DNA cleavage and binding selectivity of a heterodinuclear Pt-Cu(3-Clip-Phen) complex.
The synthesis and nuclease activity of a new bifunctional heterodinuclear platinum-copper complex are reported. The design of this ditopic coordination compound is based on the specific mode of action of each component, namely, cisplatin and Cu(3-Clip-Phen), where 3-Clip-Phen 1-(1, 10-phenanthrolin-3-yloxy)-3-(1,10-phenanthrolin-8-yloxy)propan-2-amine. Cisplatin is not only able to direct the Cu(3-Clip-Phen) part to the GG or AG site, but also acts as a kinetically inert DNA anchor. The nuclease activity of this complex has been investigated on supercoiled DNA. The dinuclear compound is not only more active than Cu(3-Clip-Phen), but is also capable of inducing direct double-strand breaks. The sequence selectivity of the mononuclear platinum complex has been investigated by primer extension experiments, which reveal that its interaction with DNA occurs at the same sites as for cisplatin. The Taq polymerase recognizes the resulting DNA damage as different from that for unmodified cisplatin. The sequence-selective cleavage has been investigated by high-resolution gel electrophoresis on a 36-bp DNA fragment. Sequence-selective cleavages are observed in the close proximity of the platinum sites for the strand exhibiting the preferential platinum binding sites. The platinum moiety also coordinates to the other DNA strand, most likely leading only to mono guanine or adenine adducts.
de Hoog
Paul
P
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Pitié
Marguerite
M
Amadei
Giulio
G
Gamez
Patrick
P
Meunier
Bernard
B
Kiss
Robert
R
Reedijk
Jan
J
D002945:Cisplatin / Q000737:chemistry; D053837:DNA Cleavage; D004278:DNA, Superhelical / Q000235:genetics; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics; D009942:Organometallic Compounds / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry*; D010618:Phenanthrolines / Q000737:chemistry*
C115240:Clip-phen; D004278:DNA, Superhelical; D009841:Oligonucleotides; D009942:Organometallic Compounds; D009944:Organoplatinum Compounds; D010618:Phenanthrolines; C531042:dichloro(1-(1,10-phenanthrolin-3-yloxy)-3-(1,10-phenanthrolin-8-yloxy)propane-2-amine)copper(II); D002945:Cisplatin