Redox pathways in DNA oxidation: Kinetic studies of guanine and sugar oxidation by para-substituted derivatives of oxoruthenium(IV)

The oxidation of nucleotides and DNA by a series of complexes based on Ru(t py)(bpy)O2+ (1) was investigated (tpy = 2,2':6',2"-terpyridine; bpy = 2,2'- bipyridine). These complexes were substituted with electron-donating or -wi thdrawing substituents in the para positions of the polypyridyl ligands so that the oxidation potentials of the complexes were affected but the reacti on trajectory of the oxo ligand with DNA was the same throughout the series . The prepared complexes were (with E-1/2(III/II) and E-1/2(IV/III) values in volts versus Ag/AgCl) Ru(4'-EtO-tpy)(bpy)O2+ (2; 0.47, 0.60), Ru(4'-Cl-t py)(bpy)O2+ (3; 0.55, 0,63), Ru(tpy)(4,4'-Me-2-bpy)O2+ (4; 0.48, 0.62), and Ru(tpy)(4,4'-Cl-2-bpy)O2+ (5; 0.58, 0.63). The complexes oxidized deoxycyt osine 5'-monophosphate at the sugar moiety (k = 0.24-0.47 M-1 s(-1)) and gu anosine 5'-monophosphate at the base moiety (k = 6.1-15 M-1 s(-1)). The rat e constants increase across these ranges in the order 3 > 1 > 4 > 2, which is the same order as the redox potentials of the complexes. The effect of t he base on these reactions was also studied, and xanthine was found to reac t with I much faster than guanine while hypoxanthine was less reactive than the sugar moiety. The complexes all oxidized oligonucleotides to generate base-labile lesions at guanine and a combination of spontaneous and base-la bile scission at the sugar functionalities. The selectivity of cleavage in duplex and single-stranded DNA was not a strong function of the substituent s on the metal complex.