Journal of Inorganic Biochemistry 93 (2003) 181–189 www.elsevier.com / locate / jinorgbio Pt(II) and Pd(II) derivatives of ter-butylsarcosinedithiocarbamate Synthesis, chemical and biological characterization and in vitro nephrotoxicity a, a a b c d e * D. Fregona , L. Giovagnini , L. Ronconi , C. Marzano , A. Trevisan , S. Sitran , B. Biondi , b F. Bordin a University Department of Inorganic, Metallorganic and Analytical Chemistry, via Loredan 4, 35131 Padova, Italy b University Department of Pharmaceutical Sciences, via Marzolo 5, 35131 Padova, Italy c University Department of Environmental Medicine and Public Health, via Giustiniani 2, 35128 Padova, Italy d Institute of Chemistry and Inorganic Technologies and Advanced Materials, C.N.R., Research Area, Corso Stati Uniti 4, 35127 Padova, Italy e Biopolymers Research Centre, C.N.R., via Marzolo 1, 35131 Padova, Italy Received 6 June 2002; received in revised form 5 September 2002; accepted 23 September 2002 Abstract This work reports on the synthesis, characterization and biological activity of new coordination compounds of the type [M(TSDTM)X ] (M5Pt(II), Pd(II); X5Cl, Br; TSDTM5ter-butylsarcosine(S-methyl)dithiocarbamate) and [Pd(TSDT)X] (TSDT5ter- 2 n butylsarcosinedithiocarbamate) in order to study their behavior as potential antitumor agents. All the synthesized compounds were 1 13 characterized by means of elemental analysis, FT-IR, H and C-NMR spectroscopy and thermogravimetric analysis, suggesting a chelate S,S 9 structure of the TSDTM / TSDT ligand in a square-planar geometry. Finally, the synthesized complexes have been tested for in vitro cytotoxic activity against human leukemic HL60 and adenocarcinoma HeLa cells; the most active compound [Pt(TSDTM)Br ], 2 characterized by IC values very similar to those of the reference compound (cisplatin), was also tested for in vitro nephrotoxicity 50 showing a very low renal cytotoxicity as compared to cisplatin itself.  2002 Elsevier Science Inc. All rights reserved. Keywords: Platinum(II) complexes; Palladium(II) complexes; Cytotoxic activity; Nephrotoxicity 1. Introduction high effectiveness, there are some clinical problems related to the use of cisplatin in the curative therapy, such as Most of the major classes of pharmaceutical agents severe normal tissue toxicity and the frequent occurrence contain examples of metal compounds which are in current of initial and acquired resistance to the treatment [4]. An clinical use [1] and new areas of application are rapidly important side effect of cisplatin is nephrotoxicity, which emerging. results from injury to renal tubular epithelial cells and can Platinum(II) complexes are now amongst the most be manifested as either acute renal failure or a chronic widely used drugs for the treatment of cancer; four syndrome characterized by renal electrolyte wasting [5]. injectable Pt(II) diamine compounds (cisplatin, carbop- These renal adverse effects are correlated to platinum latin, nedaplatin and oxalilplatin) have been approved for binding and inactivation of thiol-containing enzymes [6]. clinical use and several others cis-diamine complexes are Continuous efforts are still being made to reduce the in clinical trials, including an oral Pt(IV) complex [2]. toxicity of platinum anticancer complexes toward normal Today, cisplatin is one of most effective drugs used for the cells, circumventing acquired resistance to cisplatin and treatment of testicular, ovarian, small cell lung, bladder, decreasing its nephrotoxicity [7]. cervical and head and neck carcinomas [3]. Despite its The interest in the chemical and biochemical properties of platinum and palladium complexes with thiocarbonyl donors stems from the use of sulfur ligands as detoxicant *Corresponding author. Tel.: 139-49-827-5159; Fax: 139-2700-500- agents against metal-containing drugs [8–12]. For a long 560. E-mail address: dolores.fregona@unipd.it (D. Fregona). time, dithiocarbamates have been evaluated for their 0162-0134 / 02 / $ – see front matter  2002 Elsevier Science Inc. All rights reserved. PII: S0162-0134(02)00571-8