The objective is to design chiral metal complexes as site-specific probes to examine with molecular detail the variations in structure of DNA along the strand. Chiral metal complexes will be developed that recognize and chemically target DNA conformations. Using these probes, we will map the local variations in DNA secondary structure that occur in constructed plasmids and native DNAs. We may then determine rules governing the local conformations adopted by short DNA sequences and whether and how local variations in DNA secondary structure might play a role in the expression of genetic information. The application of these site-specific complexes will be usedful as well pharmacologically and as tools in molecular biology. Recognition is based on binding to DNA by the family of chiral tris- and bis(phenanthroline) metal complexes either by intercalation, in a groove bound mode, or by coordination. Enantiomeric discrimination is found for each mode. Coupling recognition to site-specific reaction has been accomplished through photoactivated oxidative chemistry. We have developed, based on the enantiospecific intercalation, a photoactivated complex that cleaves left-handed sites, through groove binding, a complex that cleaves, with photoactivation and enantioselectively, A-form polynucleotides and through direct coordination, chiral probes for homopurine sites. We will prepare new metal complexes using mixed substituted phenanthroline and diimine ligands to examine systematically the effects of size, charge, hydrophobicity, and in particular, directed hydrogen bonding on sequence and site-selectivity; to delineate structurally and dynamically the interactions with different helical forms through binding and helical unwinding experiments, NMR, crystallography, and photophysical techniques; to characterize and correlate cleavage with binding. A novel double-stranded conformation-specific nuclease will also be developed to cleave gene segments. We can then apply these molecular tools to examine the structure of DNA. Plasmids with short defined inserts that vary in length and base sequence will be constructed and mapped with the probes to determine factors required to adopt regions of unique structure. Native DNA substrates will also be examined to determine as a function of supercoiling, protein binding, and site deletion both local and distal effects on structure, and to correlate sites of biological activity with conformationally distinct structures recognized by the chiral metal complexes.
| Boyle, Kelsey M; Barton, Jacqueline K (2018) A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair-Deficient Cancers. J Am Chem Soc 140:5612-5624 |
| Nano, Adela; Boynton, Adam N; Barton, Jacqueline K (2017) A Rhodium-Cyanine Fluorescent Probe: Detection and Signaling of Mismatches in DNA. J Am Chem Soc 139:17301-17304 |
| Bailis, Julie M; Weidmann, Alyson G; Mariano, Natalie F et al. (2017) Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells. Proc Natl Acad Sci U S A 114:6948-6953 |
| Boynton, Adam N; Marcélis, Lionel; McConnell, Anna J et al. (2017) A Ruthenium(II) Complex as a Luminescent Probe for DNA Mismatches and Abasic Sites. Inorg Chem 56:8381-8389 |
| Arnold, Anna R; Grodick, Michael A; Barton, Jacqueline K (2016) DNA Charge Transport: from Chemical Principles to the Cell. Cell Chem Biol 23:183-197 |
| Boyle, Kelsey M; Barton, Jacqueline K (2016) Targeting DNA Mismatches with Rhodium Metalloinsertors. Inorganica Chim Acta 452:3-11 |
| Boynton, Adam N; Marcélis, Lionel; Barton, Jacqueline K (2016) [Ru(Me4phen)2dppz](2+), a Light Switch for DNA Mismatches. J Am Chem Soc 138:5020-3 |
| Weidmann, Alyson G; Barton, Jacqueline K (2015) A monofunctional platinum complex coordinated to a rhodium metalloinsertor selectively binds mismatched DNA in the minor groove. Inorg Chem 54:9626-36 |
| Weidmann, Alyson G; Komor, Alexis C; Barton, Jacqueline K (2014) Targeted Chemotherapy with Metal Complexes. Comments Mod Chem A Comments Inorg Chem 34:114-123 |
| Komor, Alexis C; Barton, Jacqueline K (2014) An unusual ligand coordination gives rise to a new family of rhodium metalloinsertors with improved selectivity and potency. J Am Chem Soc 136:14160-72 |
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