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Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch
Author(s) -
Boyle Kelsey M.,
Nano Adela,
Day Catherine,
Barton Jacqueline K.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201900042
Subject(s) - dna mismatch repair , cisplatin , cytotoxicity , cytotoxic t cell , dna , cancer research , colorectal cancer , cancer , biology , chemistry , microbiology and biotechnology , genetics , in vitro , chemotherapy
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 the RhPPO ‐DNA lesion, RhPPO is on average five times more potent than cisplatin. Importantly, the biological target and profile for RhPPO differs from that of cisplatin. A fluorescent metalloinsertor, RhCy3 , was used to demonstrate that the cellular target of RhPPO is the DNA mismatch. RhCy3 represents a direct probe for MMR‐deficiency and correlates directly with the cytotoxicity of RhPPO across different cell lines. Overall, our studies clearly indicate that RhPPO and RhCy3 are promising anticancer and diagnostic probes for MMR‐deficient cancers, respectively.