Targeting DNA mismatches with metalloinsertors

Abstract

Deficiencies in the mismatch repair pathway are assocd. with several types of cancers, as well as resistance to commonly used chemotherapeutics Our lab. has developed bulky rhodium complexes that target DNA mismatches through metalloinsertion. These octahedral complexes include an expansive tetracyclic arom. ligand that can only be accommodated by DNA at a thermodynamically destabilized mismatch site. The first generation compd., Rh(bpy)_2chrysi^(3+) (chrysi = 5,6-chrysenequinone diimine), binds 80% of all possible DNA mismatches and with remarkable specificity for the mismatched site. High resoln. crystals structures of metal complexes bound to single base mismatches within a DNA oligonucleotide duplex reveal the distinctive binding mode of metalloinsertion at the mismatched site, where the mismatched bases are ejected, replaced by the metallonsertor. The family of metalloinsertors shows both selective inhibition of cellular proliferation and selective cytotoxicity of cells deficient in mismatch repair. Targeting of genomic DNA mismatches provides a unique cell-selective strategy in the design of novel chemotherapeutics.