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

Abstract

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 Pt(II) 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 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.

• Authors: Michaela Frybortova, Olga Novakova, Jana Stepankova, Vojtech Novohradsky, Dan Gibson, Jana Kasparkova, Viktor Brabec
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 126 Pg. 46-54 (Sep 2013) ISSN: 1873-3344 [Electronic] United States
• PMID: 23770803 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• DNA Adducts
• Ligands
• Methylamines
• Organoplatinum Compounds
• transplatin
• Platinum
• methylamine
• Cisplatin

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Base Sequence
• Binding Sites
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cell-Free System
• Cisplatin (chemistry, pharmacology)
• DNA Adducts (chemistry)
• Female
• Humans
• Ligands
• Methylamines (chemistry)
• Molecular Conformation
• Molecular Sequence Data
• Organoplatinum Compounds (chemical synthesis, pharmacology)
• Platinum (chemistry)
• Structure-Activity Relationship
• Transcription, Genetic