Theoretical study on the bifunctional substitution reactions between gold(III) dithiocarbamate derivative Au(DMDT)Cl2 (DMDT = N,N-dimethyldithiocarbamate) and target molecules

Abstract

The complex Au(DMDT)Cl2 (DMDT=N,N-dimethyldithiocarbamate) is one of the most potential anticancer drugs with the strong cytotoxicity. However, the mechanisms of its monofunctional adducts as the active species for the formation of bifunctional adducts have not been established, thus substitution reactions between hydrated [Au(DMDT)(H2O)Cys(S, N)]2+, [Au(DMDT)(H2O)Cys(N, O)]2+, and [Au(DMDT)(H2O)G]2+ and target molecules were studied by our laboratory at the DFT level using B3LYP hybrid functional and IEF-PCM solvation model. Firstly, the reactant complex (RC) via similar trigonal bipyramidal transition state (TS) structure generates product complex (PC), and with the structural analysis towards RC, PC and TS, we know the hydrogen bond (H-bond) playing an indispensable role in the stabilization of these complexes for the bifunctional substitutions. In addition, it is worth noting that there is competition of intrinsic kinetic among different active sites of cysteine. In the bifunctional substitution reactions, the result appears to be that the N7 of guanine is the strongest site and superior to active sites (S, N) of cysteine. The soft metal center Au prefers S site of cysteine over N site interactions with hydrated [Au(DMDT)(H2O)Cys]2+ complexes and the O site of cysteine is the weakest for all reactions in the aqueous solution. Besides, the [Au(DMDT)GG]2+ head-to-head path has the lowest free energy of activation at 3.7kcal/mol and its head-to-tail path at 6.2kcal/mol, while the [Au(DMDT)GA]2+ head-to-head path has the lowest barrier of 13.3kcal/mol, and then the following head-to-tail path at 18.9kcal/mol. There was something else: the calculations show the TS for amino group acts as the attacking group to be more stable than that for sulphydryl, when the monofunctional adduct [Au(DMDT)G(H2O)]2+ acts as the reactant. A favorable reaction pathway of bifunctional substitution process is proposed by our theoretical computation.