A theoretical study on transition state of the antitumor drug: Gold(III) dithiocarbamate derivative interaction with cysteine and DNA purine bases

Interactions of hydrated AuIII(DMDT)Cl2 (DMDT = N,N-dimethyldithiocarbamate) complexes with sulfur-containing cysteine and DNA purine bases are performed using the density functional theory (DFT) with the B3LYP/(LanL2DZ + 6-31G(d,p)/6-311++G (2d,2p)) functional. The calculated energy profiles show that the corresponding activation barriers for the substitution reactions of the chloroaqua complex are far lower than those of the diaqua complex except adenine. Remarkably, there exist intrinsic kinetic competitions among three active sites (S, N and O) of cysteine. The N and S sites of cysteine are equally favorable and superior to N7 of guanine in the reactions of the chloroaqua complex, whereas N7 of guanine is the strongest and the soft metal center Au prefers N site of cysteine over S in those of the diaqua complex, and the O site is the weakest in all reactions. Moreover, to estimate the environmental effect, the investigation of the activation free energies for the substitution reactions in dependence of the dielectric constant ε (4, 24 and 78.39) is systematically performed, and it is demonstrated that the environmental effect has only an impact on the reactions of the diaqua complex binding to cysteine to some extent. Lastly, the natural orbital population analysis (NPA) performed in this work proves that the change in electron density between the metal center and ligands has occurred in the reactions.