Structure of the Complex of [Ru(tpm)(dppz)py]²⁺ with a B‐DNA Oligonucleotide—A Single‐Substituent Binding Switch for a Metallo‐Intercalator

Abstract

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.

Cell‐Selective, Apoptosis‐inducing Rhodium(III) Crown Thiaether Complexes

“…However, it should be noted that a much higher slope of 0.85 was reported for the analogous [(tpm)RhCl(dppz)]Cl 2 complex. [12] A lower slope value of 0.34 is observed for the dpq complex, in accord- [31,32] for UV/ Vis titration data of [( [9] ance with the findings of the 1 H NMR and UV/Vis titrations, and indicates a weaker intercalative binding mode for 7. Competition between intercalation and alternative groove-binding or covalent-binding modes cannot be ruled out on the basis of this evidence.…”

“…The model assumes non-cooperative, nonspecific binding with the existence of one type of discrete binding 3 + , where tpm = tris(pyrazolyl)methane, py = pyridine, H 2 metOMe = l-methionyl methyl ester, respectively. [31,32] The…”

Initial DNA Interactions of the Binuclear Threading Intercalator Λ,Λ‐[μ‐bidppz(bipy)4Ru2]4+: An NMR Study with [d(CGCGAATTCGCG)]2

“…Recent crystal and NMR structure studies of monomeric Ru II compounds interacting with oligonucleotide duplexes suggest that intercalation is sequence dependent, and that additional binding sites on the DNA may be exploited 8. 9…”

“…[7] Recent crystal and NMR structure studies of monomeric Ru II compounds interacting with oligonucleotide duplexes suggest that intercalation is sequence dependent, and that additional binding sites on the DNA may be exploited. [8,9] Abstract: Binuclear polypyridine ruthenium compounds have been shown to slowly intercalate into DNA, following a fast initial binding on the DNA surface. For these compounds, intercalation requires threading of a bulky substituent, containing one Ru II , through the DNA base-pair stack, and the accompanying DNA duplex distortions are much more severe than with intercalation of mononuclear compounds.…”

The Structure of Linkers Affects the DNA Binding Properties of Tethered Dinuclear Ruthenium(II) Metallo‐Intercalators

“…Although the 3‐pyNH 2 ‐based complex binds by intercalation with affinities that are comparable to the parent compound, the coordinated 4‐pyNH 2 complex is a low affinity, non‐intercalating, groove binder. NMR studies revealed that this is due to unfavourable interactions made by the 4‐NH 2 of the coordinated pyridine projecting into the minor groove of the duplex . This suggests that 4‐py‐based connectivity within the tether of 6 may have an unfavourable effect on its binding characteristics.…”