Reactivity of the [Au(C^N^C)Cl] complex in the presence of H2O and N-, S- and Se-containing nucleophiles: a DFT study

Abstract

Gold complexes are promising compounds used in cancer chemotherapy. Besides their steric features, which enable biomolecule interactions, the redox instability and the high affinity of gold with cellular nucleophiles influence the biological action in these complexes. Both features were herein theoretically investigated for the [Au(C^N^C)Cl] probe complex (C^N^C = 2,6-diphenylpyridine) using HO, CHSH/CHS, CHSe and meim-4-H (4-methylimidazole) as biomimetic nucleophiles. Based on the results, the lowest energy reaction path followed two consecutive steps: (1) chloride-exchange ([Formula: see text] = 4.14 × 10 M s) and (2) reduction of the resulting Au(III) metabolite to the corresponding Au(I) analog with chelate ring-opening ([Formula: see text] =+0.15 V-data based on the reaction with CHSe). These findings bring new insights about the mechanism of the Au(III) complex/biomolecule interaction in the cell, which is responsible for triggering biological responses.

Recent Advances in Gold(III) Chemistry: Structure, Bonding, Reactivity, and Role in Homogeneous Catalysis

“…236,237 The substitution of the chloride ligand in square-planar (C^N^C)AuCl 71 238,239 by water has been studied computationally. 43 It is thought to follow a dissociative interchange mechanism, in which the elongation and breaking of the Au-Cl bond plays the primary role, via transition state TS1 Prolonged heating leads to the reductive elimination product, decafluorobiphenyl. There was no reaction with PhB(OH) 2 .…”

“…41 However, in several instances, even Au(III) complexes stabilized by C^N^C or N^N^N pincer ligands were found to be susceptible to reduction on reaction with nucleophiles. 42,43 Photolysis of gold(III) halide complexes, and even exposure to diffuse daylight, can lead to reductive elimination, including the reductive elimination of C-Cl bonds and of Cl 2 . [44][45][46][47] While platinum is similar to gold in being subject to relativistic effects, these are much less pronounced.…”

A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent

“…The geometry was optimized in solution (using PCM approach) at B3LYP/SDD(f)/6‐31+G(2df) level. The same computational protocol was successfully applied for Au I and Au III complexes in our previous studies [69–75] . The vibrational frequencies were also calculated at the very same level of theory and the force constants estimated from the Hessian matrix using the Seminario method, [76] as implemented in the Visual Force Field Derivation Toolkit (VFFDT) program [77] .…”

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey

“…The cyclometalated complexes 35a-35c, 36a-36f, 37a-37c (Figure 17) feature a remarkable redox activity, giving rise to peculiar pathways of protein targeting. Theoretical investigations on the structure and reactivity of such complexes [95][96][97][98] are reported below (vide infra, Section 3.2. Redox stability).…”

“…Distinctive features of Au(III) anticancer complexes, which make them unique, are their redox instability and the high affinity of gold towards cellular nucleophilic targets. An exceptionally detailed computational study focused on the interaction of [Au(CˆNˆC)Cl] probe complex (CˆNˆC = 2,6-diphenylpyridine) with water and the biomolecular targets represented by simplified molecular models CH 3 SH/CH 3 S − , CH 3 Se − , and 4-methylimidazole (Figure 17, structure 35a, Scheme 1) [95]. DFT calculations permitted to conclude that the lowest energy reaction path is composed of two consecutive processes: (a) the substitution of chloride by the nucleophile and (b) the reduction of the resulting Au(III) complex to the corresponding Au(I) derivative with the opening of the chelate ring.…”