The goal of this research program is the design and application of transition metal complexes to target specific sites on DNA. Such designs form the basis for novel chemotherapeutics targeted to nucleic acids with improper base-pairing motifs and provide new tools to probe DNA structure and recognition. Experimental methods include synthetic chemistry of coordination complexes and ligands, biochemical techniques to probe site-specific binding, and structural methods such as NMR and crystallography.
We have designed a series of octahedral rhodium (III) complexes containing the intercalating ligands phenanthrene quinone diimine (phi), chrysene-5,6-quinone diimine (chrysi) and benzo[a]phenazine-5,6- quinone diimine (phzi). The phi complexes bind nonspecifically to DNA primarily by intercalation in the major groove. The chrysi and phzi complexes bind DNA with high affinity and selectivity for mismatched base pairs. With photoactivation, the complexes promote direct DNA strand scission at the site of intercalation, and this photocleavage serves to mark the site of binding.
These complexes are currently being used for Single Nucleotide Polymorphism (SNP) detection with fluorescently labeled DNA. From these, we are creating chemotherapeutic and luminescent agents to target and irreversibly modify DNA. Our current focus here is the application of transition metal probes in vivo.
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