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

作者：Frybortova Michaela; Novakova Olga; Stepankova Jana; Novohradsky Vojtech; Gibson Dan; Kasparkova Jana; Brabec Viktor^*

来源：Journal of Inorganic Biochemistry, 2013, 126: 46-54.

DOI：10.1016/j.jinorgbio.2013.05.009

• Platinum(II)-based agents
• Activation of trans geometry
• Cytotoxicity
• DNA adducts

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)(2)Cl-2], 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 Pt-II drug. The results indicate that trans-[Pt(CH3NH2)(2)Cl-2] 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)(2)Cl-2] 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 Pt-II 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.

• 出版日期2013-9