Monofunctionally DNA-binding platinum(II)-based moieties are critical components of potent antitumor-active platinum-intercalator hybrid agents.   In these electrophilic groups, the metal center is coordinated by a single chloro leaving group, two ammine ligands or a diamine, and an amidine N-donor, which serves as the linkage between the metalating and intercalating moieties.  Previous studies have shown that the rate at which platinum reacts with nuclear DNA is a critical determinant of the cell kill potential of these hybrid agents.  In this study, we have performed density functional theory (DFT) level calculations at the RB3LYP level of theory using the LANL2DZ basis set to study complex aquation and DNA nucleobase interactions of a small set of electrophilic warheads.  The major goal of the study was to predict the effects of varying the non-leaving groups.  Ammine (NH3), ethane-1,2-diamine (en), propane-1,3-diamine (pn), and N,N,N',N'-tetramethylethylenediamine (tmeda) were introduced.  Geometry optimizations on reactants and products/adducts and transition state analyses were performed.   The relative order of free activation energies for complex aquation was found to be pn < en, NH3 < tmeda. The second substitution reaction, i.e. replacement of the aqua ligand with guanine-N7, showed the same trend.  Hydrogen bonding was a major contributor to complex and transition state stability in the majority of structures.  Based on these results, the pn-containing analogue was predicted to be the most and the tmeda-substituted complex the least DNA-reactive moiety, which nicely correlates with the biological activity of the hybrid agents.  DFT calculations are suitable for predicting the genotoxicity of DNA-targeted platinum-acridines.

Computational studies of the electrophilic �warheads� in platinum-intercalator antitumor agents

247th National Meeting (2014)

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