Seeking selective DNA binding through synergistic design of ruthenium(II) complexes

Abstract

Ruthenium(II) polypyridyl complexes are inherently stable, chiral and in many cases fluorescent. These characteristics make them excellent probes for DNA where they interact with DNA through physical interactions. However, their binding is nonselective. Therefore, complexes that can be tailored to bind DNA selectively are of great interest. Sequence selective polyamides comprising of 1-methylimidazole (Im) and 1-methylpyrrole (Py), recognise and bind Watson-Crick base pairs via the minor groove thus conjugating these molecules to ruthenium(II) polypyridyl complexes may produce fluorescent metal complexes that can target and binding to specific sequences of DNA. These sequence selective polyamides are made from Py, Im and/or 1-methyl- 5-hydroxypyrrole (Hp) monomers connected by protein-like glycosidic bonds. Like amino acids, they too have an amino- and carboxy- terminus, which gives them directionality when they bind to DNA. In this thesis, the synthesis, resolution, characterisation and DNA affinity of ruthenium(II) complexes with a DNA sequence selective polyamide are reported. Complexes based on the analogues of [Ru(phen)2(dpq)]2+, (where phen = 1,10-phenanthroline and dpq = dipyrido[6,7-d:2'3''-f]quinoxaline), have been synthesised and coupled by a combination of solution and solid phase chemistry. They contain two phen ligands as the ancillary components and a substituted dpq ring through which a sequence selective polyamides containing Im and Py rings is attached. The complexes, I-/I"-[Ru(phen)2polyamide 1](PF6)2 (where polyamide 1 = 3-[(1-methyl-4-{4-[(1-methyl-4-{3-[(dipyrido[6,7-d:2',3''-f]quinoxaline-2-carbonyl)-amino]-propionyl amino}-1H-imidazole-2-carbonyl)-amino]-butyrylamino}-1H-pyrrole-2-carbonyl)- amino]-propionic acid) and I>-/I"-[Ru(phen)2(polyamide 2)](PF6)2 (where polyamide 2= 3-[(1-methyl-4-{4-[(1-methyl-4-{3-[(dipyrido[6,7-d:2',3''-f]quinoxaline-2-carbonyl)-amino]-hexanoylamino}-1H-pyrrole-2-carbonyl)-amino-1H-pyrrole-2-carbonyl}-amino)-1H-pyrrole-2-carbonyl]-amino}-propionic acid) are enantiomerically enriched. Each complex has been characterised by proton nuclear magnetic resonance spectroscopy (1H NMR), nuclear Overhauser spectroscopy (NOESY), electrospray ionisation mass spectrometry (ESI-MS) and circular dichroism (CD) and their DNA binding interactions have been studied by linear dichroism (LD). Anticancer activity was determined using L1210 murine leukemia cells and preliminary antibacterial activity was studied using Kirby-Bauer disk assays using Staphylococcus aureus, Streptomyces griseus, Escherichia coli and Pseudomonas aeroginosa bacterial strains.

Date of Award	2011
Original language	English