Insight into the Substitution Mechanism of Antitumor Au(I) N-Heterocyclic Carbene Complexes by Cysteine and Selenocysteine

Abstract

We carried out a detailed theoretical study on the mechanism of the carbene ligand substitution by cysteine and selenocysteine residues in an Au(I) bis-N-heterocyclic carbene complex in order to model the initial stages of the mechanism of action of this promising class of antitumor metallodrug. Both neutral and deprotonated capped Cys and Sec species were considered as possible nucleophiles in the ligand exchange reaction on the metal center to model the corresponding protein side chains. Energies and geometric structures of the possible transition states and reactant− and product− adducts involved in the substitution process have been calculated using density functional theory and local MP2. Reaction and activation enthalpies and free energies have been evaluated and indicate a slightly exothermic and exergonic process with reasonably low barriers, 21.3 and 19.6 kcal mol −1 , respectively, for capped Cys and Sec, in good agreement with the experimental data available for the reaction with free amino acids. The results suggest a mechanism for the ligand exchange reaction involving an anionic thiolate or selenothiolate species coupled to an explicit proton transfer to the leaving carbene from the acidic component of the buffer. The presence of a buffer is necessary both in in vitro experiments and under physiological conditions, and its proton reservoir behavior reveals the importance of the environmental effects in carbene substitution by biological nucleophiles.

Molecular dynamics simulation of the Pb(II) coordination in biological media via cationic dummy atom models

“…Although these outcomes might represent a limitation to the employment of non-bonded topological schemes for the description of Pb(II) coordination by sulfur ligands, it should be also taken into account that the binding of thiol at metal centers may often be followed by deprotonation, leading to the corresponding thiolate complex. Several theoretical and experimental evidences have confirmed that a marked decrease of the thiol pKa occurs upon coordination at even soft metal centers such as Au(I) [66][67][68][69], Au(III) [70] and also Pb(II) [23]. Thus, the use of empirical force field implemented with non-bonded potentials describing the Pb(II) coordination at sulfur ligands may still be considered valuable by assuming the thiolate, and not thiol, as the metal-binding form.…”

Reactivity of arsenoplatin complex versus water and thiocyanate: a DFT benchmark study

“…In the present study, we assessed seven among the routinely employed and recently developed density functionals for their capability to predict the structure and reactivity of Cl-Pt(NH = C(CH 3 )-O) 2 As(OH) 2 , arsenoplatin (AP), in order to point out the adequate level of theory to use in future investigations on its mechanism of action. In particular, we considered the widely used hybrid GGA functional B3LYP [44,45] and its variant including Grimme's empirical dispersion correction B3LYP-D3 [46], the meta-GGA functional originally designed to study transition metal complexes M06-L [47], the Minnesota hybrid meta-GGA functional M06-2X [48], the one-parameter hybrid GGA functional PBE0 [49] and two more recent range-separated hybrid functionals which have been shown to provide good results for transition metal systems CAM-B3LYP [50] and ωB97X [51], which are known to give a good description of geometries and reaction profiles for transition or heavy metal-containing compounds [52][53][54][55][56], including structure and reactivity of transition metal complexes [57,58], and particularly antitumor Pt-based compounds [32,[59][60][61]. We also considered the influence of the use of three basis sets differing in their size and for the number of polarization and diffuse functions.…”

Covalent and non-covalent albumin binding of Au(i) bis-NHCsviapost-synthetic amide modification

“…This observation is in accord with the literature, which provides support for the notion that increasing steric hindrance reduces the rate of ligand exchange between cysteine and Au bis-NHCs. 31,32 Further support for this conclusion came from analogous NMR spectral studies involving complex 8; again, no discernible NHC ligand exchange in presence of cysteine was observed over the course of the study (see Fig. S4 †).…”