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 binding mode. The cytotoxicity of isomer 1 was comparable to that of cisplatin, whereas isomer 2 was slightly less active. Excision-repair-deficient xeroderma pigmentosum group A cells were four times more sensitive to both isomers than normal cells, thus implicating cellular DNA as the cytotoxic target. Replication mapping experiments showed that both isomers interact preferentially with guanine residues at py-G-py sites. Oligodeoxyribonucleotides containing unique N7-guanine monofunctional adducts of the more cytotoxic isomer 1 were prepared and investigated for chemical reactivity, stability and DNA conformational alterations. The results showed that the ability of thiourea to labilize the monofunctional adducts depends upon the DNA secondary structure, but not upon the sequence context. Monofunctional adducts evolve to bidentate adducts in single-stranded oligonucleotides, but they are stable in double-stranded oligonucleotides and produce conformational distortions selectively located at the 5'-adjacent base pair. This study gives new insight into the mechanism of action of trans platinum-iminoether complexes, enabling for the first time comparison between different ligand isomers.
Boccarelli
A
A
Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Bari, Italy.
Coluccia
M
M
Intini
F P
FP
Natile
G
G
Locker
D
D
Leng
M
M
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D018983:DNA Footprinting; D004273:DNA, Neoplasm / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D013237:Stereoisomerism; D013890:Thiourea / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D006131:Growth Inhibitors; D008024:Ligands; D009841:Oligonucleotides; D009944:Organoplatinum Compounds; C121813:dichlorobis(ethyl iminoacetate)platinum(II); D013890:Thiourea