Computational study on the mechanisms of action of the potential anticancer drug trans-isopropylaminedimethylaminedichloroplatinum (trans-IPADMADP) and its cis isomer with DNA purine bases

The monofunctional and bifunctional bindings of the potential anticancer drug trans-isopropylaminedimethylaminedichloroplatinum (trans-IPADMADP) and its cis isomer to purine base in DNA are explored by using density functional theory and IEF-PCM solvation models. The computed lowest free energy barrier in the aqueous solution is 14.0/11.6 kcal/mol (from trans-Pt-chloroaqua complex to trans-/cis-monoadduct) for guanine(G), and 11.7/13.3 kcal/mol (from trans-Pt-chloroaqua complex to trans-/cis-monoadduct) for adenine(A). Our calculations demonstrate that the trans reactant complexes (or isolated reactants) can generate trans- or cis-monoadducts via similar trigonal bipyramidal transition state structures, suggesting that the monoadducts can subsequently close to form the bifunctional intrastrand Pt–DNA adducts and simultaneously distort DNA in the similar way as cisplatin. Our calculations show that Pt(isopropylamine)(dimethylamine)G22+ head-to-head path has the lowest free energy of activation at 17.6 kcal/mol, closely followed by the Pt(isopropylamine)(dimethylamine)GA2+ head-to-head path at 19.6 kcal/mol when the monofunctional cis-Pt-G complex serves as the reactant; while the Pt(isopropylamine)(dimethylamine)G22+ head-to-tail adduct has the lowest barrier of 20.5 kcal/mol, closely followed by the Pt(isopropylamine)(dimethylamine)GA2+ head-to-tail adduct at 23.0 kcal/mol if the monofunctional trans-Pt-G complex is the reactant. lculated relatively lower activation energy barrier than that of cisplatin theoretically confirm that trans-[PtCl2(isopropylamine)(dimethylamine)] is a potential anticancer drug as described by experiment.