Rates of Platination of AG and GA Containing Double-Stranded Oligonucleotides: Insights into Why Cisplatin Binds to GG and AG but Not GA Sequences in DNA

Abstract

The reactions of the self-complementary 14-base-pair duplexes 5‘-d(AATTAGTACTAATT)-3‘ (-AG-) and 5‘-d(AATTGATATCAATT)-3‘ (-GA-) with 15N-cisplatin, (cis-[PtCl2(15NH3)2]) (pH 6.0, T = 298 K) and cis-[Pt(15NH3)2(OH2)2]2+ (pH 4.9, T = 288 K), have been investigated using [1H,15N] HSQC 2D NMR spectroscopy. Reactions involving cisplatin progress via the hydrolysis product cis-[PtCl(NH3)2(OH2)]+. Two major -AG- monofunctional adducts, G(6)/Cl and A(5)/Cl, form at rates of 1.06 ± 0.06 and 0.149 ± 0.014 M-1 s-1, respectively. The major Pt-GA- monofunctional adduct G(5)/Cl forms at a rate of 0.023 ± 0.002 M-1 s-1, and several minor adducts, including A(6)/Cl (0.0054 ± 0.0010 M-1 s-1), are observed. Closure from the monofunctional/Cl adducts proceeds via an aquated species for both -AG- and -GA-. The rates of hydrolysis from the G/Cl adducts to the G/H2O species are (1.55 ± 0.05) × 10-5 s-1 with -AG- and (0.198 ± 0.008) × 10-5 s-1 with -GA-, and the rates of closure to the chelates are (9.8 ± 0.9) × 10-5 and (0.69 ...