing-based manufacturing processes and targeting biological proteins, among other applications.  Another approach to engineer adaptive materials involves controlling degradation rates, and the second part of this talk will describe the synthesis, thermomechanical characterization, and degradation profiles of poly(β-amino ester) networks.  By adjusting monomer composition, networks were obtained with degradation times scales that spanned hours to months.  Synthetically accessible and highly tunable, this polymer platform offers enormous opportunities, from sacrificial template materials for biomanufacturing to commodity materials that degrade after their useful lifetime.  Ultimately, by intertwining concepts from small molecule and peptide chemistry with polymer science and engineering, we aim to advance polymer and peptide building blocks, and thereby contribute to next generation materials and technologies for healthcare and beyond.

Graphene-based Materials for Applications in Heterogeneous Catalysis, Water Treatment and Solar Water Desalination

Dr. Samy El Shall | Virginia Commonwealth University

Professor Eric Herbst

This talk will address the development of three classes of graphene-based materials as (1) support for metal nanoparticle catalysts in heterogeneous catalysis, (2) sorbent materials for the removal of heavy metal ions from polluted water, and (3) photothermal energy converter materials for efficient solar water desalination.

In heterogeneous catalysis, we will discuss the superior catalytic activity of Pd nanoparticles supported on reduced graphene oxide (RGO) nanosheets for carbon-carbon cross-coupling reactions. Second, the enhanced catalytic activity for the Fe-based nanoparticle catalysts supported on graphene in the Fischer-Tropsch Synthesis of liquid transportation fuels will be presented. Finally, the superior catalytic activity and selectivity of Pd nanoparticles supported on a sandwich-type nanocomposite consisting of Metal-Organic Frameworks (MOFs) wrapped with thin RGO nanosheets for the biomass-refining of liquids derived from lignocelluloisc sources will be presented.

For the removal of heavy metals from water, we will discuss the development of chemically modified graphene-based adsorbents containing highly efficient chelating groups such as diamine, imino and thiourea for the effective extraction of the toxic metal ions mercury (II), lead (II) and arsenic (V) from wastewater.

For photothermal energy conversion, we will discuss the development of a new generation of highly efficient, flexible, low weight, highly porous and cost effective Plasmonic Graphene Polyurethane (PGPU) nanocomposite materials for solar steam generation through the efficient evaporation of water surface pools. The PGPU nanocomposites contain metallic nanoparticles that exhibit very strong solar absorption. The polyurethane (PU) foam provides a hydrophilic surface with abundant microporous structure, excellent thermal insulation properties, and facile and scalable synthesis. The high solar thermal evaporation efficiency, excellent stability and long-time durability make the PGPU nanocomposites excellent candidates for solar-steam-generation applications and seawater desalination.

Two-Dimensional Carbides and Nitrides (MXenes) Challenge Graphene (Location: Monroe Hall Rm 110)

Dr. Yury Gogotsi | Drexel University

Professor Sen Zhang

ABSTRACT

Two-dimensional (2D) materials with a thickness of a few nanometers or less can be used as single sheets, or as building blocks, due to their unique properties and ability to assemble into a variety of structures. Graphene is the best-known example, but several other elemental 2D materials (silicene, borophene, etc.) have been discovered. Numerous compounds, ranging from clays to boron nitride (BN) and transition metal dichalcogenides, have been produced as 2D sheets. By combining various 2D materials, unique combinations of properties can be achieved which are not available in any bulk material. The family of 2D transition metal carbides and nitrides (MXenes) has been expanding rapidly since the discovery of Ti3C2 in 2011 [1]. Approximately 30 different MXenes have been synthesized, and the structure and properties of numerous other MXenes have been predicted using density functional theory (DFT) calculations [2]. Moreover, the availability of solid solutions on M and X sites, control of surface terminations, and the discovery of ordered double-M MXenes (e.g., Mo2TiC2) offer the potential for synthesis of dozens of new distinct structures.

This presentation will describe the synthesis of MXenes by selective etching of layered ceramic precursors, including various MAX phases. Delamination into single-layer 2D flakes and assembly into films and 3D structures, as well as their properties will be discussed. Synthesis-Structure-Properties relations of MXenes will be addressed on the example of Ti3C2.

The versatile chemistry of the MXene family renders their properties tunable for a large variety of applications [3]. Oxygen or hydroxyl- terminated Menes, such as Ti3C2O2, have been shown to have redox capable transition metals layers on the surface and offer a combination of high electronic conductivity with hydrophilicity, as well as fast ionic transport [4].  This, among many other advantageous properties, makes the material family promising candidates for energy storage and related electrochemical applications [5], but applications in plasmonics, electrocatalysis, biosensors, water purification/ desalination and other fields are equally exciting. In particular, capacitive deionization and membrane desalination and purification will be addressed.

Hecht Lecture: Redesign of Vancomycin for Resistant Bacteria

Professor Dale Boger | Scripps Research Institute; La Jolla, CA

Professor Sid Hecht

ABSTRACT

A summary of studies on the total synthesis and evaluation of the vancomycin family of glycopeptide antibiotics, their ligand binding pocket redesign to address the underlying molecular basis of resistance, and their subsequent peripheral tailoring to address the emerging public health problem of vancomycin resistance will be presented.

