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

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Davies, MS
Berners-Price, SJ
Hambley, TW
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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 ± 0.17) × 10-5 s-1 for -AG- and -GA-, respectively. The rates of ring closure from A/Cl monofunctional species, treated as direct to chelate, are (0.16 ± 0.06) × 10-5 (-AG-) and (2.1 ± 0.7) × 10-5 s-1 (-GA-). The rate constants found for the reactions between the oligonucleotides and cis-[Pt(15NH3)2(OH2)2]2+ are, for formation of the G/H2O monofunctional adducts, 0.42 ± 0.01 (-AG-) and 0.50 ± 0.01 M-1 s-1 (-GA-). Formation of A/H2O adducts is not observed for either -AG- or -GA-. Rates of ring closure from the G/H2O adducts are (3.71 ± 0.05) × 10-5 (-AG-) and (0.162 ± 0.005) × 10-5 s-1 (-GA-). The rate of formation of monofunctional adducts from cis-[Pt(15NH3)2(OH2)2]2+ are similar for -AG- and -GA-, whereas for cisplatin a clear preference is observed for -AG- over -GA-. Closure to form the bifunctional adduct is more rapid in the case of -AG- than -GA- for both cisplatin and cis-[Pt(15NH3)2(OH2)2]2+, but the difference is greater for cis-[Pt(15NH3)2(OH2)2]2+. It is concluded that the bifunctional intrastrand adduct profile observed when cisplatin binds to DNA is substantially controlled by the rate of formation of monofunctional adducts at the different X-purine-purine-X sequences. A slow rate of closure also contributes to the nonformation of the bifunctional GpA adduct.

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Journal of the American Chemical Society

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