New family of rhodium metalloinsertors with improved selectivity and potency against DNA mismatch repair deficient cell lines

Abstract

Rhodium metalloinsertors are a unique family of complexes that selectively bind DNA base pair mismatches. We have seen crystallog. that insertion of the sterically expansive chrysi (5, 6- chrysenequinone diimine) ligand into DNA at a mismatched site leads to the ejection of the mismatched bases. This unique lesion may serve as the biol. target within the cell. Previously, it has been shown that rhodium metalloinsertors preferentially increase cell death and inhibit proliferation of mismatch repair (MMR) - deficient colorectal cancer cell lines over their MMR- proficient counterparts. Recently, a new family of rhodium metalloinsertors contg. a rhodium- oxygen bond has been shown to have improved potency in the nanomolar range as well as increased cytotoxic selectivity toward MMR- deficient cells. This family appears distinct from previous metalloinsertors in that both the Δ- and %λ- isomers of these complexes bind mismatched DNA with similar affinities. Current research is focused on extending the family to include new complexes that will allow us to explain in detail the basis for the high cell selectivity and potency of this new family.