Synthesis, characterization, and biological evaluation of new tetrazole-based platinum(II) and palladium(II) chlorido complexes - Potent cisplatin analogues and their trans isomers

Abstract

Two series of tetrazole-containing platinum(II) and palladium(II) chlorido complexes, trans-[ML2Cl2] (M = Pt, Pd) and cis-[PtL2Cl2]center dot nH(2)O (n = 0, 1), where L is 1- or 2-substituted 5-aminotetrazole, have been synthesized and thoroughly characterized. Configuration of platinum(II) complexes obtained from the reaction of 5-aminotetrazoles with K2PtCl4 has been found to vary depending on the nature of tetrazole derivatives and reaction conditions. According to in vitro cytotoxic evaluation, only platinum complexes display noticeable antiproliferative effect, and their cytotoxicity depends strongly on their geometry and hydrophobicity of the carrier ligands. The most promising complexes are cis-[Pt(1-apt)(2)Cl-2]center dot H2O and cis-[Pt(2-abt)(2)Cl-2]center dot H2O, where 1-apt is 5-amino-1-phenyltetrazole and 2-abt is 5-amino-2-tert-butyltetrazole. In comparison with cisplatin, they show comparable cytotoxic potency against cisplatin-sensitive human cancer cell lines, cis-[Pt(2-abt)(2)Cl-2]center dot H2O performing substantially higher activity against cisplatin-resistant cell lines. Cell cycle studies in H1299 cell line ;indicated that cis-[Pt(2-abt)(2)Cl-2]center dot H2O induced apoptosis launched from G2 accumulations. The DNA interaction with cis-[Pt(1-apt)(2)Cl-2]center dot H2O was followed by UV spectroscopy, circular dichroism, hydrodynamic and electrophoretic mobility studies. Both cis-[Pt(1-apt)(2)Cl-2]center dot H2O and cis-[Pt(2-abt)(2)Cl-2]center dot H2O complexes appeared to be significantly less toxic than cisplatin in mice, while only compound cis-IPt(1-apt)(2)Cl-2]center dot H2O displayed noticeable efficacy in vivo. (C) 2012 Elsevier Inc. All rights reserved.