The kinetic competition of sulfur and nitrogen nucleophiles L in the substitution reactions of cisplatin derivatives, cis-[Pt(II)(NH(3))(2)(X)(OH(2))](n)(+) + L --> cis-[Pt(II)(NH(3))(2)(X)(L)](m)(+) + H(2)O (X = Cl(-), H(2)O), has been studied using density functional theory and continuum dielectric calculations. The calculations reveal an intrinsic kinetic preference of platinum(II) for nitrogen over sulfur ligands. However, biologically relevant substituents can mask this preference for nitrogen nucleophiles. Investigation of the activation free energies of the substitution reactions in dependence of the dielectric constant epsilon demonstrates the microenvironment to be crucial in the binding of cisplatin to its intracellular targets. The fused aromatic heterocycle of guanine stabilizes the transition state for platination at a smaller epsilon more efficiently than do the functional groups of amino acid residues. The results of this work suggest a relatively facile platination of guanine-N7 sites of DNA in regions of low epsilon, particularly in the proximity of histone cores.