Photoactivated DNA modifications by platinum(IV) azide complex in cell-free media

The complex trans,trans,trans-[Pt(N-3)(2)(OH)(2)(NH2)(py)] (I) is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When I is photoactivated in cells, it is highly toxic: pronouncedly more cytotoxic than the (PtI)-I-I anticancer drug cisplatin including towards cisplatin-resistant human ovarian cancer cells (Mackay, F.S., et al., Proc. Natl. Acad. Sci. USA, 2007, in press). We demonstrate in the present work that while cisplatin forms mainly intrastrand cis di-guanine cross-links on DNA between neighboring nucleotides, photoactivated complex I forms trans di-guanine (PtI)-I-I adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. The trans diazido Pt-IV complex I therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.