Activation of trans geometry in bifunctional mononuclear platinum complexes by a non-bulky methylamine ligand

•Transplatin analogue containing non-bulky methylamine ligands is cytotoxic.•trans-[Pt(CH3NH2)2Cl2] forms markedly more cross-links than transplatin.•DNA binding of new trans complex and transplatin correlates with their cytoxicity.

In order to shed light on the mechanism that underlies activity of bifunctional mononuclear PtII analogs of transplatin we examined in the present work a DNA binding mode of the analog of transplatin, namely trans-[Pt(CH3NH2)2Cl2], in which NH3 groups were replaced only by a small, non-bulky methylamine ligand. This choice was made because we were interested to reveal the role of the bulkiness of the amines used to substitute NH3 in transplatin to produce antitumor-active PtII drug. The results indicate that trans-[Pt(CH3NH2)2Cl2] forms a markedly higher amount of more distorting intrastrand cross-links than transplatin which forms in DNA preferentially less distorting and persisting monofunctional adducts. Also importantly, the accumulation of trans-[Pt(CH3NH2)2Cl2] in tumor cells was considerably greater than that of transplatin and cisplatin. In addition, the results of the present work demonstrate that the replacement of ammine groups by the non-bulky methylamine ligand in the molecule of ineffective transplatin results in a radical enhancement of its activity in tumor cell lines including cisplatin-resistant tumor cells. Thus, activation of the trans geometry in bifunctional mononuclear PtII complexes can be also accomplished by replacement of ammine groups in transplatin by non-bulky methylamine ligands so that it is not limited only to the replacement by relatively bulky and stereochemically more demanding amino ligands.

Graphical abstractThe replacement of ammine groups by the non-bulky methylamine ligand in ineffective transplatin results in a radical enhancement of its activity in tumor cell lines. There is a correlation between DNA binding modes of transplatin and its analog containing the methylamine ligands and their toxicity in the tumor cell lines.Figure optionsDownload full-size imageDownload as PowerPoint slide