Ligand effects on platinum binding to DNA. A comparison of DNA binding properties for cis- and trans-[PtCl2(amine)2] (amine = NH3, pyridine).
The DNA binding properties of cis- and trans-[PtCl2(pyridine)2] have been examined and compared with their NH3 analogs, cis- and trans-DDP. The presence of a planar ligand reduces the rates of DNA binding but does not greatly affect the overall conformation of CT DNA, as measured by circular dichroism spectroscopy. The sequence specificity of trans-[PtCl2(py)2] includes alternating purine-pyrimidine sequences. The sequence specificity is further different between the two pyridine isomers, and the steric effects of two cis-pyridine groups are demonstrated by the appearance of relatively few binding sites in the 49-bp duplex. The effects of the pyridine ligand are further manifested by a greatly enhanced DNA-DNA interstrand cross-linking efficiency for the trans isomer, with a cross-link per adduct frequency of between 0.14 and 0.23, depending on the rb of the sample. The unwinding of closed circular pUC19 DNA by trans-[PtCl2(pyridine)2] is also more efficient than that by either DDP isomer, with an unwinding angle calculated at phi = 17 degrees (compare cis-DDP with phi = 13 degrees and trans-DDP with phi = 9-10 degrees). In contrast, little unwinding is induced by cis-[PtCl2(pyridine)2], with phi = 4 degrees. These results in particular invert the standard cis/trans structure-activity relationships observed previously for [PtCl2(NH3)2]. The results are discussed with respect to the previously demonstrated effect of activation of the trans-platinum geometry using sterically hindered ligands.
Department of Chemistry, Vermont Cancer Center, University of Vermont, Burlington 05405.
Y
Y
Zou
B
B
Van Houten
N
N
Farrell
D001483:Base Sequence; D002945:Cisplatin / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D008024:Ligands; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D003432:Cross-Linking Reagents; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin