EFFECTS OF GEOMETRIC ISOMERISM AND LIGAND SUBSTITUTION IN BIFUNCTIONAL DINUCLEAR PLATINUM COMPLEXES ON BINDING-PROPERTIES AND CONFORMATIONAL-CHANGES IN DNA

The DNA binding profile of a series of dinuclear platinum complexes [{ trans-PtCl-(L)(2)}2H2N(CH2)(n)NH2](2+) (L = NH3 or py; 1,l/t,t/NH3 and 1,l/t,t/py, respectively) and [{cis-PtCl-(NH3)(2)}2H2N(CH2)(n)NH2](2) (1,l/c,c/NH3) was examined to compare the effects of geometrical iso merism and the presence of ligands other than NH3 in the coordination sphere. Steric effects, because of the geometry of the leaving groups cis to the diamine bridge or the presence of planar pyridine ligands, result in diminished binding to calf thymus DNA for these isomers. In contrast, the pyridine derivative shows a distinct binding preference for poly(dG-dC). poly(dG-dC) in comparison to both NH3 isomers. Both N H3 complexes induce the B --> Z transition in poly(dG-dC). poly(dG-dC) , but the presence of a pyridine ligand stabilizes the B conformation. The bifunctional binding of the NH3 isomers results in unwinding of s upercoiled pUC19 plasmid DNA equivalent to cis-DDP, while the unwindin g of the pyridine derivative is approximately twice that of the mononu clear trans-[PtCl2(py)(2)]. DNA-DNA interstrand cross-linking is very efficient for all three agents, but sequencing studies indicated that only the 1,l/t,t/NH3 derivative is capable of forming a (Pt,Pt) intras trand cross-link to the adjacent guanines of a d(GpG) sequence. The ef fects on DNA caused by bifunctional binding of dinuclear complexes are compared with those from the mononuclear [PtCl2(NH3)(2)] isomers. The results are discussed with respect to the antitumor activity of the d inuclear series.