Structural characterization, DNA interactions, and cytotoxicity of new transplatin analogues containing one aliphatic and one planar heterocyclic amine ligand

Publikace: JOURNAL OF MEDICINAL CHEMISTRY 49, 2640-2651 Autoři: Ramos-Lima, FJ., Vrana, O., Quiroga, AG., Navarro-Ranninger, CN., Halamikova, A., Rybnickova, H., Hejmalova, L., Brabec, V. Rok: 2006

Abstrakt

We report in the present work new analogues of clinically ineffective transplatin in which one ammine group was replaced by aliphatic and the other by a planar heterocyclic ligand, namely trans-[PtCl2-(isopropylamine)(3-(hydroxymethyl)-pyridine)], 1, and trans-[PtCl2(isopropylamine)(4-(hydroxymethyl)-pyridine)], 2. The new compounds, in comparison with parent transplatin, exhibit radically enhanced activity in tumor cell lines both sensitive and in particular resistant to cisplatin. Concomitantly, the DNA binding mode of I and 2 compared to parent transplatin and other antitumor analogues of transplatin in which only one ammine group was replaced is also different. The results also suggest that the reactions of glutathione and metallothionein-2 with compounds 1 and 2 do not play a crucial role in their overall biological effects. In addition, the monofunctional adducts of 1 and 2 are quenched by glutathione considerably less than the adducts of transplatin, which may potentiate cytotoxic effects of these new platinum complexes.