We report the synthesis of three new complexes related to the achiral [Ru(tpm)(dppz)py](2+) cation (tpm=tripyridazole methane, dppz=dipyrido[3,2-a:2',3'-c]phenazine, py=pyridine) that contain an additional single functional group on the monodentate ancillary pyridyl ligand. Computational calculations indicate that the coordinated pyridyl rings are in a fixed orientation parallel to the dppz axis, and that the electrostatic properties of the complexes are very similar. DNA binding studies on the new complexes reveal that the nature and positioning of the functional group has a profound effect on the binding mode and affinity of these complexes. To explore the molecular and structural basis of these effects, circular dichroism and NMR studies on [Ru(tpm)(dppz)py]Cl(2) with the octanucleotides d(AGAGCTCT)(2) and d(CGAGCTCG)(2), were carried out. These studies demonstrate that the dppz ligand intercalates into the G(2)-A(3) step, with {Ru(tpm)py} in the minor groove. They also reveal that the complex intercalates into the binding site in two possible orientations with the pyridyl ligand of the major conformer making close contact with terminal base pairs. We conclude that substitution at the 2- or 3-position of the pyridine ring has little effect on binding, but that substitution at the 4-position drastically disrupts intercalative binding, particularly with a 4-amino substituent, because of steric and electronic interactions with the DNA. These results indicate that complexes derived from these systems have the potential to function as sequence-specific light-switch systems.
The interaction of the ethylene-bipyridyldiylium-naphthaphenazine dication, dqdppn, with several hexa- and octanucleotide duplexes has been studied using CD and NMR. Taken together, these studies reveal that with the hexanucleotide, dqdppn intercalates into the terminal base pair, and causes a large twisting of the terminal base pair. In contrast, with all three octanucleotides, dqdppn intercalates more centrally within the sequence. The NMR-derived structures of two of the binding complexes demonstrate that dqdppn intercalates from the major groove in an unusual 'side-on' geometry, rather than threading through the helix. An analysis of these results indicates that the preferred binding site is not sequence-specific, but primarily at the most conformationally flexible DNA step.
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