Dinuclear Platinum Complexes Form a Novel Intrastrand Adduct with d(GpG), ananti−synConformation of the Macrochelate As Observed by NMR and Molecular Modeling

Dinuclear platinum complexes form a unique array of DNA adducts including (Pt,Pt) interstrand and (Pt,Pt) intrastrand cross-links. A (Pt,Pt) intrastrand adduct between two adjacent guanines is the structural analog of the major adduct formed by cis -DDP. In this study, we examined the kinetics of formation and structure of the (Pt,Pt) intrastrand adduct by following the interaction of [{ trans -PtCl(NH 3 ) 2 } 2 {μ-H 2 N(CH 2 ) n NH 2 }] 2+ (1,1/t,t, n = 2−6) with d(GpG) using NMR spectroscopy and by molecular modeling. Initial coordination, to either the 5‘-G or the 3‘-G, is relatively fast compared to the second binding step, ring closure to the macrochelate adduct ( i . e ., [1,1/t,t]−d(GpG)−N7(1),N7(2)). The rate of ring closure depends on the chain length of the diamine linker. Complexes linked by a longer diamine chain ( n = 4−6) react faster and produce a higher yield of macrochelate compared to the shorter n = 2, 3 diamine linkers. The structure of the (Pt,Pt) intrastrand adduct is significantly different from the cis -DDP−d(GpG) chelate. The major difference is the presence of a syn -orientated G base (observed for 1,1/t,t−(GpG) macrochelates of n = 3 and n = 6). For the macrochelate of [1,1/t,t, n = 3], i . e ., [{ trans -PtCl(NH 3 ) 2 } 2 {μ-H 2 N(CH 2 ) 3 NH 2 }]{d(GpG)−N7(1),N7(2)}, the sugar conformation of the 5‘-G(G1) is 28% S, whereas for 3‘-G(G2) this value is much higher (69% S). In the corresponding n = 6 macrochelate these values are 55% S and 30% S for G(1) and G(2), respectively. The orientation of the two G bases in the [1,1/t,t]−d(GpG) chelates is best described as tectonic or “stepped head-to-head”. The structure helps explain the flexible bending in DNA induced by the dinuclear platinum complexes in contrast to the rigid directed bend into the major groove caused by cis -DDP.