Quantifying Oxygen’s Role in Promoting Aggressive Cancer Phenotypes With a Paper-Based 3D Culture Platform

Professor Matt Lockett | UNC Chapel Hill

Professor Rebecca Pompano

Abstract:

Oxygen is a master regulator of many cellular processes. In tissues, gradients of oxygen and nutrients extend radially from blood vessels. The gradients in these diffusion-dominated environments increase greatly when a blood vessel is occluded, or in the case of the tumors when the rate of proliferation outpaces the rate of vascularization. The extent of hypoxia in tumors has been correlated with cancer aggressiveness, drug resistance, and invasiveness. Gradients of oxygen are also believed to direct cellular invasion from the solid tumor mass to neighboring healthy tissue.

Despite the pivotal role that oxygen plays in tumor biology, there are a limited number of in vitro assays able to quantify cellular morphology, gene- and protein-expression, or drug sensitivities in well-defined oxygen gradients. Due to the lack of experimental tools, many studies compare cellular differences at a single normoxic (21% O2) and hypoxic (~0.2% O2) condition. Monolayer cultures are also commonly used in these normoxia-hypoxia comparisons. These experiments provide a simplified view of oxygen-mediated regulation, overlooking the importance of gradients by exposing cells to a single oxygen and nutrient concentration. Evaluating a limited number of oxygen tensions has led to the inadequate interpretation that cellular responses to oxygen are a binary phenomenon, eliciting a particular hypoxic phenotype or not.

We are developing a 3D culture platform utilizing paper-based scaffolds to prepare tissue- or organ-like structures. We are able to engineer extracellular environments with specific oxygen or nutrient gradients and to tease apart the nuanced responses of cells in gradients of different steepness and shape. In this talk, I will highlight the paper-based culture platform as well as other technologies we are developing to address three long-standing questions in tumor biology. First is the role that oxygen gradients play in directing cellular movement. We have recently shown that oxygen is a chemo-attractant in diffusion-dominated environments, and are exploring what additional extracellular conditions (e.g., gradient steepness, the presence of overlapping nutrient gradients) promote this directed invasion. Second is the oxygen-mediated mechanisms through which hypoxic cells become drug resistant. In particular, we use invasion assays and tumor-like structures to evaluate the relationship between oxygen tension, active resistance (upregulation of drug efflux pumps), and passive resistance (altered metabolism or halted proliferation). Third is the relationship between hypoxia and hormone responsiveness in estrogen receptor alpha-positive (ER+) breast cancers.

Screening, Isolation, and Characterization of Antibiotic Natural Products

Professor Amanda Wolfe | University of North Carolina Asheville

Professor Mike Hilinski

Abstract

The increased emergence of bacterial resistance over the past two decades has greatly reduced the effectiveness of nearly all clinical antibiotics, bringing infectious disease to the forefront as a dire threat to global health. To combat these infections, new antibiotics need to be rapidly discovered, and bacterial natural products have reemerged as an abundant source of novel bioactive molecules. Herein, the isolation and evaluation of over 400 bacteria from bulk and rhizosphere soil native to western North Carolina and the southwestern U.S. in a novel and robust liquid-based high-throughput antagonism assay against Staphylococcus aureus and Escherichia coli is presented. Over 300 bacterial species were screened in monoculture, and 12% and 15% were found to produce antibiotics capable of ≥30% growth inhibition of Staphylococcus aureus or Escherichia coli respectively. 69 of those bacteria were subjected to 16s rRNA sequencing and found to be majority Pseudomonas (30%) and Serratia (17%) bacteria, and Aquitalea, Brevundimonas, Chryseobacterium, Herbaspirillum, and Microbacterium bacteria, which are currently not known to be antibiotic producers. More than 10 producing bacteria have been subjected to large scale culture and extraction techniques to isolate the produced antibiotic. One of those, a Pseudomonas sp., was found to produce the natural product pseudopyronine B, and we have further improved the antibiotic activity of this natural product through SAR evaluation of the alkyl side chains.

Highly Sterically-Crowded Subvalent Group 14 Compounds: Unexpected Structures and High Reactivity with Small Molecules

Professor Philip Power | University of California at Davis

Professor Robert Gilliard

A series of new compounds, MAr2 (M = Ge, Sn, or Pb; Ar = terphenyl ligands) display structures and structural trends that are counter-intuitive with regard to steric effects. These trends are also reflected in their spectroscopic properties and in their reaction chemistry. It was found that the presence or absence of substituents at apparently-remote sites on the ligands can exert a large influence on the course of the reactions, as well as on the structural characteristics of the group 14 element environment. Their reactions with a range of olefins and carbon monoxide, which showed unexpected trends, will be shown. In addition, the reactions of the related subvalent hydrides, ArMH, with a range of olefins and alkyne molecules, as well as the unexpected compounds that are formed, will be presented. A notable feature of their behavior is their ability to induce unexpected isomerizations in the olefin substrates. Finally, it is proposed that many of the peculiar properties of the compounds is related to the presence of dispersion force interactions of their ligand substituents.