Abstract
Platinum complexes play an important role in the development of anticancer drugs. Their cytotoxicity can be influenced by the nature of the leaving ligands, due to the hydrolysis reaction that occurs prior to the binding of the platinum complex to DNA. Also, non-leaving groups such as lipophilic diamines may affect cellular uptake. In this work, we describe the synthesis of platinum(II) complexes having oxalato and long chain aliphatic N-alkyl ethylenediamines as ligands. The products were characterized by elemental analyses, infrared spectroscopy and 1H, 13C and 195Pt NMR spectroscopy. Biological activity was assessed against tumor cell lines (A549, B16-F1, B16-F10, MDA-MB-231) and non-tumor cell lines (BHK-21 and CHO). The length of the carbon chain affects the cytotoxicity and the oxalato complexes were less cytotoxic than the respective chloride-containing analogues.
Highlights
Cisplatin and carboplatin are widely used anticancer drugs for the treatment of testicular, ovarian, head, neck and non-small-cell lung cancer.[1,2,3] their clinical usefulness has frequently been limited by severe side effects, such as nephrotoxicity, ototoxicity and neurotoxicity, and by the emergence of cancer cells resistant to cisplatin. 4-6Carboplatin was designed to overcome the severe side effects of cisplatin, and, the replacementOver the last decades, many other platinum drugs have been developed in an attempt to improve the toxicity profile and, in particular, to obtain a drug that is able to overcome resistance
The platinum complexes with chloride and ethylenediamine derivatives (1, 2, 3 and 4) were prepared by a procedure analogous to that reported earlier by our research group for the propanodiamine derivatives.[13,14]
The platinum complexes with oxalato (5, 6, 7 and 8), in their turn, were obtained from the chloride precursors (Scheme 1) using an extension of Dharas method.[15]
Summary
Cisplatin and carboplatin are widely used anticancer drugs for the treatment of testicular, ovarian, head, neck and non-small-cell lung cancer.[1,2,3] their clinical usefulness has frequently been limited by severe side effects, such as nephrotoxicity, ototoxicity and neurotoxicity, and by the emergence of cancer cells resistant to cisplatin. 4-6Carboplatin was designed to overcome the severe side effects of cisplatin, and, the replacementOver the last decades, many other platinum drugs have been developed in an attempt to improve the toxicity profile and, in particular, to obtain a drug that is able to overcome resistance. Non-leaving groups can confer different characteristics to platinum compounds, improving their cytotoxic activity by modifying cellular uptake and the way the complex interacts with DNA.[11] Amphiphilic diamines with a long, N-alkyl chain may present surfactant properties. It has been shown that the length of the carbon chain affects cytotoxity and cellular uptake of the chloride complexes.[13] The impact of a different leaving group (oxalato) on the cytotoxic activity of the products was investigated in the present work using several cell lines such as breast and lung cancer cells.
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