We use rational design and synthetic organic chemistry to create compounds with interesting physical properties including fluorescence emission, structure-selective DNA binding, and anti-cancer activity. Our current emphasis is on the development of small molecule ligands that bind to and stabilize non-duplex structures like G-quadruplex and i-motif DNA. Molecules that bind to these structures with high affinity and specificity are used to probe their biological function, and may provide new leads for anti-cancer drugs. In addition to the study of non-covalent binding interactions, we are interested in modified oligonucleotides. One such example is the preparation of well-defined DNA-DNA interstrand cross-links (ICLs) that result from anti-cancer therapies utilizing bi-functional alkylating agents. Our approach to this synthetic challenge involves the incorporation of a stable ICL precursor (as a modified base) into duplex DNA, which can be activated for cross-link formation by oxidation or photolysis. We are also developing modified bases to provide new fluorescent probes for DNA structure and dynamics. In addition to synthesis, our lab uses a variety of biophysical, photophysical, and biological techniques to evaluate the properties of each target molecule.
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