The first and second substitution reactions between hydrolyzed trans/cis-[PtCl2(isopropylamine)(2)], trans/cis-[Pt(isopropylamine)(2)Cl(H2O)](+), and trans/cis-[Pt(isopropylamine)(2)(H2O)(2)](2+) and purine bases guanine and adenine are explored using the B3LYP hybrid functional and IEF-PCM solvation models. For the first substitution, the calculated lowest free energy barrier is 11.4/12.2kcal/mol (from trans-Pt-chloroaqua complex to trans/cis-monoadduct) for guanine, and 14.2/14.2kcal/mol (from trans-Pt-chloroaqua complex to trans/ cis-monoadduct) for adenine. The computed lowest free energy barrier of monoaquated complexes is always lower than that of diaquated complexes in the first substitution. Our calculations for the first substitution demonstrate, for the first time, that the trans reactant complexes (or isolated reactants) can generate trans- or cis-monoadducts via identical or very 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 same way as cisplatin. Our calculations confirm that the transplatin analogue leads to conformational alterations in double-helical DNA similar to those induced by cisplatin. In other words, it is likely that the transplatin analogue has the same mechanism of action as cisplatin binding to DNA targets. For the second substitution, the Pt(isopropylamine)(2)GA(2+) head-to-tail path has the lowest free energy of activation at 17.2 kcal/mol, closely followed by the Pt(isopropylamine)(2)GG(2+) head-to-tail path at 23.7 kcal/rnol when the monofunctional cis-Pt-G complex serves as the reactant, while the Pt(isopropylamine)2GA2+ head-to-head adduct has the lowest barrier, of 13.3kca1/mol, closely followed by the Pt(isopropylamine)(2)GG(2+) head-to-head adduct at 17.6 kcal/mol if the monofunctional trans-Pt-G complex is the reactant. The theoretically determined activation energy is lower than that of cisplatin, which confirms that trans-[PtCl2(isopropylamine)(2)] is a potential anticancer drug as suggested by experiment. The structural analysis for reactant complexes, product complexes, and transition states shows that hydrogen bonds play an important role in stabilizing these species for the first and second substitution.