Activation of trans geometry in bifunctional mononuclear platinum complexes by a non-bulky methylamine ligand
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
23770803
DOI
10.1016/j.jinorgbio.2013.05.009
PII: S0162-0134(13)00122-0
Knihovny.cz E-resources
- Keywords
- Activation of trans geometry, Cytotoxicity, DNA adducts, Platinum(II)-based agents,
- MeSH
- DNA Adducts chemistry MeSH
- Cell-Free System MeSH
- Cisplatin chemistry pharmacology MeSH
- Transcription, Genetic MeSH
- Humans MeSH
- Ligands MeSH
- Methylamines chemistry MeSH
- Molecular Conformation MeSH
- Molecular Sequence Data MeSH
- Cell Line, Tumor MeSH
- Organoplatinum Compounds chemical synthesis pharmacology MeSH
- Platinum chemistry MeSH
- Antineoplastic Agents chemical synthesis pharmacology MeSH
- Base Sequence MeSH
- Binding Sites MeSH
- Cell Survival drug effects MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Adducts MeSH
- Cisplatin MeSH
- Ligands MeSH
- methylamine MeSH Browser
- Methylamines MeSH
- Organoplatinum Compounds MeSH
- Platinum MeSH
- Antineoplastic Agents MeSH
- transplatin MeSH Browser
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.
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