Ruquia Ahmed-Schofield is focusing on model studies to investigate a methodology for the construction of spirocyclic amines. The methodology is based upon the photodecomposition of cyclic derivatives of Barton PTOC [((1 H)-pyridine-2-thione)-oxycarbonyl] esters in the presence of nucleophilic amines. The attractive feature of the strategy lies in its potential for short, versatile, and efficient synthesis. Depending upon the structural nature of the nucleophile, an array of products is possible. Some of the photoproducts have structural features that are found in several interesting and biologically active compounds. The successful outcome of this research may lead to the use of the methodology in the synthesis of numerous structural derivatives of compounds with pharmaceutical activities.
Zinc is required for many biological processes due to its role as a key component of hundreds of enzymes as well as a structural component of thousands of regulatory proteins including transcription factors. Not surprisingly, zinc deficiency has adverse clinical manifestations including immune disorders, growth retardation and cognitive impairment. Because of the wide-ranging roles of zinc, the connections between these clinical symptoms and specific biochemical systems or pathways have been difficult to establish. However, the major inflammation pathway leading to the activation of the transcription factor Nuclear Factor kappa B (NFκB) has been identified as an important candidate for immune impairments due to the large number of proteins containing zinc binding domains in its transduction pathway.
The zinc-binding domains found in the NFκB pathway are small structural motifs, which facilitate a wide variety of specific macromolecular interactions. In most cases, zinc binding induces folding of these motifs, which are largely unfolded in the unbound state. Given the coupled nature between metal binding and folding and the relatively small size of these domains, zinc-binding domains are an ideal motif to study protein-macromolecular interactions. This coupling provides a natural mechanism for potentially linking the zinc status of a cell and the activities of proteins containing zinc-binding domains with appropriate functions.
My research aims at understanding the role of zinc in the immune system particularly how zinc-binding domains regulate inflammation. By characterizing the metal binding affinities, structures, protein-macromolecular interactions, and mechanisms of the proteins essential for signaling the NFκB transduction pathway, we hope to understand how zinc regulates the activation or deactivation of key immune factors.
The parasite that causes malaria feeds on human blood during some stages of its life cycle. The heme group (iron containing porphyrin) is toxic to the parasite. The parasite removes the heme group by polymerizing it into a nontoxic polymer called hemazoin. Esther Gibbs' research, in collaboration with Bob Pasternack at Swarthmore College, investigates the kinetics of formation of hemazoin as a function of pH and temperature.
Project 1: Design, Synthesis, and Evaluation of small molecule DNA ligase inhibitors (in collaboration with Dr. Alan Tomkinson, University of Maryland School of Medicine)
DNA ligases are enzymes responsible for forming phosphodiester bonds in DNA molecules, which is necessary for DNA synthesis and repair. This project examines small molecule DNA ligase inhibitors as a potential new class of cancer drugs. Ongoing work at Goucher on this medicinal chemistry project includes the chemical synthesis of novel inhibitors and the evaluation of those molecules using two different kinds of enzyme assays.
Project 2: Novel Substrates for the Ni-Catalyzed Intramolecular [4+4] Cycloaddition of Bisdienes.
The synthesis of 8-membered rings continues to be an area of active research due to the considerable challenges associated with their construction. [4+4] cycloadditions are forbidden by the Woodward-Hoffman rules under thermal conditions, but they can be carried out photochemically, or in the presence of a transition metal catalyst. Paul Wender (Stanford University) first reported Ni-catalyzed intramolecular [4+4] cycloadditions in 1986, but very little has been done with this reaction since. Greco is working on expanding the scope of the reaction by varying the tether length between the reacting partners and incorporating heteroatoms into the tether.
For more information about these projects, click here.
The expression of genes in living cells is carried out by proteins that can recognize and bind to specific nucleotide sequences in DNA. These proteins then act in various ways to extract genetic information from the DNA in a highly regulated manner. Judy Levine's research focuses on understanding the mechanisms by which DNA-binding proteins are able to recognize specific signals in DNA and carry out their specific functions. Recognition may involve chemical as well as structural features of DNA, such as its ability to be deformed into bent or kinked conformations. These features of DNA may also play important roles in the subsequent action of DNA-binding proteins during gene expression. Levine's experimental approach uses chemical techniques to investigate the structures of protein-DNA complexes in order to gain insight into the mechanisms by which they function.
Of particular interest to Levine (among other DNA-binding proteins) is an enzyme called RNA polymerase, which binds to DNA and moves along it, transcribing the genetic information in the DNA into a corresponding RNA molecule. Very little is known about the structure of the transcribing enzyme complex or the mechanics of its motion as it progresses along a DNA molecule. Investigation of this process by the chemical techniques mentioned above is an important step toward the ultimate goal of understanding how this biological "machine" may be regulated in living cells.
Scott Sibley's research interest focuses on the synthesis and photophysical characterization of highly fluorescent near-infrared emissive dyes for potential use as in vivo imaging agents. He is also studying the mechanism of inhibition of protein aggregation via the use of small molecules.
Photochromism is the reversible light-induced transformation of a chemical species between two forms that have different absorption spectra. Simplistically, it is a term used to describe the reversible color change upon exposure to light. Dithienylethenes are one class of photochromic compounds that have been extensively studied and modified to attain specific desired properties such as its luminescence, magnetic properties, electrochemical properties, refractive index, conductivity, etc. Upon exposure of a 1,2-dithienylethene derivative to the appropriate wavelength of UV light, the ring open isomer undergoes a cyclization reaction. This alteration in bond configuration results in significant modifications to the molecule's geometric and electronic properties and is the cause of a color change. The Schultz Lab is taking advantage of these molecular changes to develop systems that have unique chemical properties after irradiation with light.
My research interests lie mainly in the area of synthetic organic chemistry and include the design, synthesis, and investigation of molecules that have the potential to be useful chemosensors and drug delivery agents.
1. Chemosensors: Chemosensors are molecules that selectively recognize specific chemical species and have recently attracted much interest. They are highly relevant for environmental and biological reasons. Examples of environmental impacts include detection of the fluoride ion, which is present in drinking water and as a byproduct from the hydrolysis of nerve agents such as sarin. The chemosensors utilize functional groups that are known to bind specific ions. As examples, three coordinate organoboron derivatives bind fluorine selectively over other anions and the aza-15-crown-5 substituent has been shown to bind the cations of alkaline earth metals (Mg2+, Ca2+, Ba2+) selectively over alkali metals. This binding process modifies the bonding structure in the molecule and allows the system to undergo the photochromic reaction to induce a noticeable color change.
2. Drug Delivery Agents: Light is an efficient trigger to release biologically active compounds because it offers precise spatial and temporal control of the released chemical or drug. The changes in bonding architecture upon the photochemical reaction of dithienylethenes can allow for the release of certain chemicals or drugs if it is properly tuned.