Stereospecificity and enantioselectivity in the binding of the platinum(II) complex [PtCl2(tmdz)] (tmdz = 5,5,7-trimethyl-1,4-diazacycloheptane) to dinucleotides and oligonucleotides.
The two stereoisomers formed on reaction of each of the enantiomers of [PtCl2(tmdz)] with d(GpG) have been identified by using one- and two-dimensional 1H NMR spectroscopy. For both isomers formed with the R enantiomer the 3'-H8 shifts are downfield from those for the 5'-H8. For the S enantiomer the reverse is observed, showing that the bulky tmdz ligand determines the pattern of shifts. Models of these isomers generated by molecular mechanics show that the bulky tmdz ligand limits the rotation of the guanine bases and enforces right-handed (R2) canting for both isomers formed by the R enantiomer and left-handed (L1) canting for those formed by the S enantiomer. The pattern of H8 shifts is the opposite to that expected for these cantings; this suggests that other factors may play a role in determining these shifts. The interactions between the tmdz and d(GpG) ligands are also shown by molecular mechanics and the broadness of the H8 NMR signals to influence the tendency of the coordinated guanine bases to rotate about their Pt-N7 bonds. Reaction of each of the enantiomers with a 52 base-pair nucleotide, with a total of six GpG binding sites, resulted in the formation of only one of the stereoisomers in each case, the first reported case of complete stereoselectivity, or stereospecificity, in the reaction of Pt complexes with DNA. The observed stereoisomers were identified by comparison with the properties of the d(GpG) complexes. Molecular mechanics models of the adducts with duplex DNA show that the nonformation of one stereoisomer is consistent with the steric bulk of the tmdz ligand preventing closure from the monofunctional adduct to the bifunctional adduct. Enantioselectivity is also observed in that the R enantiomer forms more monofunctional adducts than bifunctional (59:41), whereas the S enantiomer forms more bifunctional adducts (27:73). The origins of this enantioselectivity must be at the level of monofunctional adduct formation and this has been investigated by molecular mechanics modelling.
Munk
Vivienne P
VP
Centre for Heavy Metals Research, School of Chemistry, University of Sydney, NSW 2006, Australia.
Diakos
Connie I
CI
Messerle
Barbara A
BA
Fenton
Ronald R
RR
Hambley
Trevor W
TW
D001483:Base Sequence; D015226:Dinucleoside Phosphates / Q000737:chemistry*; D007536:Isomerism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D015226:Dinucleoside Phosphates; D008024:Ligands; D009841:Oligonucleotides; D009944:Organoplatinum Compounds