Oligonuclear polypyridylruthenium(ii) complexes incorporating flexible polar and non-polar bridges: synthesis, DNA-binding and cytotoxicity

Abstract

The paper reports the synthesis and characterisation of a series of flexible di-bidentate bridging ligands in which two 4-methyl-2,2′-bipyridine groups are linked at the 4′-position by polymethylene (bb_n), linear polyether (bbO_n) or linear alkylamine (bbN_n) chains of varying length (n). The enantiomers (ΔΔ/ΛΛ) of the rac forms of the ruthenium(II) dinuclear complexes incorporating these ligands – i.e. [{Ru(phen)₂}₂(μ-BL)]⁴⁺ (phen = 1,10-phenanthroline; BL = bb_n, bbO_n or bbN_n) – have been isolated by reaction of Δ- or Λ-[Ru(phen)₂(py)₂]²⁺ (py = pyridine) with the respective bridging ligands. Mononuclear species - in which only one of the bidentate moieties of the bridging ligand is coordinated – have also been isolated, as well as trinuclear and tetranuclear species involving the bb₇ bridge. Fluorescence displacement studies of the DNA-binding of the dinuclear complexes containing the bbO_n and bbN_n bridges generally revealed a lower affinity than their bb_n analogues for an oligonucleotide containing a single bulge site; the mononuclear complexes showed a lower affinity - and the trinuclear and tetranuclear complexes a higher affinity – than the dinuclear species, revealing an interesting interplay of lipophilicity, electrostatics and size in the complex/nucleic acid interaction. Cytotoxicity studies of these complexes against a murine leukaemia cell line revealed that the presence of the polyether or polyamine links in the chain lowered the cytotoxicity compared with their polymethylene analogues, and that the bb₇-bridged trinuclear and tetranuclear complexes showed considerably enhanced cytotoxicity compared with the dinuclear Rubb₇ analogue.