Institute of Pharmacy, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.
Department of Internal Medicine V (Hematology and Oncology), Medical University Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.
Dalton Trans. 2022 Jan 25;51(4):1395-1406. doi: 10.1039/d1dt03528b.
The significance of the halido ligand (Cl, Br, I) in halido[3-ethyl-4-phenyl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2-imidazol-2-ylidene]gold(I) complexes (2-4) in terms of ligand exchange reactions, including the ligand scrambling to the bis[3-ethyl-4-phenyl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2-imidazol-2-ylidene]gold(I) complex (5), was evaluated by HPLC in acetonitrile/water = 50:50 (v/v) mixtures. In the presence of 0.9% NaCl, the bromido (NHC)gold(I) complex 3 was immediately transformed into the chlorido (NHC)gold(I) complex 2. The iodido (NHC)gold(I) complex 4 converted under the same conditions during 0.5 h of incubation by 52.83% to 2 and by 8.77% to 5. This proportion remained nearly constant for 72 h. The halido (NHC)gold(I) complexes also reacted very rapidly with 1 eq. of model nucleophiles, , iodide or selenocysteine (Sec). For instance, Sec transformed 3 in the proportion 73.03% to the (NHC)Au(I)Sec complex during 5 min of incubation. This high reactivity against this amino acid, present in the active site of the thioredoxin reductase (TrxR), correlates with the complete inhibition of the isolated TrxR enzyme at 1 μM. Interestingly, in cellular systems (A2780cis cells), even at a 5-fold higher concentration, no increased ROS levels were detected. The concentration required for ROS generation was about 20 μM. Superficially considered, the antiproliferative and antimetabolic activities of the halido (NHC)Au(I) complexes correlate with the reactivity of the Au(I)-X bond (2 < 3 < 4). However, it is very likely that degradation products formed during the incubation in cell culture medium participated in the biological activity. In particular, the high-cytotoxic [(NHC)Au(I)] complex (5) distorts the results.
在乙腈/水 = 50:50（v/v）混合物中，通过 HPLC 评估了卤化物（Cl、Br、I）配体在卤化物[3-乙基-4-苯基-5-(2-甲氧基吡啶-5-基)-1-丙基-1,3-二氢-2-咪唑-2-亚基]金（I）配合物（2-4）中的配体交换反应中的重要性，包括配体到双[3-乙基-4-苯基-5-(2-甲氧基吡啶-5-基)-1-丙基-1,3-二氢-2-咪唑-2-亚基]金（I）配合物（5）的重排。在存在 0.9%NaCl 的情况下，溴化物（NHC）金（I）配合物 3 立即转化为氯化物（NHC）金（I）配合物 2。在相同条件下，碘化物（NHC）金（I）配合物 4 在 0.5 h 的孵育期间通过 52.83%转化为 2，通过 8.77%转化为 5。在 72 h 内，这一比例基本保持不变。卤化物（NHC）金（I）配合物也与 1 eq.的模型亲核试剂反应非常迅速，例如，Sec 在 5 分钟的孵育时间内将 3 转化为（NHC）Au（I）Sec 配合物的比例为 73.03%。这种对存在于硫氧还蛋白还原酶（TrxR）活性部位的氨基酸的高反应性与对 1 μM 分离的 TrxR 酶的完全抑制相关。有趣的是，在细胞系统（A2780cis 细胞）中，即使在高 5 倍的浓度下，也没有检测到 ROS 水平的增加。生成 ROS 的浓度约为 20 μM。表面上看，卤化物（NHC）Au（I）配合物的抗增殖和抗代谢活性与 Au（I）-X 键的反应性相关（2 < 3 < 4）。然而，在细胞培养基中孵育过程中形成的降解产物很可能参与了生物活性。特别是，高细胞毒性的[(NHC)Au(I)]配合物（5）扭曲了结果。
