Effects of trans-pyridine ligands on the interactions of Ru~(II) and Ru~(III) ammine complexes N7-coordinated to purine nucleosides and DNA

摘要

DNA binding by trans-[(H_2O)(Pyr)-(NH_3)_4Ru~(II)]~(2+) (Pyr=py, 3-phpy, 4-phpy, 3-bnpy, 4-bnpy) is highly selective for G~7 with K_G=1.1x10~4 to 2.8x10~4, with the more hydrophobic Pyr ligands exhibiting slightly higher binding. A strong dependence on ionic strength indicates that ion-pairing with DNA occurs prior to binding. At #mu#=0.05, d[Ru~(II)-DNA]/dt=k[Ru~(II)][DNA], where k=0.17-0.21 M~(-1) s~(-1) with the various Pyr ligands. The air oxidation of [(py)(NH_3)_4Ru~(II)]_n-DNA to [(py)(NH_3)_4Ru~(III)]_n-DNA at pH 6 occurs with a pseudo-first-order rate constant of k_(obs)=5.6x10~(-4) s~(-1) at #mu#=0.1, T=25 deg C. Strand cleavage of plasmid DNA appears to occur by both Fenton/Haber-Weiss chemistry and by base-catalyzed routes, some of which are independent of oxygen. Base-catalyzed cleavage is more efficient than O_2 activation at neutral pH and involves the disproportionation of covalently bound Ru~III and, in the presence of O_2, Ru-facilitated autoxidation to 8-oxoguanine. Disproportionation of [py(NH_3)_4Ru~(III)]_n-DNA occurs according to the rate law: d[Ru~(II)-G_(DNA)]/dt=k_0[Ru~(III)-G_(DNA)] + k_1[Ru~(III)-G_(DNA)][OH]~-, k_0=5.4x10~(-4) s~(-1) and k_1=8.8 M~(-1) s~(-1) at 25 deg C, #mu#=0.1. The appearance of [(Gua)(py)(NH_3)_4Ru~(III)] under argon, which occurs according to the rate law: d[Ru~(III)-G]/dt=k_0[Ru~(III)-G_(DNA)] + k_1[OH~-][Ru~(III)-G_(DNA)] (k_0=5.74x10~(-5) s~(-1), k_1=1.93x10~(-2) M~(-1) s~(-1) at T=25 deg C, #mu#=0.1), is consistent with lysis of the N-glycosidic bond by Ru~(IV)-induced general acid hydrolysis. In air, the ratio of [Ru-8-OG]/[Ru-G] and their net rates of appearance are 1.7 at pH 11, 25 deg C. Small amounts of phosphate glycolate indicate a minor oxidative pathway involving C4' of the sugar. In air, a dynamic steady-state system arises in which reduction of Ru~(IV) produces additional Ru~(II).