NEQC: Núcleo de Estudos em Química Computacional, Department of Chemistry, Federal University of Juiz de Fora, Campus Universitário Martelos, 36.036-900 Juiz de Fora, Minas Gerais, Brazil.
NQTCM: Núcleo de Química Teórica e Computacional de Macaé, Polo Ajuda, Universidade Federal do Rio de Janeiro, Campus UFRJ-Macaé, 27.971-525 Macaé, Rio de Janeiro, Brazil.
Inorg Chem. 2021 Mar 1;60(5):3181-3195. doi: 10.1021/acs.inorgchem.0c03521. Epub 2021 Feb 18.
The action mechanism of anticancer gold(III) complexes is a multi-step process and depends on their redox stability. First, the gold(III) complex undergoes a ligand exchange reaction in the presence of cellular thiols, such as those available in the active site of the enzyme TrxR, and then, the Au → Au reduction occurs. Most experimental and theoretical studies describe these processes under chemical conditions without considering the enzyme structure effect. In the present study, molecular models are proposed for the [Au(C^N^C)(SHCys-R)] adduct, with the [Au(C^N^C)] moiety bonded to the Cys498 residue in the C-terminal arm of the TrxR. This one represents the product of the first ligand exchange reaction. Overall, our results suggest that the exchange of the auxiliary ligand (for instance, Cl to S-R) plays a primary role in increasing the reduction potential, with the enzyme structure having a small effect. The parent compound [Au(C^N^C)Cl] has ° = -1.20 V, which enlarges to -0.72 V for [Au(C^N^C)CHSH] and to -0.65 V for the largest model studied, Au-trx. In addition to the effect of the enzyme structure on the redox stability, we also analyze the Au transfer to the enzyme using a small peptide model (a tetramer). This reaction is dependent on the Cys497 protonation state. Thermodynamics and kinetic analysis suggests that the C^N^C ligand substitution by Cys497 is an exergonic process, with an energy barrier estimated at 20.2 kcal mol. The complete transfer of the Au ion to the enzyme's active site would lead to a total loss of enzyme activity, generating oxidative damage and, consequently, cancer cell death.
抗癌金(III)配合物的作用机制是一个多步骤的过程，取决于其氧化还原稳定性。首先，金(III)配合物在细胞硫醇的存在下发生配体交换反应，例如在 TrxR 的活性位点中存在的硫醇，然后发生 Au → Au 还原。大多数实验和理论研究在没有考虑酶结构影响的化学条件下描述这些过程。在本研究中，提出了 [Au(C^N^C)(SHCys-R)] 加合物的分子模型，其中 [Au(C^N^C)] 部分与 TrxR C 端臂中 Cys498 残基结合。这代表了第一个配体交换反应的产物。总的来说，我们的结果表明，辅助配体的交换（例如，Cl 到 S-R）在增加还原电位方面起着主要作用，而酶结构的影响较小。母体化合物 [Au(C^N^C)Cl] 的 ° = -1.20 V，对于 [Au(C^N^C)CHSH] 扩大到 -0.72 V，对于研究的最大模型 Au-trx 扩大到 -0.65 V。除了酶结构对氧化还原稳定性的影响外，我们还使用小肽模型（四聚体）分析了 Au 向酶的转移。该反应取决于 Cys497 的质子化状态。热力学和动力学分析表明，C^N^C 配体被 Cys497 取代是一个放能过程，估计能量障碍为 20.2 kcal mol。Au 离子完全转移到酶的活性位点将导致酶活性的完全丧失，产生氧化损伤，从而导致癌细胞死亡。
