DNA-binding and molecular mechanics modelling studies of the bulky chiral platinum(II) complex [PtCl(2)(mepyrr)] (mepyrr=N-methyl-2-aminomethylpyrrolidine).
Detailed studies were carried out on the binding of the enantiomers of [PtCl(2)(mepyrr)] (mepyrr=N-methyl-2-aminomethylpyrrolidine) to dG, d(GpG) and a 52-mer oligonucleotide. The pyrrolidine ligand structure was found to be neither sufficiently rigid nor bulky to enforce a single chirality at the exocyclic amine site in this complex, resulting in the presence of diastereomers that complicated the binding studies. Reaction of the (GpG) dinucleotide with R- and S-[PtCl(2)(mepyrr)] resulted in formation of four [Pt{d(GpG)}(mepyrr)] isomers for each enantiomer as a consequence of the existence of two orientational isomers and two diastereomers. These isomers formed in different amounts most likely as a consequence of the unequal formation of the diastereomers together with stereoselectivity induced by interactions between the dinucleotide and the mepyrr ligand. The [PtCl(2)(mepyrr)] complexes displayed stereoselectivity and enantioselectivity in their reactions with a 52-mer duplex designed to allow formation of only GpG intrastrand adducts. All four bifunctional adducts formed for each enantiomer, providing further evidence of the lack of directing ability of the ligand in formation of the 1,2-intrastrand adduct. Significant amounts of monofunctional species remained in these assays suggesting that the introduction of the methyl substituent to the exocyclic amine inhibited ring-closure to the bifunctional adduct. This was not sufficient to achieve enantiospecificity, but in the case of the R-enantiomer, one of the bifunctional adducts formed in only small amounts.
Diakos
Connie I
CI
Centre for Heavy Metals Research, School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Fenton
Ronald R
RR
Hambley
Trevor W
TW
D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects*; D017931:DNA Primers; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D017931:DNA Primers; D009944:Organoplatinum Compounds; C517172:Pt(Cl)2-N-methyl-2-aminomethylpyrrolidine; D011759:Pyrrolidines; D004247:DNA