A comparison of chemical reactivity, cytotoxicity, interstrand crosslinking and DNA sequence specificity of bis(platinum) complexes containing monodentate or bidentate coordination spheres with their monomeric analogs

Abstract

The properties of a new bis(platinum) complex containing two monodentate coordinate spheres, [{trans-PtCl(NH3)2}2H2N(CH2)4NH2]Cl2 (1,1/t,t), are reported. Comparison is made with respect to chemical reactivity, in vitro biological activity in murine and tumor cells, DNA conformational changes, cross-linking efficiency, and sequence specificity between this complex and the previously reported complex containing two bidentate platinum atoms, [{Pt(mal)(NH3)}2H2N(CH2)4NH2] (2,2/c,c) as well as with their respective monomeric analogues, [PtCl(dien)]Cl and cis-[PtCl2(NH3)2](cis-DDP). While both bis(platinum) complexes are active against cis-DDP-resistant cells, the monodentate bis(platinum) complex (1,1/t,t) has a lower resistance factor that the complex with bidentate coordination spheres (2.2/c,c). More importantly, this property is repeated in a human ovarian carcinoma cell line. DNA-binding studies show that DNA interstrand cross-linking is more efficient for the 1,1/t,t complex. DNA sequencing studies employing the exonuclease activity of T4-polymerase demonstrate that there are a variety of binding sites; some are common to all complexes and some common to both bis(platinum) complexes, while the monodentate 1,1/t,t species also reacts at unique sites, not attached by any of the other complexes studied. The circular dichroism of CT DNA modified by the 1,1/t,t complex is also unique and is not seen for any of the other agents.