Development of rhodium metalloinsertors as chemotherapeutic agents

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. Rhodium metalloinsertors are octahedral complexes that bind DNA mismatches with high affinity and specificity through metalloinsertion, a binding mode through which the compds. insert into the DNA duplex from the minor groove and eject the mismatched bases. These compds. also exhibit unique cell- selective cytotoxicity, preferentially inducing necrosis in mismatch repair (MMR) - deficient cells over MMR- proficient cells. This chemotherapeutic activity, which has been confirmed across multiple assays and in different systems for comparing MMR deficiency to proficiency, has been found to be the result of specific targeting of the metalloinsertors to nuclear DNA mismatches. Most recently, a new generation of metalloinsertors with enhanced potency and selectivity has been discovered which display Rh- O coordination and a possible different binding disposition in the mismatch site as compared to earlier generation metalloinsertors.

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