In vitro cytostatic activity of palladium(II) and platinum(II) halide complexes with thiocarbamic esters

Abstract

The thiuram disulfides and dithiocarbamates are widely used in industry, agriculture and medicine [1, 2]. Moreover disulfiram (tetraethylthiuram disulfide) has been used for over 20 years in the treatment of certain patients with chronic alcoholism and the reduced form of the compound, diethyldithiocarbamate anion (DDTC) has been used in the treatment of nickel carbonyl, arsenic and thallium poisoning [3]. Recently DDTC has been found to be an effective agent in attempts to reduce the dose-limiting nephrotoxicity of cis-platin [4]. This compound has been shown also to exert a protective effect against a variety of chemically-induced malignant tumors and a unique immunopotentiating activity [5]. Bearing in mind these findings, in recent years we have undertaken to study platinum(II) and palladium(II) complexes with thiocarbamate derivatives as ligands, in order to prepare new antitumor platinum metal complexes with a better therapeutic index than cis-platin [6,7]. The present note reports a new series of platinum(II) and palladium(II) complexes containing as ligands dithiocarbamic esters of the type L =R 1R 2N · CSSR (R 1 = R 2 = R = Me, L = TMDT; R 1 = R 2 = Me, R = Et, L = DMDTE; R 1 = R 2 = R = Et, L = TEDT; R 1 = R 2 = Et, R = Me, L = DEDTM). Whereas by reacting PtX 2 and PdX 2 (X = Cl, Br) with TMDT and DMDTE, complexes of 1:1 molar ratio, MLX 2, and 1:2, ML 2X 2 have been isolated, with DEDTM and TEDT only 1:1 adducts have been obtained. On the basis of the IR data the ligands act as monodentate through the thiocarbonyl group in the 1:2 complexes; for the 1:1 a tetracoordination by one bidentate (S,S) dithiocarbamic ester molecule and two halides is suggested. The cytostatic activity was evaluated on KB cells according to protocols suggested by the National Cancer Institute (Bethesda) [8]. Results of an in vitro assay are expressed as concentration of the compound in culture medium (μg/ml) required to inhibit growth by 50% (ID 50). Some of the compounds showed significant cytostatic activity in the preliminary test. Particularly Pd(DMDTE)X 2 (X = Cl, Br), Pt(DMDTE)Br 2 and Pd(DMDTE) 2Br 2 have ID 50 values in the 0.5 - 1 μg/ml interval. The ligands alone did not show any activity From the preliminary results the palladium complexes seem to posses a higher cytostatic activity than platinum analogues.