Synthesis, interaction with double-helical DNA and biological activity of the water soluble complex cis-dichloro-1,2-propylenediamine-N,N,N 0 ,N 0 -tetraacetato ruthenium (III) (RAP) Rosario A. Vilaplana a , Fa ´tima Delmani b , Consolacio ´n Manteca c , Jose ´ Torreblanca b , Javier Moreno b , Gregorio Garcı ´a-Herdugo b , Francisco Gonza ´lez-Vı ´lchez a, * a Departamento de Quı ´mica Inorga ´ nica, Laboratorio de Quı ´mica Bioinorga ´ nica, Facultad de Quı ´mica, Universidad de Sevilla, 41071 Sevilla, Spain b Departamento de Biologı ´a Celular, Facultad de Biologı ´a, Campus Reina Mercedes, Universidad de Sevilla, 41012 Sevilla, Spain c Departamento de Tecnologı ´as Especiales Aplicadas a la Aerona ´ utica, Escuela de Ingenierı ´a Te ´cnica Aerona ´ utica, Plaza Cardenal Cisneros no. 3, Universidad Polite ´cnica de Madrid, 28040 Madrid, Spain Received 4 July 2006; received in revised form 14 July 2006; accepted 18 July 2006 Available online 4 August 2006 Abstract The effects exerted by the new complex cis-dichloro-1,2-propylenediaminetetraacetato ruthenium (III), H[RuCl 2 (PDTA–H 2 )] [1, RAP], on DNA and cultured tumor cells (ovarian carcinoma TG cell line) were studied. The comparative study of circular dichroism (CD) spectra obtained from DNA and RAP–DNA system evidences the interaction of the complex with DNA. Compound 1 also inter- acted with tumor TG cells to slow their proliferation rate. BrdU incorporation was enhanced in cells treated with compound 1, as evidenced by a single-cell electrophoresis method (comet assay), in accordance with RAP-induced DNA damage. DNA migration of compound 1-treated cells was similar to that induced by noxious agents other than cross-linking chemicals. The stability of [RuCl 2 (PDTA–H 2 )]–DNA binding is suggested by the high degree of damage that persisted after removal of compound 1 from the culture medium. Ó 2006 Elsevier Inc. All rights reserved. Keywords: Ruthenium complexes; Polyamminocarboxylic ligands; DNA; Comet assay; Antitumor complexes 1. Introduction Since Rosenberg’s pioneering contribution to cancer chemotherapy, much work has been done to develop alternative compounds to cisplatin with similar antitumor activity and less side toxicity [1–3]. Complexes based on ruthenium, one of the platinum group metals, have been proposed as potential antitumor substances [3–6]. Ruthe- nium occurs in aqueous solution mainly as Ru(II) and Ru(III). Although both ions are always six-coordinate with octahedral geometry, Ru(III) compounds can be reduced in hypoxic tumor areas into more active species that are capa- ble of rapidly binding to cellular DNA through a nucleo- base nitrogen in a similar way to platinum-based drugs [7–10]. Recent biochemical studies have demonstrated that new promising ruthenium compounds bind proteins in a tight covalent way [11]. In an effort to search for water soluble ruthenium compounds with antitumor activity, we prepared a new generation of Ru(III) complexes using polyaminocarboxy- lic molecules as chelating ligands. The resulting octahedral complexes also have one or two coordination sites occu- pied by labile entities such as chloride ligands or water 0162-0134/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2006.07.012 * Corresponding author. Tel.: +34 95 4557159; fax: +34 95 4557081. E-mail address: fgonzalezv@us.es (F. Gonza ´lez-Vı ´lchez). www.elsevier.com/locate/jinorgbio Journal of Inorganic Biochemistry 100 (2006) 1834–1841 JOURNAL OF Inorganic Biochemistry