Seminars Archive

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.

It’s Complex: Probing Protein Interactions from Single-Molecule to Cellular Scales

Julea Vlassakis | Fellow, Herr Lab| University of California, Berkeley

Professor James Landers

Abstract

Biological molecules rarely act alone. Instead, molecular complexes carry out a range of cellular functions from DNA repair to cell motility and protein folding. Dysfunction of complexes is implicated in numerous diseases. For example, altered cellular distributions of actin cytoskeletal protein monomers and complexes result in highly motile and invasive cancer cells. Such dysfunction arises biochemically, biophysically, or both. Biochemical and biophysical changes occur on the length and force scales of the complexes themselves—micro/nanoscale and ultra-low forces. Microscale tools, such as size-based electrophoretic (EP) cytometry protein separations, and piconewton-scale magnetic tweezers, can measure such small size and force changes respectively.

I will describe efforts to establish and apply microscale tools to study the function of diverse protein complexes. First, I will discuss the design of single-cell EP cytometry fractionation of actin complexes from monomers. The microscale device geometry achieves rapid, arrayed on-chip sample preparation and EP fractionation without perturbing complexes. Second, I will share how magnetic tweezers reveal that tension in Rad51-DNA protein complexes drives accurate DNA damage repair processes. Finally, we will explore the future of microscale biophysical and biochemical analysis of complexes, with a focus on chaperone protein complexes responsible for protein folding, which goes awry in Alzheimer’s disease. 

Antibody affinity reagents and reproducibility: Strategies and challenges for the renewable diagnostics and therapeutics antibodies

Professor Bhupal Ban | UVA - Antibody Engineering & Technology Core

Professor Rebecca Pompano - *NOTE: (Dell 2 Room 100)

Learning Objectives

•       Trends for isolation of monoclonal antibodies
•       Current  antibody reproducibility problem in academic institute
•       Antibody validation: Standards, policies, and practices 
•       A new mindset for affinity application, evaluation, and authorization
•       The advantages of recombinant antibody production methods over monoclonal and polyclonal antibody production methods.
•       Phage display antibody production be adapted to produce the characteristic desired in applications such as multiple epitope recognition, tissues, and phenotype functional antibodies. 
•       Learn about protein chemistry and conjugation of antibody and drug
•       Immobilize antibody onto different polymers, nanoparticles, liposome  

Interactions of antimicrobial and cell-penetrating peptides with lipid membranes

Professor Paulo Almeida | University of North Carolina at Wilmington

Professor Dave Cafiso

Antimicrobial, cytolytic, and cell-penetrating peptides, often called membrane-active peptides, belong to a variety of structural classes, including, alpha-helical, beta-sheet, unstructured, and cyclic polypeptides, among others. Those peptides were intensely studied in the 1990s and early 2000s with the hope of opening the door for urgently needed new antibiotics. For about 15 years we have studied the kinetics and thermodynamics of their interactions with lipid vesicles with the hope of understanding the mechanism of their function. In general, these peptides bind to lipid bilayers and somehow disrupt or perturb them, causing flux of ions and molecules across the membrane, and also, in some cases, translocating themselves across the membrane. In this talk, I will discuss our efforts to understand the mechanisms of these peptides and what we have learned regarding the effect of sequence on their ability to translocate across the membrane. I will conclude with the examination of a very different case, the cyclic peptide daptomycin, which is one of the few in clinical use. This peptide appears to behave very differently from all other membrane-active peptides that we have studied.

From basic chemistry to new opioid biology

Professor Jeff Aube | University of North Carolina, Chapel Hill

Professors Ken Hsu and John Lazo

The worldwide opioid crisis has occasioned efforts to develop new opioids for both existing uses (pain control) as well as new indications (itch, addiction). We have focused on the discovery of compounds able to selectively activate one of the two main intracellular pathways associated with the kappa opioid receptor. This type of activity, called “functional selectivity” or “ligand bias”, has the potential to segregate many of the ultimate biological effects of therapeutic opioids.

This project is an effort of a multidisciplinary, multi-institutional team led by the speaker and Professor Laura Bohn of the Scripps Research Institute.[1,2] It began with the development of a speculative library for screening against a range of potential biological targets based on a known but underexplored isoquinolinone synthesis. Applying this chemistry to library synthesis led to a hit compound that stoked our interest in biased ligand discovery, ultimately leading to the discovery of Triazole 1.1, a strongly biased KOR agonist with a fascinating in vitro and in vivo profile. These efforts and recent results will be described.

[1] Bohn, L.M.; Aubé, J. ACS Med. Chem. Lett, 2017, 8, 694–700.

[2] Brust, T. F.; Morgenweck, J.; Kim, S. A.; Rose, J. H.; Locke, J. L.; Schmid, C. L.; Zhou, L.; Stahl, E. L.; Cameron, M. D.; Scarry, S. M.; Aubé, J.; Jones, S. R.; Martin, T. J.; Bohn, L. M. Biased Agonists of the Kappa Opioid Receptor Suppress Pain and Itch Without Causing Sedation or Dysphoria. Sci. Signal. 2016, 9, ra117.

Jeffrey Aubé attended the University of Miami, where he did undergraduate research with Professor Robert Gawley (with whom he later co-authored the graduate text “Principles of Asymmetric Synthesis”, currently in its second edition). He received his Ph.D. in chemistry in 1984 from Duke University, working with Professor Steven Baldwin, and was an NIH postdoctoral fellow at Yale University with Professor Samuel Danishefsky. From 1986 until 2015, he held a faculty position in the Department of Medicinal Chemistry at the University of Kansas. In 2015, he retired from KU and moved to the University of North Carolina, where he is an Eshelman Distinguished Professor in the Division of Chemical Biology and Medicinal Chemistry. In addition to holding a joint appointment in the Department of Chemistry, Aubé is a member of the Center for Integrative Chemical Biology and Drug Discovery and the Lineberger Cancer Center.

Aubé’s research interests lie in the chemistry of heterocyclic compounds and their applications to problems in medicinal organic chemistry. The lab’s interests in bioorganic chemistry include collaborations in the area of opioid pharmacology (with Laura Bohn), steroid biosynthesis inhibitors (with Emily Scott), and in the discovery of anti-Mtb agents (with Carl Nathan). Aubé served as the principal investigator of the Chemical Methodology and Library Development Center program at Kansas as well as a specialized chemistry lab in the NIH’s Molecular Libraries Initiative.

Aubé has been honored for his research and scholarship by his receipt of awards from the American Chemical Society (including the Arthur C. Cope Scholar Award and the Midwest Award, bestowed by the St. Louis Section of the ACS) and for teaching (including the university-wide HOPE Award and the Kemper Fellowship for Teaching Excellence at KU). He is a fellow of both the American Association for the Advancement of Science and the American Chemical Society.

Redefining druggability using chemoproteomic platforms

Professor Dan Nomura | University of California, Berkeley

Professor Ken Hsu