Targeting DNA mismatches with rhodium metalloinsertors

Abstract

DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch-repair (MMR) deficient cancers. These rhodium metalloinsertors, bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique for small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers.

Cooperative recognition of T:T mismatch by echinomycin causes structural distortions in DNA duplex

“…Several small-molecule ligands have been found to bind to mismatched DNA which may have potential applications in the diagnosis and therapy of cancer as well as neurological diseases ( 2 ). Barton's group showed that rhodium metalloinsertors can recognise DNA mismatches with high affinity and specificity in vitro , and may target MMR-deficient cells over MMR-proficient cells ( 11 , 38 ). Their findings led them to propose the use of rhodium metalloinsertors as a basis for the development of new types of chemotherapeutic agents active against MMR-deficient cancers.…”

New Ruthenium‐Based Probes for Selective G‐Quadruplex Targeting

“…Subsequently, the discovery of the light‐switch effect of [Ru(bpy) 2 (dppz)] 2+ (dppz=dipyrido[3,2‐ a :2′,3′‐ c ]phenazine) in the presence of DNA (i.e., restoration of the luminescence of the complex upon intercalation into DNA, whereas it is not luminescent in aqueous media) marked a turning point in the field of biological application of metal complexes. The use of ruthenium(II) complexes as probes for genetic materials and cellular environment has since grown markedly and has prompted the use of other metal‐based complexes, with iridium(III), osmium(II), or rhodium(III) metal moieties, for example.…”

Selective tumor cell death induced by irradiated riboflavin through recognizing DNA G–T mismatch

“…have extensively investigated the photocleavage of DNA and RNA using ruthenium-complexes as photosensitizer that lead primarily to guanine oxidation ( 24 , 25 ). They have pioneered the development of rhodium metalloinsertors that target mismatch in DNA specifically by intercalation and induce site-specific photocleavage neighboring destabilized mismatch ( 26 , 27 ). In cellular experiment, the rhodium metalloinsertors induce an inhibition of cell proliferation preferentially in mismatch repair (MMR)-deficient cells with light or not, which represents a promising targeted therapy for patients with MMR-deficient cancer ( 28 – 30 ).…”