Theoretical study on the mechanism of reaction of novel iminoether-containing Pt(II) anticancer drugs with biological targets

The reaction mechanisms of the novel potential anticancer agents trans-[PtCl2{(E)HNC(OCH3)CH3}2](trans-EE), trans-[PtCl2(NH3){(E)HNC(OCH3)CH3}](trans-E) and trans-[PtCl2(NH3){(Z)HNC(OCH3)CH3}](trans-Z) binding to DNA purine bases and amino acid residues (AAR) are explored by utilizing DFT-B3LYP functional theory and IEF-PCM solvation models. Our calculations suggest that all reaction processes can generate very similar trigonal-bipyramidal transition state configurations. Hydrogen bonds are widespread in all species and play a key role in stabilizing these species. Complete or partial proton transfer has been found in the reactant complexes. All reactants were selected the relative stable conformations. Two kinds of reaction paths with HH (head-to-head) and HT (head-to-tail) were found in bifunctional substitution. Comparison of the activation energies of these iminoether-containing Pt(II) indicates that the anticancer activity of trans conformations are higher than cis isomers, and the trans-EE showing the highest activity. The activation energies were simulated in aqueous solution (ε = 78.39) and protein environment (ε = 4.24). Our data suggest that environment donates little effect on the activation energy which can be ignored in terms of overall reactions on some extent. Those potential drugs have a similar mechanism to cisplatin.