A pyrazolato-bridged dinuclear platinum(II) complex induces only minor distortions upon DNA-binding.
The cytotoxic, pyrazolato-bridged dinuclear platinum(II) complex [(cis-{Pt(NH3)2})2(mu-OH)(mu-pz)]2+ (pz=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 1H NMR study of the oligonucleotide d(CTCTG*G*TCTC)-d(GAGACCAGAG), cross-linked at the two G* guanines by [(cis-{Pt(NH3)2})2(mu-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 degrees , 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.
Teletchéa
Stéphane
S
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université René Descartes, UMR 8601 CNRS, 45, rue des Saints-Pères, 75270 Paris Cedex 06, France.
Komeda
Seiji
S
Teuben
Jan-Maarten
JM
Elizondo-Riojas
Miguel-Angel
MA
Reedijk
Jan
J
Kozelka
Jirí
J
D020029:Base Pairing; D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D015226:Dinucleoside Phosphates; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D017671:Platinum Compounds / Q000737:chemistry* / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry*
D003432:Cross-Linking Reagents; D015226:Dinucleoside Phosphates; D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides; D017671:Platinum Compounds; D011720:Pyrazoles; C018309:guanylyl-(3'-5')-guanosine; D004247:DNA