Cell-selective activity of rhodium metalloinsertors correlates with subcellular localization

Abstract

Deficiencies in the mismatch repair (MMR) pathway have been assocd. with various cancers, and many commonly used chemotherapeutics have decreased effectiveness against MMR-deficient cancers. There is consequently a need for chemotherapies that selectively target MMR-deficient cancer cells. Research in our lab. has uncovered a class of compds., rhodium metalloinsertors, that selectively binds to DNA mismatches with high affinity and specificity. These rhodium metalloinsertors bear an expansive arom. chrysi ligand (chrysi= chrysene-5,6-quinonediimine) which, upon mismatch binding, inserts into the DNA duplex from the minor groove and ejects the mismatched bases. These metalloinsertors exhibit selective cytotoxicity, preferentially inducing necrosis in MMR-deficient cells over MMR-proficient cells. They have been found to localize in the nuclei of MMR-deficient cells at concns. sufficient for mismatch detection, and their ability to selectively target MMRdeficient cells has been shown to be contingent upon low mitochondrial rhodium accumulation