DINUCLEAR PLATINUM COMPLEXES FORM A NOVEL INTRASTRAND ADDUCT WITH D(GPG), AN ANTI-SYN CONFORMATION OF THE MACROCHELATE AS OBSERVED BY NMR AND MOLECULAR MODELING

Dinuclear platinum complexes form a unique array of DNA adducts includ ing (Pt,Pt) interstrand and (Pt,Pt) intrastrand cross-links. A (Pt,Pt) intrastrand adduct between two adjacent guanines is the structural an alog of the major adduct formed by cis-DDP. In this study, we examined the kinetics of formation and structure of the (Pt,Pt) intrastrand ad duct by following the interaction of [{trans-PtCl(NH3)(2)}(2){mu-H2N(C H2)(n)NH2}](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, rin g 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 diami ne linker. Complexes linked by a longer diamine chain (n = 4-6) react faster and produce a higher yield of macrochelate compared to the shor ter n = 2, 3 diamine linkers. The structure of the (Pt,Pt) intrastrand adduct is significantly different from the cis-DDP-d(GpG) chelate. Th e major difference is the presence of a syn-orientated G base (observe d for 1,1/t,t-(GpG) macrochelates of n = 3 and n = 6). For the macroch elate of [1,1/t,t, n = 3], i.e., 3)(2)}(2){mu-H2N(CH2)(3)NH2}]{d(GpG)- N7(1),N7(2)}, the sugar conformation of the 5'-G (G1) is 28% S, wherea s for 3'-G (G2) this value is much higher (69% S). In the correspondin g 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 be nd into the major groove caused by cis-DDP.