Publication details
Energetics, conformation and recognition of DNA duplexes modified by methylated analougues of [PtCl(dien)]+
| Authors | |
|---|---|
| Year of publication | 2009 |
| Type | Article in Periodical |
| Magazine / Source | Chemistry – A European Journal |
| MU Faculty or unit | |
| Citation | |
| Field | Biophysics |
| Keywords | DNA, DNA recognition, DNA structures, platinum, polymerization |
| Description | In early studies of empirical structure–activity relationships, monodentate PtII complexes were considered to be biologically inactive. Examples of such inactive monodentate PtII 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 PtII 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 PtII complexes. More recently it was shown that some monodentate PtII complexes do exhibit biological effects; the active monodentate PtII complexes commonly feature bulkier amine ligands than the hitherto used dien or NH3 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 PtII 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. |