Effect of the geometry of the central coordination sphere in antitumor trinuclear platinum complexes on DNA binding

Abstract

Polynuclear platinum compounds comprise a unique class of anticancer agents with chemical and biological properties different from mononuclear platinum drugs. The lead compound of this class is bifunctional trinuclear platinum complex [{ trans-PtCl(NH 3) 2} 2μ- trans-Pt(NH 3) 2{H 2N(CH 2) 6NH 2} 2] 4+ (1,0,1/t,t,t, BBR 3464). Interestingly, the geometry of the coordination spheres in this compound affects potency. For example, the central cis unit of [{ trans-PtCl(NH 3) 2} 2μ- cis-Pt(NH 3) 2{H 2N(CH 2) 6NH 2} 2] 4+ (1,0,1/t,c,t, BBR 3499) results in substantially reduced cytotoxicity. It has been shown that the interactions of polynuclear platinum drugs with target DNA are distinct from the mononuclear-based cisplatin family. In the present work the DNA binding of 1,0,1/t,c,t in cell-free media was examined by the methods of molecular biophysics and compared to the binding of 1,0,1/t,t,t. The binding of 1,0,1/t,c,t is slower and less sequence specific. 1,0,1/t,c,t also forms on DNA long-range delocalized intrastrand and interstrand cross-links similarly as 1,0,1/t,t,t, although the frequency of interstrand adducts is markedly enhanced. Importantly, the adducts of 1,0,1/t,c,t distort DNA conformation and are repaired by cell-free extracts considerably more than the adducts of 1,0,1/t,t,t. It has been suggested that the unique properties of long-range interstrand cross-links of bifunctional trinuclear platinum complexes and resulting conformational alterations in DNA have critical consequences for their antitumor effects.