The goal of this research program is the design, construction and application of transition metal complexes which recognize and react at specific nucleic acid sites. Such design will be important in the development of new chemotherapeutic agents and new tools for biotechnology. Transition metal complexes have been constructed in the past grant period which target DNA sites non-covalently primarily based upon shape-selection, matching the shape and symmetry of the metal complex to the DNA site. Here is proposed the construction of complexes which incorporate both shape-selective elements and hydrogen bonding functionalities. Rhodium complexes containing novel ancillary ligands and the phenanthrenequinone diimine (phi) ligand will be prepared, since phi complexes of rhodium were found to bind DNA avidly by intercalation and with photoactivation to promote strand cleavage. Intercalation therefore anchors the complex in the DNA major groove and the cleavage marks the site recognized. Binuclear bis-intercalating complexes are also proposed for synthesis, so as to extend the site-size being targeted. Dipyridophenazine (dppz) complexes of ruthenium appended to oligonucleotides will be developed as diagnostic probes for nucleic acid sequences, since Ru(dppz) may luminesce only upon hybridization to the target sequence. Ruthenium complexes with a central DNA-binding domain and two tethered 'arms"""""""" for chelating additional metal ions to cleave DNA hydrolytically will also be examined towards the development of artificial restriction enzymes. Site-selectivities for all the complexes prepared will be determined in cleavage studies first on 32P- end-labeled restriction fragments and then quantitatively on oligonucleotides. Full cleavage product analysis will also be conducted. The structures of metal complexes specifically bound to their target site will be characterized using NMR and crystallography. Those complexes already designed which target sites based upon shape selection will also be applied in probing nucleic acid sites. Crystallographically characterized sequences both as oligonucleotides in solution and cloned into longer fragments will be mapped using the shape-selective probes. Conformationally distinct sites such as cruciforms, mismatches, and sites of bending will also be examined in cleavage experiments using the different structural transition metal probes. These shape-selective complexes may also be uniquely suited to probe RNA structures. Rh(phen)2phi3+ has been found to target sites of tertiary structure in tRNA and this complex will be applied first to RNA oligonucleotide structures to establish the bases for recognition and then to poorly understood RNA molecules in delineating their tertiary structures.

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National Institute of General Medical Sciences (NIGMS)
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Metallobiochemistry Study Section (BMT)
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California Institute of Technology
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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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