Timothy E. Glass

Associate Professor

323 Chemistry

Tel: (573) 882-3813

GlassT@missouri.edu

Our group has been involved in the preparation of fluorescent sensors for detection of biologically important organic compounds in aqueous media. Fluorescent sensors are compounds which produce visible fluorescence in the presence of a target molecule (analyte). Such sensors have been used to visually trace the presence of certain analytes in and around cells. These studies have proven to be invaluable for the elucidation of cellular mechanisms by giving real-time information about the environment of a cell in a non-destructive manner. However, biologically useful sensors for organic compounds have lagged behind those for metal ions and cellular conditions such as pH and pO2. The main challenge in preparing sensors for organic compounds is obtaining specific, high affinity recognition of the analyte of interest in the complex media of the cell.

We have endeavored to introduce a new paradigm in chemical sensing by exploiting the concept of cooperativity to provide the affinity and selectivity necessary for preparing biologically useful sensors. Cooperative interactions can occur when the sensor binds to multiple analytes. Cooperativity has not previously been applied to chemical sensing. Furthermore, none of the known cooperative receptors are amenable to a general chemical sensor platform. Therefore, we have designed and developed a synthetic strategy for a novel framework for cooperative recognition, termed a “pinwheel receptor.” The receptor was designed in such a way to make it generally applicable to a variety of analytes. We have shown in a simple metal binding assay that cooperative recognition gives an increased affinity for an analyte compared to a similar non-cooperative receptor. This effect has proven to be general for all of the analytes we have tested thus far. Subsequently, we introduced a modified sensor framework in which a fluorescent read-out system is integrated directly into the sensor framework in order to further extend the generality of the sensor design. Thus, any analyte which is bound cooperatively by the sensor will activate a fluorescent response.

We have recently used this strategy to build sensors which exhibit high affinity for dicarboxylic acids in aqueous solution and have demonstrated that cooperative recognition has tremendous advantages in selectivity for an analyte. These effects will be invaluable for the specific recognition of analytes in a complex medium like the cellular environment. Current targets include neurotransmitters such as dopamine and glutamate as well as the cellular redox potential. Solutions to these problems would engender a raft of biochemical studies aimed at elucidating various cellular processes. Further directions include the preparation of receptors for targets such as the carbohydrates expressed on cell surfaces. Since our cooperative sensors are designed to bind more than one analyte, they should be useful as high affinity probes for clustered membrane bound carbohydrates such as GM3 and GD3. These cell surface motifs are implicated in a variety of biological processes such as inflammation and tumor metastasis. Cooperative, receptors for such carbohydrates hold promise for selective inhibition of disease related cell-cell interactions.

We are also interested the preparation of water soluble cleft compounds as receptors. The chemistry of calix[4]naphthalenes is being explored in an effort to generate molecular tubes with the ability to recognize bio-molecules such as lipids via shape selective hydrophobic interactions. Lipids represent another class of biologically relevant analytes for which specific receptors would be valuable. Furthermore, such molecular tubes may have many potential applications including artificial zeolites and molecular wires. We have also developed metal ligands for the generation of metal coordination complexes as receptors for analytes such as nucleotides (e.g., ATP). Coordination complexes have the advantage that they are modular (generated from several interchangeable components) and their solubility characteristics can be varied.