A potent cytotoxic photoactivated platinum complex.
We show by x-ray crystallography that the complex trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(py)] (1) contains an octahedral Pt(IV) center with almost linear azido ligands. Complex 1 is remarkably stable in the dark, even in the presence of cellular reducing agents such as glutathione, but readily undergoes photoinduced ligand substitution and photoreduction reactions. When 1 is photoactivated in cells, it is highly toxic: 13-80 x more cytotoxic than the Pt(II) anticancer drug cisplatin, and ca. 15 x more cytotoxic toward cisplatin-resistant human ovarian cancer cells. Cisplatin targets DNA, and DNA platination levels induced in HaCaT skin cells by 1 were similar to those of cisplatin. However, cisplatin forms mainly intrastrand cis diguanine cross-links on DNA between neighboring nucleotides, whereas photoactivated complex 1 rapidly forms unusual trans azido/guanine, and then trans diguanine Pt(II) adducts, which are probably mainly intrastrand cross-links between two guanines separated by a third base. DNA interstrand and DNA-protein cross-links were also detected. Importantly, DNA repair synthesis on plasmid DNA platinated by photoactivated 1 was markedly lower than for cisplatin or its isomer transplatin (an inactive complex). Single-cell electrophoresis experiments also demonstrated that the DNA damage is different from that induced by cisplatin or transplatin. Cell death is not solely dependent on activation of the caspase 3 pathway, and, in contrast to cisplatin, p53 protein did not accumulate in cells after photosensitization of 1. The trans diazido Pt(IV) complex 1 therefore has remarkable properties and is a candidate for use in photoactivated cancer chemotherapy.
Mackay
Fiona S
FS
School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
Woods
Julie A
JA
Heringová
Pavla
P
Kaspárková
Jana
J
Pizarro
Ana M
AM
Moggach
Stephen A
SA
Parsons
Simon
S
Brabec
Viktor
V
Sadler
Peter J
PJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D004586:Electrophoresis; D016158:Genes, p53; D006147:Guanine / Q000737:chemistry; D006801:Humans; D008027:Light; D008968:Molecular Conformation; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D010777:Photochemistry / Q000379:methods; D010984:Platinum / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010984:Platinum; D006147:Guanine; D004247:DNA