DNA INTERACTIONS OF A NOVEL PLATINUM DRUG, CIS-[PTCL(NH3)(2)(N7-ACYCLOVIR)]

We synthesized a novel platinum drug, cis-[PtCl(NH3)(2)(N7-ACV)](+), i n which ACV is the antiviral drug acyclovir [a deoxyriboguanosine anal ogue, 9-(2-hydroxyethoxymethyl)guanine]. This new compound exhibits an tiviral efficacy in vitro and exhibits an antitumor activity profile d ifferent from that of cisplatin [Metal-Based Drugs 2:249-256 (1995)], To contribute to understanding the mechanisms underlying biological ac tivity of this new compound, we studied modifications of natural and s ynthetic DNAs in cell-free media by cis-[PtCl(NH3)(2)(N7-ACV)](+) by v arious biochemical and biophysical methods. The results indicated that the major DNA adduct of cis-[PtCl(NH3)(2)(N7-ACV)](+) was a stable mo nofunctional adduct at guanine residues. In contrast to DNA adducts of other monodentate and clinically ineffective platinum(II) compounds, the adducts of cis-[PtCl(NH3)(2)(N7-ACV)](+) terminated in vitro DNA a nd RNA synthesis. In addition, although DNA adducts of cis-[PtCl(NH3)( 2)(N7-ACV)](+) and cisplatin were different, some properties of DNA mo dified by either compound were qualitatively similar. Such similaritie s were not noticed if DNA modifications by other ineffective monofunct ional platinum(II) complexes were investigated. Thus, the DNA binding mode of monofunctional cis-[PtCl(NH3)(2)(N7-ACV)](+) was different fro m that of other monofunctional but ineffective platinum(II) complexes. It has been suggested that the unique capability of cis-[PtCl(NH3)(2) (N7-ACV)](+) to modify DNA may be relevant to a distinct antitumor eff iciency of this novel drug in comparison with cisplatin. It also has b een suggested that at least some aspects of DNA interactions of cis-[P tCl(NH3)(2)(ACV)](+) revealed in the current study could be exploited in the search for and development of new antiviral platinum complexes containing, as a part of the coordination sphere, antiviral nucleoside s.