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A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition

Junicke, Henrik and Hart, Jonathan R. and Kisko, Jennifer and Glebov, Oleg and Kirsch, Ilan R. and Barton, Jacqueline K. (2003) A rhodium(III) complex for high-affinity DNA base-pair mismatch recognition. Proceedings of the National Academy of Sciences of the United States of America, 100 (7). pp. 3737-3742. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:JUNpnas03

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Abstract

A rhodium(III) complex, rac-[Rh(bpy)(2)phzi](3+) (bpy, 2,2'-bipyridine; phzi, benzo[a]phenazine-5,6-quinone diimine) has been designed as a sterically demanding intercalator targeted to destabilized mismatched sites in double-helical DNA. The complex is readily synthesized by condensation of the phenazine quinone with the corresponding diammine complex. Upon photoactivation, the complex promotes direct strand scission at single-base mismatch sites within the DNA duplex. As with the parent mismatch-specific reagent, [Rh(bpy)(2)(chrysi)](3+) [chrysene-5,6-quinone diimine (chrysi)], mismatch selectivity depends on the helix destabilization associated with mispairing. Unlike the parent chrysi complex, the phzi analogue binds and cleaves with high affinity and efficiency. The specific binding constants for CA, CC, and CT mismatches within a 31-mer oligonucleotide duplex are 0.3, 1, and 6 x 10(7) M-1, respectively; site-specific photocleavage is evident at nanomolar concentrations. Moreover, the specificity, defined as the ratio in binding affinities for mispaired vs. well paired sites, is maintained. The increase in affinity is attributed to greater stability in the mismatched site associated with stacking by the heterocyclic aromatic ligand. The high-affinity complex is also applied in the differential cleavage of DNA obtained from cell lines deficient in mismatch repair vs. those proficient in mismatch repair. Agreement is found between photocleavage by the mismatch-specific probes and deficiency in mismatch repair. This mismatch-specific targeting, therefore, offers a potential strategy for new chemotherapeutic design.


Item Type:Article
Additional Information:Copyright © 2003 by the National Academy of Sciences. Contributed by Jacqueline K. Barton, November 26, 2002. Published online before print February 27, 2003, 10.1073/pnas.0537194100 Bioinorganic Chemistry Special Feature Financial support of this research was provided by National Institutes of Health Grant GM33309. H.J. thanks the Deutsche Akademie der Naturfoscher Leopoldina for a postdoctoral fellowship; J.R.H. and J.K. thank the National Institutes of Health for National Research Service Award predoctoral and postdoctoral fellowships, respectively.
Subject Keywords:diimine complexes, prostate-cancer, cell-lines, repair, intercalator, instability, defects
Record Number:CaltechAUTHORS:JUNpnas03
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:JUNpnas03
Alternative URL:http://dx.doi.org/10.1073/pnas.0537194100
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:979
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Nov 2005
Last Modified:26 Dec 2012 08:42

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