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DNA mismatch binding and antiproliferative activity of rhodium metalloinsertors

Ernst, Russell J. and Song, Hang and Barton, Jacqueline K. (2009) DNA mismatch binding and antiproliferative activity of rhodium metalloinsertors. Journal of the American Chemical Society, 131 (6). pp. 2359-2366. ISSN 0002-7863. PMCID PMC2747594. doi:10.1021/ja8081044. https://resolver.caltech.edu/CaltechAUTHORS:20090601-115902054

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Abstract

Deficiencies in mismatch repair (MMR) are associated with carcinogenesis. Rhodium metalloinsertors bind to DNA base mismatches with high specificity and inhibit cellular proliferation preferentially in MMR-deficient cells versus MMR-proficient cells. A family of chrysenequinone diimine complexes of rhodium with varying ancillary ligands that serve as DNA metalloinsertors has been synthesized, and both DNA mismatch binding affinities and antiproliferative activities against the human colorectal carcinoma cell lines HCT116N and HCT116O, an isogenic model system for MMR deficiency, have been determined. DNA photocleavage experiments reveal that all complexes bind to the mismatch sites with high specificities; DNA binding affinities to oligonucleotides containing single base CA and CC mismatches, obtained through photocleavage titration or competition, vary from 10^4 to 10^8 M^−1 for the series of complexes. Significantly, binding affinities are found to be inversely related to ancillary ligand size and directly related to differential inhibition of the HCT116 cell lines. The observed trend in binding affinity is consistent with the metalloinsertion mode where the complex binds from the minor groove with ejection of mismatched base pairs. The correlation between binding affinity and targeting of the MMR-deficient cell line suggests that rhodium metalloinsertors exert their selective biological effects on MMR-deficient cells through mismatch binding in vivo.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja8081044DOIArticle
http://pubs.acs.org/doi/full/10.1021/ja8081044PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747594/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2009 American Chemical Society. Published In Issue February 18, 2009; Article ASAP January 28, 2009; received: October 16, 2008; publication Date (Web): January 28, 2009. Financial support for this work from the NIH (GM33309 to J.K.B.) is gratefully acknowledged. The authors also thank Dr. Jonathan Hart for his synthesis of [Rh(NH_3)_4chrysi]OTf_3.
Funders:
Funding AgencyGrant Number
NIHGM33309
Issue or Number:6
PubMed Central ID:PMC2747594
DOI:10.1021/ja8081044
Record Number:CaltechAUTHORS:20090601-115902054
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20090601-115902054
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14345
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:19 Aug 2009 01:25
Last Modified:08 Nov 2021 23:11

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