Reaction of the antitumor drug cis-diamminedichloroplatinum(II) with the trinucleotide d(GpApG): Identification of the two main products and kinetic aspects of their formation

The two main products (total yield over 95%) that are obtained in the reaction of cis-diamminedichloroplatinum(II) with the trinucleotide d(GpApG) have been characterized by high-field proton NMR (300 and 500 MHz; using the pH dependence of the chemical shift of the nonexchangeable base proton signals as well as homodecoupling and NOE techniques) and by the analysis of their enzymatically digested products with anion-exchange chromatography (FPLC) and platinum atomic absorption spectroscopy. The results indicate the formation of both cis-Pt(NH3)2[d(GpApG)-N7(1),N7(3)] (yield 80%) and cis-Pt(NH3)2[d-(GpApG)-N7(2),N7(3)] (yield 20%). No influence due to temperature or prior hydrolysis of cis-PtCl2(NH3)2 was observed on the product ratio. The reaction of d(GpApG) with the monofunctional platinum compound [PtCl(dien)]Cl, mimicking the first binding step of cis-PtCl2(NH3)2, provides more insight into the overall chelate formation. The observation that only an AG chelate but no GA chelate is formed agrees with other studies in which also only the AG chelate is reported. This can be explained by the geometry of the trinucleotide. ?? 1986 American Chemical Society.Chemicals/CAS: cisplatin, 15663-27-1, 26035-31-4, 96081-74-2