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Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch

Boyle, Kelsey M. and Nano, Adela and Day, Catherine and Barton, Jacqueline K. (2019) Cellular Target of a Rhodium Metalloinsertor is the DNA Base Pair Mismatch. Chemistry: a European Journal, 25 (12). pp. 3014-3019. ISSN 0947-6539. http://resolver.caltech.edu/CaltechAUTHORS:20190114-083314706

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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 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 RhPPOacross different cell lines. Overall, our studies clearly indicate that RhPPO and RhCy3 are promising anticancer and diagnostic probes for MMR‐deficient cancers, respectively.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/chem.201900042DOIArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. Accepted manuscript online: 07 January 2019; Manuscript accepted: 04 January 2019; Manuscript received: 03 January 2019. We gratefully acknowledge Dr. Julie Bailis, for providing the cell lines used in this study. We thank NIH and the Moore Foundation for financial support and the Department of Defense for supporting K.M.B. through the National Defense Science & Engineering Graduate Fellowship program. The authors declare no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHUNSPECIFIED
Gordon and Betty Moore FoundationUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Subject Keywords:Antitumor agent; cellular uptake; cytotoxicity; DNA recognition
Record Number:CaltechAUTHORS:20190114-083314706
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20190114-083314706
Official Citation:K. M. Boyle, A. Nano, C. Day, J. K. Barton, Chem. Eur. J. 2019, 25, 3014. doi: 10.1002/chem.201900042
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:92241
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:14 Jan 2019 20:55
Last Modified:01 Mar 2019 22:47

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