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

In order to shed light on the mechanism that underlies activity of bifunctional mononuclear Pt^II 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(CH ₃NH₂)₂Cl₂] forms a markedly higher amount of more distorting intrastrand cross-links than transplatinwhich forms in DNA preferentially less distorting and persisting monofunctional adducts. Also importantly, the accumulation of trans-[Pt(CH₃NH₂) ₂Cl₂] in tumor cellswas 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 bifunctionalmononuclear Pt^II complexes can be also accomplished by replacement of ammine groups in transplatin by non-bulkymethylamine ligands so that it is not limited only to the replacement by relatively bulky and stereochemically more demanding amino ligands.