Project 1: Photoisomerizable Inhibitors
Off target effects represent one of the greatest challenges to chemotherapeutic and chemical diagnostic use. Several strategies have been employed to reduce the potential negative side effects. Chief among them is targeting the therapeutics to the tumor site. One means of targeting therapeutics is to label or encapsulate a therapeutic for localized delivery to the desired tissue. However, such a strategy is certainly tissue or tumor specific. Another more universal strategy involves treatment with a prodrug throughout the body followed by generation of the active form of the drug only in the desired tissue. Our group is interested in the incorporation of photoactivatable functional groups into molecules of potential therapeutic importance as a means of spatial and temporal control of drug release.
Project 2: Evolution and Small Molecule Manipulation of Functional RNAs
The comprehensive strategy shown in Figure 1 is being used to discover metal scaffolds that can be utilized to study and modulate RNA function. As an initial study, stable metal complexes based on known RNA binders of the Rev Response Element (RRE) RNA of HIV-1 will be designed and tested for efficacy. This region of RNA is responsible for control of RNA export in HIV-1 and has recently been validated as a target for RNA binding small molecule therapeutics. Rev binds a specific stem-loop structure of the RRE. A subsequent nucleation of Rev around this site prevents further RNA splicing and facilitates RNA transport. Disruption of the Rev-RRE interaction results in reduced viral growth. Synthesis of transition metal analogues of known RNA binders in an abbreviated and convergent way will allow rapid access to a large number of structurally diverse ligand spheres in an efficient fashion.
Project 3: Isolation, Characterization, and Development of Small Molecule Inhibitors of Bacterial Proteins with Ties to Pathogenesis
Our collaborators at Lehigh University have used bioinformatics approaches to identify promising candidate proteins for the study of bacterial pathogenesis. Preliminary studies indicate that several of these domains are involved in bacterial pathogenesis by virtue of their membrane binding or catalytic activity. Once isolated and purified, we hope to characterize the exact role these proteins play in microbial pathogenesis and design inhibitors, with the intention of reducing their virulence.
Project 4: Development of Chiral Tetradentate Lewis Acid CatalystsWe have synthesized and crystallized several novel tetradentate metal complexes. The X-ray structures of these complexes suggest that they are excellent candidates for Lewis acid catalysis. Fortunately, the tetradentate nature of the ligand renders them chiral-at-metal, making them potentially useful as chiral Lewis acid catalysts. Given the number of reactions that can be catalyzed by Lewis acids, their potential is vast. We are examining the scope of reactivity these complexes.
Project 5: Synthesis of Transition Metal Analogues of Natural Products
Natural products are a tremendously rich resource for new molecules with interesting and useful biological properties. However, their synthesis is often difficult and it can be exceptionally challenging to derivatize these molecules to fine-tune their biological properties. In particular, ring junctions and highly substituted carbons pose special synthetic challenges. My group is substituting transition metals for these highly complex carbon centers, which will allow streamlined syntheses of the natural products and their derivatives. Additionally, by adding the metal in the last step of the synthesis, our group can easily tune the electronic and geometric properties of our compounds by changing metals and oxidation states.
Project 6: Synthetic Transition Metal Catalysis in Live Cells
We have long been interested in the ability of transition metal catalysts to cross cell membranes and perform any number of interesting reactions. To date, transition metal catalysts have been used for allyl carbamate cleavage and azide reduction in live cells. Our group is looking to expand the number available reactions, find new catalysts, and improve the catalysts that are currently known using targeting and photoactivation strategies. In collaboration with the Meggers group at Philipps University Marburg and the Elliott Group at SMCM, we have recently expanded this approach from single cell studies to the full C. elegans organism. Currently, my group is working with Professor Mertz to expand the number of uses for small molecule transition metal catalysis in live cells.