Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch. Issue 12 (29th January 2019)

• Record Type: Journal Article
• Authors: Boyle, Kelsey M.; Nano, Adela; Day, Catherine; Barton, Jacqueline K.
• Is Part Of: Chemistry. Volume 25:Issue 12(2019)
• Page Start: 3014
• Page End: 3019
• Publication Date: 2019-01-29
• Subjects: antitumor agents -- cancer -- cellular uptake -- cytotoxicity -- DNA recognition; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201900042
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Defects in DNA mismatch repair (MMR) are commonly found in various cancers, especially in colorectal cancers. Despite the high prevalence of MMR‐deficient cancers, mismatch‐targeted therapeutics are limited and diagnostic tools are indirect. Here, we examine the cytotoxic properties of a rhodium metalloinsertor, [Rh(phen)(chrysi)(PPO)] 2+ (RhPPO ) in 27 diverse colorectal cancer cell lines. Despite the low frequency of genomic mismatches and the non‐covalent nature of theRhPPO ‐DNA lesion, RhPPO is on average five times more potent than cisplatin. Importantly, the biological target and profile forRhPPO differs from that of cisplatin. A fluorescent metalloinsertor, RhCy3, was used to demonstrate that the cellular target ofRhPPO is the DNA mismatch.RhCy3 represents a direct probe for MMR‐deficiency and correlates directly with the cytotoxicity ofRhPPO across different cell lines. Overall, our studies clearly indicate thatRhPPO andRhCy3 are promising anticancer and diagnostic probes for MMR‐deficient cancers, respectively. Abstract : Targeting DNA mismatches : Rhodium metalloinsertors are a versatile family of complexes that selectively bind to DNA mismatches in vitro. A range of cytotoxicities was found for the metalloinsertor with higher potency than cisplatin across a panel of colorectal cell lines, and a fluorescent analogue was used to confirm that the DNA mismatch is the primary biological target for the metalloinsertor in cells.