Cytotoxicity and DNA binding mode of new platinum-iminoether derivatives with different configuration at the iminoether ligands

The platinum-iminoether complexes trans-[PtCl2{E-HN=-C(OEt)Me}(2)] (1) and trans-[PtCl2{Z-HN=C(OEt)Me}(2)] (2), differing in the configuration of the iminoether ligands, were investigated for cytotoxicity towards human tumor cell lines, the involvement of DNA as a cytotoxic target, and their DNA bin ding mode. The cytotoxicity of isomer 1 was comparable to that of cisplatin , whereas isomer 2 was slightly less active. Excision-repair-deficient xero derma pigmentosum group A cells were four times more sensitive to both isom ers than normal cells, thus implicating cellular DNA as the cytotoxic targe t. Replication mapping experiments showed that both isomers interact prefer entially with guanine residues at py-G-py sites. Oligodeoxyribonucleotides containing unique N7-guanine monofunctional adducts of the more cytotoxic i somer 1 were prepared and investigated for chemical reactivity, stability a nd DNA conformational alterations. The results showed that the ability of t hiourea to labilize the monofunctional adducts depends upon the DNA seconda ry structure, but not upon the sequence context. Monofunctional adducts evo lve to bidentate adducts in single-stranded oligonucleotides, but they are stable in double-stranded oligonucleotides and produce conformational disto rtions selectively located at the 5'-adjacent base pair. This study gives n ew insight into the mechanism of action of trans platinum-iminoether comple xes, enabling for the first time comparison between different ligand isomer s.