Cytotoxicity, DNA binding, and reactivity against nucleosides of platinum (II) and (IV) spermine compounds

Abstract

We describe the synthesis and characterization of a [sperH 4][PtCl 4] 2 salt and of five binuclear platinum (II) and (IV)-spermine compounds of formula [(PtCl 2) 2(sper)], cis-[(Pt(CH 2(COO) 2)(sper)], and cis-[(PtCl 4) 2(sper)], (CBDCA= 1,1′-cyclobutanedicarboxylate, cis-trans-c0s[(PtCl 2(OH) 2) 2(sper)], and cis-[(PtCl 4) 2(sper)], respectively. The 1H and 195Pt-NMR analysis of the complexes formed between these compounds and nucleosides indicated that the Pt centers show preferential binding to the N(7) of guanosine and adenosine residues, also being capable of forming bridged structures through the N(7) and N(1). The synthesized Pt-spermine compounds do not form complexes with cytidine residues at 37°C. The circular dichroism, melting, and electrophoretic data of the compounds—DNA complexes show that the Pt(IV)-spermine complezes induce lower DNA conformational changes than their Pt(II) analogs. These results correlate with the IC 50 values obtained against MDA-MB 468 and HL-60 human cancer cells which are higher than those of cis-DDP. The [sperH 4][PtCl 4] 2 salt produces a high level of DNA modification and exhibits IC 50 values lower than those of cis-DDP.