My research interests ask interdisciplinary questions that use the methods of physical chemistry to explore questions of biophysical interest. I am particularly interested in the design and characterization of transition metal complexes that bind to DNA in a way that halts replication of DNA. Shutting down DNA function is one approach to stopping the growth of cancerous cells.

Two important features of a functional binding complex are the site specificity and binding strength. Site specificity means that a binding complex successfully identifies harmful DNA sequences and the complex remains indefinitely if the binding is strong. One binding mechanism that is known to stop DNA replication is intercalation, where the metal complex becomes inserted between the base pairs in DNA. Figure 1 shows three possible binding mechanisms by a ruthenium polypyridyl complex, including intercalation.

Figure 1: Three binding mechanisms of a ruthenium complex to DNA. N. (Turro, J. Barton and D. Tomalia, Acc. Chem. Res., 1991, 24332-340)

Ruthenium polypryridyl complexes are known to be chemically stable, fluorescent, and soluble in aqueous solutions and possess planar ligands making them excellent potential DNA binders. A schematic drawing of a ruthenium polypyridyl complex is shown in Figure 2. This complex is of particular interest because of the hydrogen bonding potential of the carboxylic acid functional group which may influence DNA base pair specificity.

Figure 3 shows a schematic drawing of a dimer ruthenium polypyridyl complex that has the potential to bind by a
'threading' mechanism depicted in Figure 4. There is some evidence that binding via a threading mechanism is quasi-irreversible which is useful because the complex will stay bound. Not much is known about the binding strength and binding mechanisms of polyintercalators and is an area of particular interest.

Figure 2: A schematic representation of an octahedral ruthenium polypyridyl complex modified with a carboxylic acid functional group (COOH).

 

Figure 4: A schematic representation of a dimer complex becoming threaded into the helix of DNA.

Currently in my lab ultraviolet-visible absorption spectroscopy, viscosity titrations and fluorescence spectroscopy are used to investigate binding strengths and binding mechanisms. In a research setting there
is no single correct approach to a problem, unlike problems students face in their coursework, research progresses in unpredictable directions shaped by students' interests and interpretations of experimental results. Students interested in pursuing a research project are invited to contact me by e-mail or come by my office. (Return to Glazier homepage)