Synthesis, characterization, interaction with DNA and cytotoxicity of the new potential antitumour drug cis-K[Ru(eddp)Cl-2]

Abstract

The new potential antitumour soluble drug K[Ru(eddp)Cl-2].3H(2)O, (eddp = ethylenediamine-N,N'-di-3-propionate) has been isolated and characterized. The analysis of the interaction of this complex with pBR322 plasmid DNA by circular dichroism, spectroscopy shows that the ruthenium complex initially induces alteration of both CD positive and negative features resembling those previously observed for monofunctional platinum complexes. Further addition of drug at r(i) higher than 0.50 suggests appreciable conformational alterations of typical secondary structure of B-type DNA, implying loss of DNA helicity and unwinding of the double helix. The results reported herein about the binding of K[Ru(eddp)Cl-2] to the named plasmid performed by electrophoresis indicate that the Ru(III) center preferentially forms initial monofunctional adducts with this plasmid. In addition, the DNA binding data suggest that the plasmid is cleaved by K[Ru(eddp)Cl-2] in the presence of physiological concentrations of ascorbate. These results support the hypothesis that reactive Ru(II) species may be formed from Ru(III) upon incubation with a reductant agent such as ascorbate. The testing of the cytotoxic activity of this complex against several human cancer cell lines evidenced that K[Ru(eddp)Cl-2] complex had a remarkable and selective antiproliferative effect against the cervix carcinoma HeLa and colon adenocarcinoma HT-29, behaving in these two cases as an antineoplastic drug. (C) 2003 Elsevier Inc. All rights reserved.