DNA binding of the anti-cancer platinum complex trans-[{Pt(NH3)2Cl}2μ-dpzm]2+

Abstract

The DNA binding of the dinuclear platinum complex trans-[{Pt(NH3)2Cl}2μ-dpzm]2+ (di-Pt), linked with the 4,4′-dipyrazolylmethane (dpzm) linker, was examined by 1H and 195Pt NMR and transcription assays. At 60 °C, di-Pt reacts with guanosine two-fold slower (t1/2: 1 h) than cisplatin (t1/2: 0.5 h). With adenosine, the di-Pt complex reacts much slower (t1/2: 7 h) forming a range of different adducts through the N7 and either the N1 or N3 positions of the nucleoside. From 1H NMR analysis of the major product of the reaction of di-Pt with the oligonucleotide d(ATGCAT)2, purified by HPLC, it was determined that the dinuclear platinum complex can readily form a 1,2-GG interstrand DNA cross-link. Transcription assays using di-Pt and the lac UV5 promoter indicated that the metal complex forms an array of adducts vastly different from cisplatin. The two greatest blockages occurred at adenine residues, with possible interstrand and intrastrand AA and AG adducts being formed. These results indicate that unlike other platinum based anti-cancer agents, di-Pt binds to DNA with a preference for adenine bases.