Dinuclear ruthenium(ii) complexes with flexible bridges as non-duplex DNA binding agents

Abstract

The stereoisomers of a series of dinuclear ruthenium(ii) complexes [{Ru(phen)(2)}(2)(micro-BL)](4+) (phen = 1,10-phenanthroline) with flexible bridging ligands (BL) bb2 {1,2-bis[4(4'-methyl-2,2'-bipyridyl)]ethane}, bb5 {1,5-bis[4(4'-methyl-2,2'-bipyridyl)]pentane}, bb7 {1,7-bis[4(4'-methyl-2,2'-bipyridyl)]heptane}, and bb10 {1,10-bis[4(4'-methyl-2,2'-bipyridyl)]decane} have been synthesised. Their binding to a control dodecanucleotide, d(CCGGAATTCCGG)(2), and a tridecanucleotide, d(CCGAGAATTCCGG)(2), which contains a single adenine bulge have been studied using fluorescence displacement assays involving intercalating and groove-binding dyes, equilibrium dialysis and binding affinity chromatography. The fluorescence intercalator displacement (FID) assay indicated that LambdaLambda-[{Ru(phen)(2)}(2)(micro-bb7)](4+) had the greatest binding affinity with all the oligonucleotides, whereas an analogous fluorescence technique using a minor-groove binding dye, equilibrium dialysis and affinity binding chromatography showed that DeltaDelta-[{Ru(phen)(2)}(2)(micro-bb7)](4+) had the strongest binding. An (1)H NMR study of the binding of the DeltaDelta-enantiomer of [{Ru(phen)(2)}(2)(micro-bb7)](4+) to d(CCGAGAATTCCGG)(2) confirmed the selectivity of the metal complex for the bulge site and provided the basis for an energy-minimised binding model of the dinuclear ruthenium complex with the single adenine bulge containing trinucleotide. The binding model demonstrated the ability of the flexibly-linked complex to follow the curvature of the DNA minor groove.

Mechanism of Cytotoxicity and Cellular Uptake of Lipophilic Inert Dinuclear Polypyridylruthenium(II) Complexes

“…However, other mechanisms, for example, modification of cell membrane function and cell adhesion, have been proposed. [11,43] In agreement with studies by Kelly and co-workers [44] and our own previous studies, [19] the results of our ITC experiments demonstrate that the dinuclear complexes have a moderately strong affinity for DNA. Furthermore, the results of this study indicate that the binding is entropically driven and enthalpically opposed.…”

“…[19,21] Tetraethylammonium chloride monohydrate, tetra-n-pentylammonium chloride, tetra-n-butylammonium chloride, tetrapropylammonium chloride, chloroquine diphosphate, ammonium chloride, chlorpromazine hydrochloride, filipin (from Streptomyces fulrissimus) and 5-(N,N-dimethyl) amiloride hydrochloride were purchased from Aldrich. Dimethyl sulfoxide (DMSO; biological grade), CT-DNA, procainamide hydrochloride, oligomycin A, 2-deoxy-d-glucose, bovine serum albumin (BSA) and sodium azide were purchased from Sigma.…”

“…H NMR studies of the binding of this family of complexes to various oligonucleotides have shown that they bind in the DNA minor groove, particularly at nonduplex sites, such as bulges. [19] Binding of these complexes to CT-DNA is entropically favoured and enthalpically opposed, which is consis- tent with groove binding. [20] Further studies have shown that while the binding affinity of shorter chain-length analogues is higher in bulge-containing oligonucleotides, longer chainlength analogues display no preference for bulge sites over standard duplex DNA.…”

The interesting DNA-binding properties of three novel dinuclear Ru(II) complexes with varied lengths of flexible bridges

“…Because the two metal centers are rigidly linked and consequently can not follow the curvature of the DNA, only one metal center may bind deeply to the DNA with the second metal center projecting out of the DNA [21][22][23][24][25][26][27][28][29][30][31][32][33][34]. The other kind of dinuclear Ru(II) complexes carrying a flexible chain should overcome the limitations and potentially allow both the metal centers to bind optimally to the DNA [35][36][37][38][39][40][41]. Since the chain length of the linker for dinuclear Ru(II) complexes has been reported to be a crucial factor in determining the binding efficiency [17], we have synthesized three novel dinuclear Ru (II) complexes with different lengths of flexible bridges as linkers of the two [Ru(bpy) 2 (pip)] 2+ {bpy = 2,2′-bipyridine; pip = 2-phenylimidazo [4,5-f] [1,10]phenanthroline}-based subunit [42], and studied their DNA binding properties.…”

Photoactive RuII–Polypyridyl Complexes that Display Sequence Selectivity and High‐Affinity Binding to Duplex DNA through Groove Binding

“…Keywords: DNA · groove binding · luminescence · molecular recognition · ruthenium affinity through major-groove binding, [11] whereas Keene and collaborators have explored the application of optically resolved mono-and dinuclear Ru II complexes as minorgroove binding probes for canonical duplexes, mismatches, and hairpins. [12] In recent work, the Thomas and Otsuki groups have demonstrated that a dinuclear Ru II complex, which is structurally related to the minor-groove binder berenil, functions as a colorimetric sensor for DNA sequence and structure. [13] However, the effect of hydrogen-bonding moieties on the physical and biophysical properties of such systems is virtually unstudied.…”