title: Biological effects of simple changes in functionality on rhodium metalloinsertors.
abstract: 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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Alyson G
authors.initials: AG
authors.lastname: Weidmann
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Komor
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Barton
mesh_terms: D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000187:drug effects / Q000235:genetics*; D012238:Rhodium / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000502:physiology*
chemical_list: D004247:DNA; D012238:Rhodium
keywords: DNA repair; intercalator; metal DNA; mismatches