Synthesis of Platinum Complexes from N-Benzyl-2-Aminoethanethiol Derivatives

Twelve new platinum(II) complexes, analogs of cisplatin, containing a 2-aminoethanethiol N-substituted by several benzyl groups have been prepared and characterized in good yields. The ligands were obtained by reaction between 2-aminoethanethiol hydrochloride and different benzyl halides


INTRODUCTION
Cisplatin ( Fig. 1) is an important drug in the fight against cancer. In association with other types of drugs, it is highly effective in the treatment of different kinds of neoplasias [1,2,3]. The biological activity of cisplatin was discovered by Rosenberg et al. at the end of the 1960s [4]. Due to its side effects, the appearance of resistance, and low solubility [5,6,7], new platinum complexes have been synthesized such as carboplatin, oxaliplatin, and nedaplatin ( Fig. 1). Carboplatin shows the same level of activity as cisplatin in the treatment of some kinds of cancer and is much less nephrotoxic and emetic [8]. Oxaliplatin has been approved for the treatment of colorectal cancer in France, and nedaplatin has received approval for use in Japan. Oxaliplatin and nedaplatin have yet to demonstrate significant advantages over cisplatin or carboplatin [9]. This fact shows how it is important to develop new platinum complexes that could effectively act in a larger number of tumors. At the same time, those complexes should present less severe side effects and they should be active in resistant cells lines.
Since some substituted ethylenediamine platinum complexes have shown antitumor activity against a variety of cell tumors [10,11], and also aromatic compounds have shown the possibility of intercalation between DNA bases [12], we synthesized complexes containing a platinum center bound to ethylenediamine derivatives that demonstrated cytotoxicity in vitro in carcinoma buccal human cells [13]. Based on those results, we decided to synthesize platinum(II) complexes
The dichloro platinum(II) complexes 11-15 (65-88% yield) were synthesized by the reaction of these ligands with K 2 [PtCl 4 ] in water at room temperature for 24 h and isolated by filtration. For the complexes, one can see in their IR spectra absorptions corresponding to γ Pt-N, γ Pt-S, and γ Pt-Cl between 500-550, 440-476, and 300-338 cm -1 , respectively, in addition to the absorptions observed for the ligands. In the 1 H NMR spectrum of these complexes, signals were observed between δ 2.1-2.8 and 3.0-3.1, corresponding to the CH 2 SH and CH 2 NH, signals between δ 4.0-4.8 in the case of benzyl CH 2 , and finally signals in the region of δ 7.1-8.2 for the aromatic hydrogens. The compound 14 also showed a signal at δ 3.8 attributable to the OCH 3 .
The complexes 21 and 22 were prepared in order to compare their cytotoxic activity in relation to the complexes 11-20, containing N-benzyl groups. They were synthesized by the same procedure described above for the complexes 11-20 in 84 and 82% yield. IR spectra of the complex 21 and 22 showed absorptions corresponding to NH and CH aliphatic at 3193 and 2929 cm -1 , respectively. 1 H NMR signals were observed at δ 2.8 corresponding to CH 2 SH and CH 2 NH, respectively.

Synthesis of Complexes 11-15 and 21: General Procedure
The appropriate ligand (1 mmol) was dissolved in water (5 mL) and added slowly with stirring to a solution of K 2 PtCl 4 (415 mg, 1 mmol) in water (10 mL). After 24 h in the dark at room temperature, the yellow solid formed was filtered off, washed with water, and dried. In the preparation of the complex 21, the ligand 2-aminoethanothiol hydrochloride and sodium bicarbonate (84 mg, 1 mmol) were previously dissolved in water (5 mL

Synthesis of Complexes 16-20 and 22: General Procedure
A solution of K 2 PtCl 4 (415 mg, 1 mmol) and KI (664 mg, 4 mmol) in water (10 mL) was stirred in the dark at room temperature for 30 min, after which the appropriate ligand (1 mmol) dissolved in water (5 mL) was added slowly. After stirring in the dark at room temperature for 24 h, the brown product was isolated by filtration and recrystalized from acetone/water. In the preparation of the complex 22 the ligand 2-aminoethanothiol hydrochloride and sodium bicarbonate (1 mmol) were previously dissolved in water (5 mL