Coligand tuning of the DNA binding properties of bioorganometallic (η6-arene)ruthenium(ii) complexes of the type [(η6-arene)Ru(amino acid)(dppz)]n+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine), n = 1–3

Abstract

The DNA binding of cationic complexes of the type [(η⁶-arene)Ru(Aa)(dppz)] (CF₃SO₃)_n (arene = C₆H₆, Me₃C₆H₃, C₆Me₆; dppz = dipyrido[3,2-a:2′,3′-c]phenazine; n = 1, Aa = AcH₋₁cysOH 4–6; n = 2, Aa = AcmetOH 7–9; n = 3, Aa = H₂metOMe 10–12) containing S-coordinated amino acids (HcysOH = L-cysteine, HmetOH = L-methionine) has been studied by UV-vis titration and 2D-NOESY. Stable intercalative binding is indicated for these complexes by their steady decrease in absorbance at maxima between 350 and 390 nm on titration with CT DNA and the bathochromic shifts of these absorption maxima. Taking 4–12 and the analogous (η⁶-C₆Me₆)Ru^II complexes of the tripeptides HglyglycysOH (n =1, 13) and HglyglymetOH (n = 2, 15; HglyOH = glycine) into account, typical DNA binding constant (K_b) ranges can be established for (η⁶-arene)Ru^II complexes: 5.3 × 10⁴–1.6 × 10⁵ M⁻¹ for monocations, 6.3 × 10⁵–9.9 × 10⁵ M⁻¹ for dications and 1.6 × 10⁶–5.5 × 10⁶ M⁻¹ for trications. These K_b values clearly reflect a strengthening of electrostatic interactions with the negatively charged phosphodiester backbone of DNA as the total cation charge increases. A consistent trend to higher K_b values is also apparent for the coligand series C₆H₆ < Me₃C₆H₃ < C₆Me₆ with the relative increase being, in general, more pronounced for C₆H₆/Me₃C₆H₃ pairs. The strong electronic influence of the coligand on dppz intercalation is also reflected by marked increases ΔT_m of 18.2–18.5 °C in the CT DNA thermal denaturation temperature for di- and tri-cationic (η⁶-C₆Me₆)Ru^II complexes. Upfield ¹H NMR chemical shifts and characteristic NOE cross peaks for the dppz protons of the 1 ∶ 1 complex formed between 9 and d(GTCGAC)₂ are consistent with a side-on intercalation adjacent to T₂ from the major groove.