Cooley Lab

Chemical Synthesis, Bioinorganic Chemistry and Polymer Chemistry

Professor: Christina Cooley, Ph.D.

Overview: 

Research in the Cooley lab applies the power of synthetic organic chemistry to solve problems in biology and human health. Students in my lab will have the opportunity to design and synthesize new molecules and assess their ability to detect and treat human disease under the following two major project areas.

Our primary research area is in the development of new methods to amplify molecular signals as a way to detect biomolecular interactions and potentially, disease. We have developed fluorogenic monomers that are not fluorescent in monomer form, but glow when incorporated into a polymer synthesized by various methods, for example by atom transfer radical polymerization (ATRP). Polymer fluorescence is quantifiable by fluorescence readers or visible to the naked eye, and tracks with the concentration of polymerization initiator, which serves a model analyte.

This fluorogenic polymerization subgroup has many current research directions ranging from fundamental organic synthesis and polymerization studies to detection applications. Current projects are aimed toward the synthesis of new monomers to improve physical properties such as water solubility, development and evaluation of alternative light-initiated fluorogenic polymerization platforms, optimization of the fluorogenic polymerization approaches for analyte detection, and application to the direct detection of proteins and biomolecular interactions. Students working in this area will apply a range of organic, polymer and biochemical techniques, from the chemical synthesis of small molecules and free-radical polymerization techniques initiated by various methods from metal catalysts to irradiation with visible light, to analysis and characterization of the polymers formed by gel permeation chromatography, nuclear magnetic resonance spectroscopy, and fluorescence analysis methods.

The Cooley lab has a second subgroup in the general field of therapeutic drug delivery, utilizing the sensing of reactive oxygen species (ROS) for prodrug activation and therapeutic release in diseased tissues. A prodrug is a “caged” version of a drug that is inactive until release to the free drug is achieved under specific biological conditions. We have synthesized and evaluated prodrugs of AA 147, which activates a stress-responsive signaling pathway as a therapeutic target for treatment following reperfusion events such as heart attacks and strokes. These prodrugs of AA 147 are selectively uncaged by the presence of reactive oxygen species (ROS), which occur at high levels during reperfusion events. We are also exploring other types of releasable AA 147 prodrugs to improve pharmacodynamics properties for in vivo animal studies, and the synthesis of fluorogenic ROS sensors for collaborative chemical applications. Students in this area will gain experience with small-molecule synthesis and characterization, and analyze their therapeutic release profile under biological conditions.

Lambert Lab

Organic Chemistry

Professor: Joseph B. Lambert, Ph.D.

Amber is the fossilized end product of resinous materials exuded by plants millions of years ago.  It is found on every continent except Antarctica.  There are at least five chemically distinct types of amber, depending on the botanical material from which the original exudate came from.  Nuclear magnetic resonance (NMR) spectroscopy can distinguish these different botanical sources and provide a means of determining authenticity of amber and learning about its geographical sources.

More generally, exudates are complex mixtures of organic compounds produced by plants, usually as the result of injury or disease.  Secreted as liquids, exudates may harden to solids in hours to months on the surface of the plant.  These materials have found numerous practical applications throughout human history, and they provide a molecular window to the classification of plants (taxonomy).  We have found that exudates are remarkably robust and consistent in their molecular constitution within a single plant and from plant to plant within a given species.  There are several, distinct chemical constitutions of exudates.  Resins, which can form amber through fossilization, are composed of terpenoid compounds.  Gums are made of polysaccharides.  Gum resins like frankincense and myrrh contain both materials.  Kinos contain phenols.  Although these four chemical groups are the largest, there are several other smaller but distinct chemical groups.

We are carrying out a worldwide survey of plant exudates from all plant families, and of amber, necessitating field acquisition of materials and analysis by NMR in the lab.  We also are examining the effect of heat on the molecular structure of amber and its slightly younger colleague, copal.  Heat has been used to alter the properties of amber prior to carving.  Spectroscopic examination of artificially heated samples may clarify how structure change with heating.

Shearer Lab

Bioinorganic Chemistry; Computational Chemistry; X-ray Spectroscopy

Type: Inorganic Chemistry
Professor: Jason Scherer, Ph.D.

