DNA interactions of new cytotoxic tetrafunctional dinuclear platinum complex trans, trans-[{PtCl 2(NH 3)} 2(piperazine)

Abstract

A new tetrafunctional dinuclear platinum complex trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] with sterically rigid linking group was designed, synthesized and characterized. In this novel molecule, the DNA-binding features of two classes of the platinum compounds with proven antitumor activity are combined, namely trans oriented bifunctional mononuclear platinum complexes with a heterocyclic ligand and polynuclear platinum complexes. DNA-binding mode of this new complex was analyzed by various methods of molecular biology and biophysics. The complex coordinates DNA in a unique way and interstrand and intrastrand cross-links are the predominant lesions formed in DNA in cell-free media and in absence of proteins. An intriguing aspect of trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] is that, using a semi-rigid linker, interstrand cross-linking is diminished relative to other dinuclear platinum complexes with flexible linking groups and lesions that span several base pairs, such as tri- and tetrafunctional adducts, become unlikely. In addition, in contrast to the inability of trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] to cross-link two DNA duplexes, the results of the present work convincingly demonstrate that this dinuclear platinum complex forms specific DNA lesions which can efficiently cross-link proteins to DNA. The results substantiate the view that trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] or its analogues could be used as a tool for studies of DNA properties and their interactions or as a potential antitumor agent. The latter view is also corroborated by the observation that trans, trans-[{PtCl 2(NH 3)} 2(piperazine)] is a more effective cytotoxic agent than cisplatin against human tumor ovarian cell lines.