The Barton group utilizes coordinatively saturated, substitution-inert, octahedral metal complexes to probe the structure and dynamics of double-helical DNA. Specifically, we design, synthesize, and study novel metal complexes capable of specific interactions with target sites in DNA duplexes. Two classes complexes form the focus of our research efforts: Rh complexes, which photocleave the DNA backbone near the site of binding, and Ru complexes, which luminesce upon DNA binding. Compared with organic DNA-binding agents, these metal complexes offer a uniquely modular system, allowing combinations of recognition elements to be assembled on a single rigid, three-dimensional scaffold.
By tuning the shape and functionality of these metal complexes, we have developed a series of Rh complexes capable of DNA sequence recognition through intercalation. More recent efforts have led to the discovery of a new class of metal complexes capable of recognizing single base mismatches. These complexes, dubbed metalloinsertors and exemplified by Rh(bpy)(chrysi)3+ and Rh(bpy)2(phzi)3+, bind with high specificity and affinity to single base mismatches in DNA duplexes. Their mode of binding, elucidated through NMR studies and crystallography, constitutes the first observation of DNA insertion by a small molecule: the sterically expansive chrysi ligand inserts into the pi-stack of the DNA duplex from the minor groove and ejects the mispaired bases from the helix into the major groove.
Metal complexes that recognize specific sites in DNA have great potential to be used in biological applications including early cancer diagnostics and chemotherapeutics.
Among the Rh complexes, Rh(L)2(chrysi)3+ have been successfully employed to detect single nucleotide polymorphisms (SNP). They have also been shown to preferentially inhibit the proliferation of mismatch repair (MMR)-deficient cells over MMR-proficient ones. Currently, we are designing new bifunctional conjugates of Rh complexes to use as highly selective drug delivery systems.
Luminescent Ru complexes have been used extensively in mechanistic studies of cellular uptake. More efforts are being directed toward the development of Ru-based luminescent reporters of MMR-deficient cancer cells.
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