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A Pyrazolato‐Bridged Dinuclear Platinum( II ) Complex Induces Only Minor Distortions upon DNA‐Binding
Author(s) -
Teletchéa Stéphane,
Komeda Seiji,
Teuben JanMaarten,
ElizondoRiojas MiguelAngel,
Reedijk Jan,
Kozelka Jiří
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200500923
Subject(s) - chemistry , stereochemistry , dna , platinum , adduct , crystallography , duplex (building) , guanosine , base pair , nucleotide , helix (gastropod) , biochemistry , biology , organic chemistry , ecology , snail , gene , catalysis
The cytotoxic, pyrazolato‐bridged dinuclear platinum( II ) complex [( cis ‐{Pt(NH 3 ) 2 }) 2 (μ‐OH)(μ‐pz)] 2+ (p z =pyrazolate) has been found to cross‐link two adjacent guanines of a double‐stranded DNA decamer without destabilizing the duplex and without changing the directionality of the helix axis. A 1 H NMR study of the oligonucleotide d(CTCTG*G*TCTC)‐d(GAGACCAGAG), cross‐linked at the two G* guanines by [( cis ‐{Pt(NH 3 ) 2 }) 2 (μ‐pz)] 3+ , and molecular dynamics simulations of the explicitly solvated duplex were performed to characterize the structural details of the adduct. The dinuclear platinum cross‐link unwinds the helix by approximately 15°, that is, to a similar extent as the widely used antitumor drug cisplatin, but, in contrast to the latter, induces no significant bend in the helix axis. The Watson–Crick base‐pairing remains intact, and the melting temperature of the duplex is unaffected by the cross‐link. The helical twist is considerably reduced between the two platinated bases, as becomes manifest in an unusually short sequential H1′–H1′ distance. This unwinding also affects the sugar ring of the guanosine in the 3′‐position to the cross‐link, which presents an N⇌S equilibrium. This is the first cytotoxic platinum complex that has been successfully designed by envisioning the structural consequences of its binding to DNA.