The objective of the proposed work is to develop tris(phenanthroline) metal complexes as stereoselective probes for DNA helicity and as chiral drugs that bind to and modify either right- or left-handed DNA duplexes. We have already observed enantiomeric selectivity by (phen)3Zn2+ and ruthenium complexes in DNA intercalation. This chiral discrimination in drug binding will now be applied to i) establish the conditions under which the left-handed helix is formed; ii) describe the DNA duplex structure (both left- and right-handed) and characterize stereospecific intercalation into the helix; and iii) prepare reagents that modify the DNA duplex with high stereoselectivity. Sequence dependent conformational changes in the duplex structure, such as to left-handed Z-DNA, require clarification since they may be important in regulating gene expression. Intercalating agents in general have been useful in probing regular B-DNA structure and clinically as antitumor chemotherapeutic agents. Enantiomeric complexes of ruthenium, osmium, platinum and cobalt with phenanthroline, disubstituted-phenanthrolines and phenanthrenes as ligands will be prepared to obtain chiral metallointercalators that differ in charge, hydrophobicity, hydrogen bonding ability and, importantly, in the steric bulk of the non-intercalated ligands. The compounds will be resolved by chiral chromatography and characterized with respect to structure and spectroscopic parameters. Using dialysis and equilibrium pelleting experiments, binding parameters governing the interaction of the chiral complexes with both right- and left-handed DNA will be determined. The systematic variation of the structure of the enantiomeric complexes and its correlation with selective DNA binding will provide a gauge in solution for both the helical sense and groove size. A comparison in binding between enantiomers to DNAs of defined sequence, DNAs modified with antitumor drugs, and DNAs in protein-bound complexes will be made to establish unambiguously where the left-handed helix is formed. The chiral ruthenium complexes will be used as a chromosomal stain for fluorescence microscopy. NMR, fluorescence and crystallography will be conducted to describe in detail intercalation of the enantiomeric pair into each of the DNA helices. Finally either through a redox-active tris(phenanthroline) metal complex or by attaching a reactive moiety onto the chiral intercalator, stereoselective nicking will be examined.
| 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 |
| 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 |
| 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 |
| 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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