Toxicity in tumor cells, DNA binding mode, and resistance to decomposition by sulfur nucleophiles of new dinuclear bifunctional trans-PtII complexes containing long alkane linkers

Abstract

In an effort to design dinuclear PtII compounds that maintain the target (DNA) binding profile of the trans-oriented dinuclear bifunctional PtII complexes containing aliphatic linker chains but are less susceptible to metabolic decomposition, the new, long-chain dinuclear PtII complexes—[{trans-PtCl(dien)}2-μ-(CH2) n ]2+ (n = 7,10,12, dien = diethylenetriamine)—were synthesized. The toxicity of these metallodrugs was examined in ovarian tumor cell lines. The results showed that the activity of these complexes increased with growing length of the linker; the activity of complex containing the longest linker (n = 12) was comparable with that of cis-diamminedichloridoplatinum(II) (cisplatin). This observation correlated with the results of DNA binding studies performed in cell-free media. The results of these studies demonstrated that the growing length of the aliphatic bridge promoted more distorting conformational alterations induced in DNA. Attention was also paid to the reactivity of {[Pt(dien)Cl]2-alkane} compounds with glutathione (GSH). The results of these experiments support the thesis that the dinuclear structure of {[Pt(dien)Cl]2-alkane} complexes remains stable in the presence of S-containing compounds without undergoing chemical degradation as previously observed for some di/trinuclear bifunctional PtII complexes. This enhanced stability represents a favorable property which may contribute to reduce side effects and increase therapeutic efficacy of the dinuclear {[Pt(dien)Cl]2-alkane} compounds.