Structural insights into the DNA binding properties of Ruthenium Polypyridyl complexes

McQuaid, K. ORCID: https://orcid.org/0000-0002-3222-5584 (2020) Structural insights into the DNA binding properties of Ruthenium Polypyridyl complexes. PhD thesis, University of Reading. doi: 10.48683/1926.00120360

Abstract/Summary

Ruthenium polypyridyl complexes are a class of ruthenium centred coordination complexes that are identified by their coordinate sphere of polypyridine ligands, such as phen or TAP (phen = 1,10-phenanthroline, TAP = 1,4,5,8-tetraazaphenanthrene), and by their wealth of photophysical properties. Heteroleptic variations on this, such as [Ru(phen)2(dppz)]2+, have shown prospective utility in a range of remedial therapeutics and diagnostics based predominantly on their ability to bind to and intercalate into DNA and its many morphologies. In this thesis, a deeper understanding of these binding modes is strived for so as to better develop a next generation of metallic therapeutic agents. A small range of derivatives, based on the parent complex [Ru(TAP)2(dppz)]2+, are structurally characterised in absence and presence of the DNA decamer d(TCGGCGCCGA) to better understand how substitution affects intercalation. X-ray crystallographic data of the systems shows that incorporation of simple electron withdrawing substituents onto the distal ring of dppz (such as -C≡N or -NO2) can direct base pairing at adjacent steps, causing previously flipped out nucleobases to reform a complete binding cavity. Next the complex rac-[Ru(TAP)2(11-CN-dppz)]2+ is shown to stabilise and bind, with topological preference, to the G-quadruplex forming sequence d(TAGGGTTA), binding adjacent to the G-stack. Crystallography elucidates a number of enantiospecific interactions that direct the folded topology, and is used to explain the motif-specific luminescence response of a light switch analogue complex. Further structural studies led to a second G-quadruplex structure containing the parent complex and a truncated sequence. Unlike the first, this structure contains no guanine interaction but contains multiple novel T/A binding modes such as semi-intercalation, mismatch binding, and major groove binding, all of which are compared to the potential binding pockets in the loop regions of telomeric DNA. Lastly, a number of polypyridyl complexes are investigated in relation to their G-quadruplex binding efficacy. Of particular note is the complex Λ-[Ru(phen)2(Aqphen)]2+ which is demonstrated to greatly inhibit polymerisation of a G-quadruplex sequence in vitro and then shown using an immunofluorescence assay, to bind strongly to G-quadruplexes in vivo, displacing the G-quadruplex specific BG4 antibody.

Item Type	Thesis (PhD)
URI	https://reading-clone.eprints-hosting.org/id/eprint/120360
Identification Number/DOI	10.48683/1926.00120360
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy
Date on Title Page	2019
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