Research in the Shearer Group is broadly centered on understanding how the electronic structure of biologically and industrially relevant transition metal species contribute to their reactivity and physical properties. Central to our work is the synergistic use of synthetic, spectroscopic and computational chemistry. Although we perform some work with naturally occurring biological systems or industrial catalysts, we primarily study synthetic mimics of these systems to probe a specific aspect of their chemistry. Briefly outlined below are two projects currently being undertaken by the Shearer Group.

 1. Probing Nickel Containing Superoxide Dismutase. Nickel containing superoxide dismutase (NiSOD) catalyzes the conversion of highly toxic superoxide (O2–) into dioxygen and hydrogen peroxide by making use of a NiII/NiIII redox couple. In the reduced NiII oxidation state the nickel-site is contained in a distorted square planar NiN2S2 coordination environment with ligands derived from Cys2, Cys6, the N-terminal amine nitrogen and an amidate nitrogen from Cys2. An unusual feature of the NiSOD active site that we have been probing is the fact that one of the coordinated Cys sulfur ligands is protonated, forming a Ni-S(H+)-Cys moiety. A number of roles for this moiety can be envisioned; our hypothesis is that protonation of the Cys sulfur ligand poises the nickel site for reactivity. We postulate that protonation raises the energy of orbitals that are predominantly nickel in character allowing for electron transfer from NiII to O2–, thus generating O22– (peroxide) and NiIII. To test this hypothesis, we are preparing a number of metallopeptide based mimics of NiSOD along with small transition metal complexes that can support reversible Ni-S(H+)-Cys formation. By spectroscopically examining the influence of sulfur protonation in such mimics, we seek to understand the role(s) of the Ni-S(H+)-Cys moiety in NiSOD reactivity, and Ni-S-R containing compounds in general.

2. Understanding Transition Metal Ligand Bonds Through the Lens of Valence Bond Theory. In modern chemical physics quantum mechanical descriptions of chemical bonding are described through three main models: molecular orbital, density functional, and valence bond (VB) theory. All of these approaches have distinct benefits and disadvantages. VB theory has the advantage of placing bonding in terms that chemists understand (covalent vs ionic bonding), and thus yields intuitive descriptions of bonding. However, it has only been in the past decade that VB theory methods have advanced to the point where larger systems of chemical interest can be tackled at a sufficiently high level of theory to yield accurate solutions. We have taken advantage of these recent advances in VB theory to explore the bonding, energetics, and reactivity of transition metal complexes involved in organometallic transformations. For example, we have recently investigated reductive elimination from [CuR4]– complexes (R = alkyl) and discovered a number of “hidden” features concerning the chemistry of such species. For example, one surprising aspect of such reactions is that they are not reductive eliminations in any physically meaningful sense of the word; instead they can be viewed as admixtures of radical C-C couplings and simple Lewis acid/base reactions.

Urbach Group

Supramolecular Chemistry; Biosensing; Diagnostics; Drug Formulation

Website: Urbach Group
Professor: Adam Urbach, Ph.D.

The chemistry of pharmaceuticals and medical diagnostics is designed to recognize a specific protein in a complex mixture, such as blood, and to stick to that protein.  Pharmaceuticals block the normal function of that protein. Medical diagnostics measure the quantity of that protein. The Urbach lab develops new chemistry for the recognition of specific proteins, and we use this chemistry to solve important biomedical problems. Students are involved in experimental design and implementation, problem solving, data analysis, presentation, and publication.

Students in the Urbach research group learn a range of techniques, which can include organic synthesis to make peptides, bioconjugates, hydrogels, and modified proteins; NMR spectroscopy; mass spectrometry; microcalorimetry; fluorescence spectroscopy; circular dichroism spectroscopy; and X-ray crystallography. This combination of methods and approaches offers students a breadth of technique and depth of study that is an excellent foundation for further study in organic chemistry, biophysical chemistry, medicinal chemistry, biochemistry, bioengineering, and biotechnology.

Current projects include: 1) Developing new chemistry to recognize proteins and proteins on the basis of their amino acid sequences. Our discoveries have established new rules for predictive protein recognition, and we are currently working to expand the range of proteins that are accessible by our compounds, and to increase the strength and selectivity of interaction. 2) Synthesizing new protein receptors with new properties. 3) Developing technology for the quality control of protein drug formulations. 4) Developing a new strategy for protein drug formulation that enables controlled time release.  Dr. Urbach is always interested in discussing new ideas with students. These projects are funded by grants from the National Institutes of Health and the Welch Foundation.