Bridging Ligand Length Controls AT Selectivity and Enantioselectivity of Binuclear Ruthenium Threading Intercalators

Abstract

The slow dissociation of DNA threading intercalators makes them interesting as model compounds in the search for new DNA targeting drugs, as there appears to be a correlation between slow dissociation and biological activity. Thus, it would be of great value to understand the mechanisms controlling threading intercalation, and for this purpose we have investigated how the length of the bridging ligand of binuclear ruthenium threading intercalators affects their DNA binding properties. We have synthesised a new binuclear ruthenium threading intercalator with slower dissociation kinetics from ct-DNA than has ever been observed for any ruthenium complex with any type of DNA, a property that we attribute to the increased distance between the ruthenium centres of the new complex. By comparison with previously studied ruthenium complexes, we further conclude that elongation of the bridging ligand reduces the sensitivity of the threading interaction to DNA flexibility, resulting in a decreased AT selectivity for the new complex. We also find that the length of the bridging ligand affects the enantioselectivity with increasing preference for the ΔΔ enantiomer as the bridging ligand becomes longer.

Thread Insertion of a Bis(dipyridophenazine) Diruthenium Complex into the DNA Double Helix by the Extrusion of AT Base Pairs and Cross‐Linking of DNA Duplexes

“…[6] For mononuclear Ru-dppz compounds, it has been shown recently by X-ray crystallography that the dppz ligand can invade the base-pair stack either by intercalation or by insertion at a mismatched site, and that in the latter case, the extruded mismatched bases stack on the ancillary ligands. [10,11] Scheme 1. [9] However, structural information on the threaded intercalated state of binuclear Ru compounds with the bidppz ligand is limited.…”

Investigation of Non-covalent Interactions of Metal Complexes with DNA in Cell-free Systems

“…Fluorescence methods can also be used to monitor dynamic processes such as the folding of oligonucleotides into quadruplex structures [77] or the threading of a dumbbell-shaped dinuclear metallointercalator through the base-pair stack of a DNA duplex [78].…”

Threading Polyintercalators with Extremely Slow Dissociation Rates and Extended DNA Binding Sites

“…PNAs and triplex-forming bicyclic oligonucleotides have been described with long lifetimes and high affinities. 10,11 While threading mono- and bisintercalators continue to be of interest, 12–15 reports of longer polyintercalators, threading or not, are rare. 16–21 …”