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Biological effects of simple changes in functionality on rhodium metalloinsertors

Weidmann, Alyson G. and Komor, Alexis C. and Barton, Jacqueline K. (2013) Biological effects of simple changes in functionality on rhodium metalloinsertors. Philosophical Transactions A: Mathematical, Physical and Engineering Sciences, 371 (1995). Art. No. 20120117. ISSN 1364-503X. PMCID PMC3685451. doi:10.1098/rsta.2012.0117.

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DNA mismatch repair (MMR) is crucial to ensuring the fidelity of the genome. The inability to correct single base mismatches leads to elevated mutation rates and carcinogenesis. Using metalloinsertors–bulky metal complexes that bind with high specificity to mismatched sites in the DNA duplex–our laboratory has adopted a new chemotherapeutic strategy through the selective targeting of MMR-deficient cells, that is, those that have a propensity for cancerous transformation. Rhodium metalloinsertors display inhibitory effects selectively in cells that are deficient in the MMR machinery, consistent with this strategy. However, a highly sensitive structure–function relationship is emerging with the development of new complexes that highlights the importance of subcellular localization. We have found that small structural modifications, for example a hydroxyl versus a methyl functional group, can yield profound differences in biological function. Despite similar binding affinities and selectivities for DNA mismatches, only one metalloinsertor shows selective inhibition of cellular proliferation in MMR-deficient versus -proficient cells. Studies of whole-cell, nuclear and mitochondrial uptake reveal that this selectivity depends upon targeting DNA mismatches in the cell nucleus.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2013 The Author(s). Published by the Royal Society. Published 17 June 2013. One contribution of 18 to a Discussion Meeting Issue ‘Photoactivatable metal complexes: from theory to applications in biotechnology and medicine’. Financial support from the NIH (GM33309) is gratefully acknowledged, and we thank the NSF for a predoctoral fellowship to A.C.K. This project benefited from the use of instrumentation made available by the Caltech Environmental Analysis Center.
Funding AgencyGrant Number
NSF Predoctoral FellowshipUNSPECIFIED
Subject Keywords:metal DNA; mismatches; DNA repair; intercalator
Issue or Number:1995
PubMed Central ID:PMC3685451
Record Number:CaltechAUTHORS:20130718-095506376
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Official Citation:Weidmann AG, Komor AC, Barton JK. 2013 Biological effects of simple changes in functionality on rhodium metalloinsertors. Phil Trans R Soc A 371:20120117.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39438
Deposited By: Tony Diaz
Deposited On:22 Jul 2013 23:33
Last Modified:09 Nov 2021 23:44

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