ABSTRACT:The first and second substitution reactions binding of the anticancer drug trans-[Pt((CH 3 ) 2 C¼ ¼NOH)((CH 3 ) 2 CHNH 2 )Cl 2 ] to purine bases were studied computationally using a combination of density functional theory and isoelectric focusing polarized continuum model approach. Our calculations demonstrate that the trans monoaqua and diaqua reactant complexes (RCs) can generate either trans-or cismonoadducts via identical or very similar trans trigonal-bipyramidal transition-state structures. Furthermore, these monoadducts can subsequently close by coordination to the adjacent purine bases to form 1,2-intrastrand Pt-DNA adducts and eventually distort DNA in the same way as cisplatin. Thus, it is likely that the transplatin analogues have the same mechanism of anticancer activity as cisplatin. For the first substitutions, the activation free energies of monoaqua complexes are always lower than that of diaqua complexes. The lowest activation energy for monoaqua substitutions is 16.2 kcal/mol for guanine and 16.5 kcal/mol for adenine, whereas the lowest activation energy for diaqua substitutions is 17.1 kcal/mol for guanine and 25.9 kcal/ mol for adenine. For the second substitutions, the lowest activation energy from transmonoadduct to trans-diadduct is 19.1 kcal/mol for GG adduct and 20.7 kcal/mol for GA adduct, whereas the lowest activation energy from cis-monoadduct to cis-diadduct is 18.9 kcal/mol for GG adduct and 18.5 kcal/mol for GA adduct. In addition, the first and second substitutions prefer guanine over adenine, which is explained by the remarkable larger complexation energy for the initial RC in combination with lower activation energy for the guanine substitution. Overall, the hydrogen-bonds play an important role in stabilizing these species of the first and second substitutions.

The monofunctional (the¯rst substitution reactions) and bifunctional (the second substitution reactions) binding of the title antitumor drugs to purine bases were studied computationally by using density functional theory and IEF-PCM solvation models. For the¯rst substitutions with guanine and adenine, our calculations demonstrate that the trans monoaqua and diaqua reactant complexes (RCs) can generate trans-or cis-monoadducts via identical or very similar trigonalbipyramidal transition-state structures, predicting that the cis-monoadducts generated by trans RCs can subsequently close by coordination to the adjacent purine bases to form 1,2-intrastrand PtÀDNA adducts and eventually distort DNA in the same way as cisplatin. Thus it is likely that the transplatin analogues have the same mechanism of anticancer activity of cisplatin. In general, the monoaqua and diaqua monofunctional substitutions prefer guanine over adenine. The calculated lowest activation free energy in aqueous solution is 15.2 kcal/mol in the monoaqua substitutions (substituted by guanine from trans-½PtfHN ¼ CðCH 3 Þ 2 g 2 ClðH 2 OÞ þ to trans/cis-monoadduct), and 11.4 kcal/mol in the diaqua substitutions (substituted by guanine from cis-½PtfHN ¼ CðCH 3 Þ 2 g 2 ðH 2 OÞ 2 2þ to cis-monoadduct). For the second substitutions, all the reactants are started from the diaqua product complexes of the¯rst substitutions substituted by guanine. The data obtained for the complexation energy di®erence between guanine and adenine RCs suggest that a thermodynamic favors the formation of GG over GA adducts by $ 5 À 12 kcal/mol in aqueous solution. Moreover, there is a kinetic preference for the formation of GG over GA adduct for the cis-monoadduct to cis-diadduct paths, while for the trans-monoadduct to trans-diadduct paths there is no certain trend biased toward GG adduct. In addition, the second substitutions of the trans-monoadduct to trans-diadduct paths have lower activation barriers than the corresponding cis-monoadduct to cis-diadduct paths. The lowest activation energy in the bifunctional substitutions from cis-monoadduct to cis-diadduct is 20.5 kcal/mol in the Pt(acetonimine) 2 GG 2þ head-to-head (HH) path, while it is 17.7 kcal/mol from trans-monoadduct to trans-diadduct in the Pt(NH 3 )(acetonimine)GA 2þ head-to-tail (HT) path. For the¯rst and second substitutions, hydrogen-bonds play an important role in stabilizing these species.