Novel cyclopalladated and coordination palladium and platinum complexes derived from a-diphenyl ethanedione bis(thiosemicarbazones): Structural studies and cytotoxic activity against human A2780 and A2780cisR carcinoma cell lines Ana I. Matesanz, Pilar Souza * Departamento de Quı ´mica Inorga ´ nica, Facultad de Ciencias, Universidad Auto ´ noma de Madrid, C/Francisco Toma ´ s y Valiente 7, 28049 Madrid, Spain Received 8 February 2007; received in revised form 24 April 2007; accepted 9 May 2007 Available online 12 June 2007 Abstract The preparation of new palladium(II) and platinum(II) complexes derived from a-diphenyl ethanedione bis(thiosemicarbazone), 1, and a-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2, is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB + ) and spectroscopic studies (IR, 1 HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum com- plexes against human A2780 and A2780cisR (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC 50 values for compounds 1, 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780cisR cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Antitumor agents; Bis(thiosemicarbazone); Platinum and palladium complexes; X-ray diffraction 1. Introduction Cisplatin is one of the leading drugs currently used in the treatment of a number of solid malignancies. For rea- sons of drug resistance, severe side effects and the limited spectrum of tumors against which cisplatin (cis-DDP) is active, there has been a widespread search for related com- plexes. Thus, thousands of cisplatin analogues have been synthesized varying the nature of the leaving groups and the carrier ligand, yet only a handful of them have been approved for clinical use [1–3]. The limited success in metal-based anticancer research appears to be caused by the relative lack in structural diver- sity encountered in the reported compounds. In recent years there has been an emergence of new structural types of compounds often with promising activity [4–7]. For instance, the substitution of the chlorido ligands by other anionic ligands could lead to the new active complexes. In fact, it is known that a simple modification in the struc- ture of a certain compound could alter its DNA binding patterns, thus affecting its anticancer activity. In this sense the thiosemicarbazonato anion may be a good option because some thiosemicarbazones themselves exhibit anti- neoplastic activity [8–13]. Thiosemicarbazones (TSCs) are a versatile type of ligands due to the number of donor atoms they possess, 0162-0134/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2007.05.013 * Corresponding author. Tel.: +34 914975146; fax: +34 914974833. E-mail address: pilar.souza@uam.es (P. Souza). www.elsevier.com/locate/jinorgbio Journal of Inorganic Biochemistry 101 (2007) 1354–1361 JOURNAL OF Inorganic Biochemistry