Ring-substituted diaqua(1,2-diphenylethylenediamine)platinum(II) sulfate reacts with DNA through a dissociable complex.
Ring-substituted diaqua(1,2-diphenylethylenediamine)platinum(II) sulfate shows unusual kinetics in its reaction with salmon testis DNA. The mechanism for diaqua[meso-1,2-bis(2,6-dichloro-4- hydroxyphenyl)ethylenediamine]platinum(II) sulfate, [Pt(H2O)2(meso-6)]2+SO4(2-), a representative of this series, has been investigated and compared with that for cis-[Pt(NH3)2(H2O)2]2+. Reactions were followed by atomic absorption, analytical HPLC of Pt-DNA digests, arrest of enzymatic DNA synthesis/degradation, ultraviolet and fluorescence spectrophotometry. Except for the formation of monofunctional DNA adducts, the kinetics of the platinum(II) complexes are comparable. The pseudo-first-order rate constant for the attack of DNA by [Pt(H2O)2(meso-6)]2+ follows the concentration of DNA in a hyperbolic fashion, which is in contrast to the linear dependence for cis-[Pt(NH3)2(H2O)2]2+. The hyperbolic dependence is typical for a dissociable DNA/drug complex preceding the coordination reaction. By studying the binding of free ligand to DNA, and by correlating ligand structures and electrostatic charges with effects on adduct formation, both the phenyl residues and the positive charge of the platinum(II) complex are shown to be crucial for the stability of the dissociable complex. A non-intercalative mode of binding to the DNA backbone is suggested. At the high concentrations of DNA found in cell nuclei, the reaction of the dissociable complex can, principally, become rate-limiting in the attack of DNA and thus reduce the cytotoxic efficiency of a drug.
Bernges
F
F
Institut für Biophysik und physikalische Biochemie, Universität Regensburg, Federal Republic of Germany.
Holler
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008274:Magnesium / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry*; D012474:Salmon; D013431:Sulfates
D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D013431:Sulfates; D004247:DNA; C042922:dichloro(1,2-bis(4-hydroxyphenyl)ethylenediamine)platinum II; D008274:Magnesium; D002945:Cisplatin