(N7)-Platination and its effect on (N1)H-acidification in nucleoside phosphate derivatives

Abstract

Pt(II) coordination, like of cis-(NH3)2Pt(II), affects the acid-base properties of guanosine derivatives. The acidity constants of such complexes are calculated by curve-fitting procedures using published 1H NMR shift data measured in aqueous solution (D2O) in dependence on pH (pD). Comparison of the pKa values of the ligands with those of the Pt(II) complexes reveals the expected behavior for (N7)-platination, i.e., (N1)H sites are acidified due to charge repulsion. These effects of Pt(II) are compared with those of Ni2+ and Cd2+, allowing predictions for the acidification of Zn2+. Studied are the cis-(NH3)2Pt(II) complexes of inosylyl(3′→5′)inosine, guanylyl(3′→5′)guanine (GpG)−, its 2′-deoxy relative d(GpG)−, and its phosphorylated derivative d(pGpG)3−. The Pt(II) effect is mostly rather symmetrical, like with d(CpGpG)2−, but it can also be quite asymmetrical, like with d(CpCpGpG)3− or in the cyclohexylamine-substituted Cisplatin complex of d(GpG)−. Potential consequences for base pairing between the platinated guanine and the complementary cytosine are discussed. It is proposed that partial deprotonation of dG under the influence of Pt(II) at physiological pH leads in water to a marked reduction in pairs with intact Watson–Crick hydrogen bonds, thereby adding to the well established thermal destabilization of double-stranded DNA by G,G intrastrand cross-links of Cisplatin.