Dinuclear complexes of platinum having anticancer properties. DNA-binding studies and biological activity of Bis(4,4′-dipyrazolylmethane- N,N′)-bis[dichloroplatinum(II) and related complexes

Abstract

Some DNA-binding experiments employing a selected number of novel dinuclear platinum complexes with the 4,4′-dipyrazolylmethane (dpzm) ligand are reported. A DNA-cleavage assay using Eco RI and Bam HI restriction endonucleases to probe the binding of the complexes at or near their unique restriction sequences of pUC9 DNA has been examined. The complex β-[Cl 2Pt(dpzm) 2PtCl 2] has a greater affinity for DNA at the Eco RI restriction sequence over the Bam HI site. To our knowledge, the preferential inhibition of Eco RI activity is unprecedented for any platinum species reported to date. Further, the dinuclear complexes β-[Cl 2Pt(dpzm)PtCl 2], β-[Cl 4Pt(dpzm) 2PtCl 4]·0.5dmf·0.5H 2O and [Cl 4Pt(dpzm) 2PtCl 2] are capable of inhibiting Eco RI activity to a far greater extent than the platinum anticancer drug cis-[PtCl 2(NH 3) 2] (cisplatin). The in vivo and in vitro anticancer properties of some of the platinum complexes are also described. The complexes α-[Cl 2Pt(dpzm) 2PtCl 2]·0.5dmf and β-[Cl 2Pt(dpzm) 2PtCl 2] display significant activity against P388 lymphocytic leukemia in mice.