Synthesis, characterization, and biological activity of DNA mismatch-targeting rhodium complexes

Abstract

DNA base pair mismatches are a promising target for chemotherapeutic design due to their relative abundance in cancers with mismatch repair (MMR) deficiencies. Rhodium metalloinsertors are a family of metal complexes that can target these mismatches with high selectivity in vitro and in cell culture. Mismatch targeting is directed by an expansive inserting ligand, 5,6-chrysiquinone diimine (chrysi), which is able to displace a thermodynamically destabilized mispair and replace it within the DNA π-stack. Recent studies have led to the development of unique metalloinsertors contg. rhodium-oxygen coordination of an ancillary ligand. This new ligand framework has been assocd. with nanomolar potency and improved selective cytotoxicity towards MMR deficient cells over MMR proficient cells. To gain addnl. insight into the surprising behavior of these complexes, this family has been further expanded through alteration of the remaining ancillary ligand, which has been varied in steric bulk and lipophilicity. This newest family of rhodium metalloinsertors has been synthesized and characterized, and the biol. activity of these complexes, including cytotoxicity and subcellular localization, has been measured. Unlike earlier generations of metalloinsertors, even the most lipophilic complexes in this family do not exhibit excessive off-target mitochondrial localization, allowing them to maintain high selective cytotoxicity towards MMR deficient cells and reduced off-target cytotoxicity in MMR proficient cells. Overall, the biol. activity of metalloinsertors contg. this Rh-O ligand coordination appears to be highly robust regardless of substitution of the ancillary ligands. This ligand framework could serve as an excellent scaffold for future conjugation to cytotoxic or fluorescent payloads for therapeutic or diagnostic use.