Energetics, conformation, and recognition of DNA duplexes modified by methylated analogues of [PtCl(dien)]+.
In early studies of empirical structure-activity relationships, monodentate Pt(II) complexes were considered to be biologically inactive. Examples of such inactive monodentate Pt(II) compounds are [PtCl(dien)]+ (dien=diethylenetriamine) and [PtCl(NH3)3]+. DNA is considered the major biological target of platinum compounds. Thus, monodentate DNA binding of Pt(II) compounds was previously expected to display insignificant biological effects because it was assumed to affect DNA conformation and downstream cellular processes markedly less than the cross-links of bifunctional Pt(II) complexes. More recently it was shown that some monodentate Pt(II) complexes do exhibit biological effects; the active monodentate Pt(II) complexes commonly feature bulkier amine ligands than the hitherto used dien or NH(3) groups. We were therefore interested in determining whether a simple but marked enhancement of the bulkiness of the dien ligand in monodentate [Pt(NO3)(dien)]+ by multiple methylation of this ligand affects the early phases in which platinum compounds exert their biological activity. More specifically, the goals of this study, performed in cell-free media, were to determine how the modification of DNA duplexes by methylated analogues of [Pt(NO3)(dien)]+ affects their energetics and how the alterations of this biophysical parameter are reflected by the recognition of these duplexes by DNA polymerases and the DNA repair system. We have found that the impact of the methylation of [Pt(NO3)(dien)]+ on the biophysical properties of DNA (thermodynamic, thermal, and conformational properties) and its biochemical processes (DNA polymerization and the repair of DNA adducts) is remarkable. Hence, we conclude that monodentate DNA binding of Pt(II) compounds may considerably affect the biophysical properties of DNA and consequently downstream cellular processes as a result of a large increase in the bulkiness of the nonleaving ligands in this class of metal complex.
Nováková
Olga
O
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i. Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Malina
Jaroslav
J
Kaspárková
Jana
J
Halámiková
Anna
A
Bernard
Vladan
V
Intini
Francesco
F
Natile
Giovanni
G
Brabec
Viktor
V
D001483:Base Sequence; D001665:Binding Sites; D002151:Calorimetry; D004247:DNA / Q000737:chemistry*; D004260:DNA Repair / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
D009944:Organoplatinum Compounds; D004247:DNA; D004259:DNA-Directed DNA Polymerase