Targeting DNA Mismatches with Coordination Complexes

Abstract

DNA base pair mismatches occur naturally in cells as a result of incorporation errors and damage. Most cells are able to identify and correct these mistakes before replication, allowing for high genome fidelity between cellular generations. In some forms of cancer, however, proteins involved in the machinery of mismatch repair (MMR) undergo mutation, making those cells unable to correct mismatches and leading to an increase in mutations. Since higher mismatch frequency serves as an early indicator of cancer progression, for many researchers mismatches have provided a novel target for the design of organic and inorganic small-molecule therapeutics. In particular, transition metal complexes have shown great promise in this context owing to their valuable spectroscopic and photophysical properties and flexibility with respect to modification of their coordination spheres. Thus far, experimental designs have ranged from targeting the thermodynamic destabilization of mismatched sites to the hydrogen-bonding pattern of specific mismatched base pairs. Here, we review the diversity, practical application, and evolution of mismatch-targeting small molecules, with an emphasis on rhodium metalloinsertors and luminescent ruthenium compounds. Importantly, we highlight the discovery of metalloinsertion, a noncovalent DNA binding mode that is specific towards destabilized sites, such as mismatches, within the DNA duplex.

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