Seminars Archive

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.

New Chemical Probe Technologies: Applications to Imaging, Target Identification and Drug Discovery

Professor Matthew Bogyo | Stanford University

Professor Ken Hsu

Hydrolases are enzymes that often play important roles in many common human diseases such as cancer, asthma, arthritis, atherosclerosis and infection by pathogens. Therefore tools that can be used to dynamically monitor their activity can be used as diagnostic agents, as imaging contrast agents and for the identification of novel classes of drugs. In the first part of this presentation, I will describe our efforts to design and synthesize small molecule probes that produce a fluorescent signal upon binding to tumor associated protease targets. We have identified probes that show tumor-specific retention, fast activation kinetics, and rapid systemic distribution making them useful for real-time fluorescence guided tumor resection and other diagnostic imaging applications. In the second half of the talk, I will present our recent advances using chemical probes to identify novel protease and hydrolase targets in pathogenic bacteria. This work has led to new imaging agents for Mycobacterium tuberculosis and the identification of novel virulence factors in Staphylococcus aureus that have the potential to be targeted with small molecules as a therapeutic strategy.

Ireland Lecture: Catalyst-Controlled Site-Selective and Enantioselective C–H Functionalization

Professor Huw Davies | Emory University

Professor Mike Hilinski

Spontaneous Formation of Oligomers and Fibrils in Large Scale Molecular Dynamics Simulations of the Alzheimer’s Peptides

Professor Carol Hall  | North Carolina State University

Professor Kateri DuBay

Spontaneous Formation of Oligomers and Fibrils in Large-Scale Molecular Dynamics Simulations of the Alzheimer’s Peptides

Protein aggregation is associated with serious and eventually-fatal neurodegenerative diseases including Alzheimer’s, Parkinson’s and the prion diseases.  While atomic resolution molecular dynamics simulations have been useful in this regard, they are limited to an examination of either oligomer formation by a small number of peptides or analysis of the stability of a moderate number of peptides placed in trial or known experimental structures. We describe large-scale molecular dynamics simulations of the spontaneous formation of fibrils by systems containing large numbers of peptides. The simulations are fast enough to enable us to follow the steps in the aggregation process from an initial configuration of random coils to oligomers and then to proto-filaments with cross-β structures. In simulations of Aβ17-42 peptides, we uncovered two fibrillization mechanisms that govern their structural conversion from disordered oligomers into protofilaments.  We also investigate the influence of crowding agents on oligomerization and fibrillization for Aβ16-22. Simulations are conducted which allow examination of the impact of naturally-derived inhibitors (resveratrol, curcumin, vanillin, and curcumin) on the oligomerization and fibrillation of A β17-36. Finally, we describe simulations of human, mouse and Syrian Movies of the aggregation process on a molecular level will be shown.

Indole Alkaloids and Phenazine Antibiotics: New Platforms for Discovery

Professor Robert Huigens | University of Florida

Professor Mike Hilinski

Abstract:

Various natural products, such as taxol, morphine and vancomycin, play a prominent role in medicine due to their ability to modulate biological targets critical to human disease. Our lab has two natural product inspired synthetic medicinal chemistry programs, driven by the structural complexity of indole alkaloids and the biological function of phenazine antibiotics. Each program aims to address major biomedical problems, including: (1) enhancing the chemical diversity of screening libraries used to drive drug discovery in high throughput screening campaigns and (2) the discovery of small molecules capable of targeting and eradicating surface-attached bacterial biofilms. Our first program aims to rapidly generate diverse and complex compounds, which can be accessed through short synthetic sequences motivated by the dramatic alteration of the inherent complex ring system of indole alkaloids. From these efforts, we have generated a library of >200 complex and diverse small molecules, which are producing an array of interesting hit compounds in diverse disease areas. Our second program aims to target bacterial biofilms, which contain specialized persister cells that are metabolically dormant and demonstrate tolerance towards every class of conventional antibiotic currently available. Biofilms are the underlying cause of chronic and recurring bacterial infections. Our lab has discovered that the marine phenazine antibiotic 2-bromo-1-hydroxyphenazine is a tunable molecular scaffold that provides access to highly potent antibacterial agents that are able to eradicate drug-resistant and antibiotic-tolerant bacterial biofilms. 

Reductive Carboxylation of Unsaturated Hydrocarbons with CO2

Professor Brian Popp | West Virginia University

Professor Mike Hilinski

ABSTRACT

Carbon dioxide is an attractive C1 synthon in chemical synthesis due to its abundance, obtainability, non-toxicity, and inherent renewability. However, it has been undervalued and underutilized for the synthetic installation of carboxyl functionality because of its unreactive nature, owing to its inherent thermodynamic stability and kinetic inertness. Traditionally the carboxyl group is accessed by organic chemists through redox manipulation and protection/deprotection reactions or through the use of strong nucleophiles that have limited functional group tolerance. By fixing carbon dioxide with unsaturated organic molecules through C–C bond formation, rapid and redox-economic synthesis of carboxylic acids and their derivatives can be realized. Nevertheless, these transformations remain rare, are poorly understood, and generally limited to more energetic alkyne substrates. The Popp Research Group uses methodological and mechanistic approaches to expand the versatility and usefulness of transition metal-catalyzed reductive olefin carboxylation. Two approaches that will be discussed in this seminar are transfer hydrometallation–carboxylation and hetero(element)carboxylation. Recent mechanistic work will be presented on an iron-catalyzed variant of the former reaction class that has revealed new details, and possibly new opportunities, for this poorly understood class of reaction. The latter manifold was only recently extended by our group to include olefins (vinyl arenes) for the first time (ACS Editors’ Choice–Org. Lett. 2016, 18, 6428). The mild method uses redox-neutral copper catalysis and a single atmosphere of CO2 to obtain boron-functionalized α-aryl carboxylic acids, including novel functionalized-NSAIDs such as bora-ibuprofen and bora-naproxen. Recent progress toward the preparation of new bora-olefin compounds, subsequent synthetic elaboration of the carbon-boron bond, and complementary experimental/computational studies to improve our mechanistic understanding of the reaction will also be presented.

Supramolecular Approaches to Advanced Functional Materials

Professor Davita Watkins | University of Mississippi

Professors Robert Gilliard & Jill Venton

Photoredox and Electrochemical Methods for C-N Bond Forming Reactions

Professor Aaron Vannucci | University of South Carolina

Professor Charlie Machan

Photoredox and Electrochemical Methods for C-N Bond Forming Reactions

C-N bonds are ubiquitous in medical, pharmaceutical, and natural products. Therefore, it is important to develop synthetic procedures that both effectively form C-N bonds and incorporate sustainable principles. These principles include the use of renewable energies sources such as sunlight, utilization of abundant transition metal catalysts, and increasing the atom economy of the reactions. Along these lines, we have utilized dual photoredox system capable of accessing diaryl amines, amines containing aliphatic groups, and tertiary amines nickel catalysis to perform aryl-amine cross-coupling reactions. Until very recently this class of C-N bond forming reactions were limited to Pd-catalyzed reactions. Our system is the first Ni-catalyzed reaction system capable of synthesizing diaryl amines, tertiary amines, and amines containing aliphatic groups. Mechanistic studies support an amine-radical-based reaction pathway that allows for the access to the range of products. Furthermore, we have developed an “anion pool” electrochemical method for the synthesis of N-substituted heterocycles. This base-free and transition-metal-free approach exhibits good atom economy and has proven widely applicable for the synthesis of substituted benzimidazoles.