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

Two series of tetrazole-containing platinum(II) and palladium(II) chlorido complexes, trans-[ML2Cl2] (M = Pt, Pd) and cis-[PtL2Cl2]·nH2O (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)2Cl2]·H2O and cis-[Pt(2-abt)2Cl2]·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)2Cl2]·H2O performing substantially higher activity against cisplatin-resistant cell lines. Cell cycle studies in H1299 cell line indicated that cis-[Pt(2-abt)2Cl2]·H2O induced apoptosis launched from G2 accumulations. The DNA interaction with cis-[Pt(1-apt)2Cl2]·H2O was followed by UV spectroscopy, circular dichroism, hydrodynamic and electrophoretic mobility studies. Both cis-[Pt(1-apt)2Cl2]·H2O and cis-[Pt(2-abt)2Cl2]·H2O complexes appeared to be significantly less toxic than cisplatin in mice, while only compound cis-[Pt(1-apt)2Cl2]·H2O displayed noticeable efficacy in vivo.

Twelve novel tetrazole-containing platinum(II) and palladium(II) chlorido complexes are synthesized and characterized. Two cis platinum(II) complexes of N-substituted 5-aminotetrazoles were shown to be at least as active as cisplatin against a range of human tumor cell lines and are much less toxic than cisplatin in vivo.Figure optionsDownload as PowerPoint slideHighlights
► Novel cisplatin analogues were obtained using 5-aminotetrazoles as carrier ligands.
► Cis Pt complexes isomerize under heating in organic solvents to give trans forms.
► Two cis Pt complexes combine high cytotoxicity in vitro and low toxicity in vivo.
► Cell cycle and biophysical studies were used to elucidate the mechanism of action.