Quantum Chemical Investigations on the Hydrolysis of Gold(III)-Based Anticancer Drugs and Their Interaction with Amino Acid Residues

Abstract

A comprehensive hydrolysis mechanism of the promising class of Au(III) anticancer drugs [Au(DMDT)Cl 2 ] (DMDT = N,N-dimethyldithiocarbamate) (R) and [Au(damp)Cl 2 ] (damp = 2-[(dimethylamino)methyl]phenyl) (R′) was done by means of density functional theory (DFT) in combination with the CPCM solvation model to explore the solution behavior and stability under physiological conditions. The activation free energies (ΔG) for the second hydrolysis, R (13.7 kcal/mol) and R′ (10.0 kcal/mol) are found to be relatively lower in comparison to the first hydrolysis, and their rate constant values are computed to be 5.62 × 10 2 and 2.90 × 10 5 s −1 , respectively. Besides these, the interaction mechanisms of aquated R and R′ with the potential protein-binding sites cysteine (Cys) and selenocysteine (Sec) were also investigated in detail. The kinetic study and activation Gibbs free energy profiles reveal that the aquated complexes of R and R′ bind more effectively to the Se site of Sec than to the S site of Cys. Intra-and intermolecular hydrogen bonding play a pivotal role in stabilizing the intermediates and transition states involved in the ligand substitution reactions of R and R′. Natural population analysis (NPA) was done to determine the charge distributions on important atoms during the hydrolysis and ligand substitution reactions.

[AuIII(N^N)Br2](PF6): A Class of Antibacterial and Antibiofilm Complexes (N^N = 2,2′-Bipyridine and 1,10-Phenanthroline Derivatives)

“…Gold-based drugs can act as prodrugs that undergo ligand substitution or participate in redox reactions before interacting with their biotargets. − Under physiological conditions, gold­(III) complexes can be at least partly hydrolyzed to give their aqueous complexes . The mechanism of action of Au III compounds is still a matter of debate and is under investigation .…”

“…Gold-based drugs can act as prodrugs that undergo ligand substitution or participate in redox reactions before interacting with their biotargets. − Under physiological conditions, gold­(III) complexes can be at least partly hydrolyzed to give their aqueous complexes . The mechanism of action of Au III compounds is still a matter of debate and is under investigation . Some insights into the biological activity of the title compounds could be inferred from DFT calculations (Tables S4–S26 and Figures S9 and S10), carried out on the complex cations of compounds 1 – 10 based on previous studies on related systems. ,− Analysis of the eigenvalues of Kohn–Sham (KS) frontier molecular orbitals at the optimized geometry (Table S25) shows that the complex cations of compounds 1 , 4 , 6 , and 9 feature the most stable lowest unoccupied molecular orbitals (KS-LUMOs), which are antibonding in nature with respect to the gold–halogen bonds (Figure S10).…”

“… 69 − 71 Under physiological conditions, gold(III) complexes can be at least partly hydrolyzed to give their aqueous complexes. 69 The mechanism of action of Au III compounds is still a matter of debate and is under investigation. 69 Some insights into the biological activity of the title compounds could be inferred from DFT calculations ( Tables S4–S26 and Figures S9 and S10 ), carried out on the complex cations of compounds 1 – 10 based on previous studies on related systems.…”