Synthesis and NMR Structural Studies of the Adduct of trans -Diamminedichloroplatinum(II) with the DNA Fragment d(GpCpG)

The reaction of trans-[Pt(NH3)2Cl2] with the sodium salt of the deoxytrinucleoside diphosphate d(GpCpG) at 37 °C in water at pH 6 leads to trans-[Pt(NH₃)₂{d(GpCpG)}] as the one major product formed after 45 h. At earlier time periods (1–2 h) two intermediates, tentatively assigned as monofunctional adducts containing platinum bound to the N7 position of G(1) or G(3), were observed by high-performance liquid chromatography (HPLC). Experiments carried out include pH-dependent titrations of the nonexchangeable base protons, two-dimensional COSY, and one-dimensional nuclear Overhauser effect proton NMR studies on 250- and 500-MHz instruments. The results indicate that the trans-diammineplatinum(II) fragment forms an intrastrand cross-link between the N7 atoms of guanosine nucleosides G(1) and G(3). In this adduct the intervening cytidine nucleotide is destacked and the G(1) deoxyribose sugar ring switches its puckering from an S (C2^/-endo) to an N (C3'-endo) conformation. This change in sugar pucker is similar to that observed for the 5'-nucleotide in cis-[Pt(NH₃)₂|d(GpG)[] intrastrand adducts on DNA. This structural information is likely to be relevant to the fact that, unlike its cis isomer, trans-DDP is inactive as an anticancer drug.