Scherfler Amelie, Schwaiger Stefan, Wurst Klaus, Kircher Brigitte, Baecker Daniel, Gust Ronald
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Department of Pharmacognosy, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
Eur J Med Chem. 2025 Dec 5;299:117919. doi: 10.1016/j.ejmech.2025.117919. Epub 2025 Jun 30.
SS-, RR-, SR- and RR/SS-configured 1,3-diethyl-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-ylidenes were introduced as new imidazoline-based N-heterocyclic carbene (NHC) ligands for the design of antitumor-active (NHC)gold(I) complexes (halido(NHC)gold(I) complexes: chlorido (5a-d), bromido (6a-d), iodido (7a-d); SS,SS-, RR,RR-, SR,SR-, and RR,SS-configured [(NHC)Au(I)] complexes: 8a-d). X-ray structures of the SS-configured complexes 5a-7a showed bis-equatorially arranged phenyl rings and disturbed columnar structures with increased Au-Au distances (>5.6 Å). The SR-configuration forced the phenyl ring in a synclinal position above the NHC plane allowing only the formation of separated dimers (5c-7c). In case of the [(NHC)Au(I)] complex 8c, single molecules were observed in the crystals. The steric and dynamic conditions reduced ligand scrambling in solution and thus increased stability. The complexes showed higher growth inhibitory effects in ovarian (A2780wt (wild-type), A2780cis (Cisplatin-resistant)) than in breast cancer cells (MDA-MB-231, MCF-7) and circumvented the Cisplatin resistance in A2780 cells (effects in A2780wt = A2780cis). Chlorido- and bromido(NHC)gold(I) complexes caused comparable effects, because of a fast Br/Cl exchange (6a-d → 5a-d). The iodido(NHC)gold(I) complexes 7a-d were more active, due to a partial degradation to 8a-d. The latter were the most cytotoxic compounds of this study. The configuration of the NHC ligand did not influence the cytotoxicity of the complexes. Enantiomers and diastereomers showed the same antimetabolic effects. On the examples of 5a-d and 8a-d, the cellular uptake was studied. The maximum gold levels in A2780wt and MDA-MB-231 cells were achieved within 30 min of incubation. At concentrations corresponding to the half maximal inhibitory concentration (IC) values of the antiproliferative effect (5a-d: 20 μM, 8a-d: 5 μM), 5b, 5c, and 5d induced almost the same gold content in A2780wt cells, which was 30-50 % lower than that of 5a. The trend of accumulation for [(NHC)Au(I)] complexes was 8d < 8a < 8b < 8c. Furthermore, 5a-d inhibited the cyclooxygenase-1 (COX-1) and thioredoxin reductase (TrxR) and upregulated the Glutathione (GSH) level in A2780wt cells. Contrarily, 8a-d did not reduce COX-1 and TrxR activity, but led to moderate GSH down-regulation. The GSH level was not lowered in favour of Glutathione disulfide (GSSG), demonstrating that 8a-d influence the formation of GSH. © 2017 Elsevier Inc. All rights reserved.
引入了SS-、RR-、SR-和RR/SS构型的1,3-二乙基-4,5-二苯基-4,5-二氢-1H-咪唑-2-亚基作为新型基于咪唑啉的N-杂环卡宾（NHC）配体，用于设计具有抗肿瘤活性的（NHC）金（I）配合物（卤代（NHC）金（I）配合物：氯代（5a-d）、溴代（6a-d）、碘代（7a-d）；SS,SS-、RR,RR-、SR,SR-和RR,SS构型的[(NHC)Au(I)]配合物：8a-d）。SS构型配合物5a-7a的X射线结构显示苯环呈双赤道排列，且柱状结构受到干扰，金-金距离增加（>5.6 Å）。SR构型迫使苯环处于NHC平面上方的顺斜位置，仅允许形成分离的二聚体（5c-7c）。对于[(NHC)Au(I)]配合物8c，在晶体中观察到单分子。空间和动态条件减少了溶液中配体的重排，从而提高了稳定性。这些配合物在卵巢癌细胞（A2780wt（野生型）、A2780cis（顺铂耐药））中显示出比乳腺癌细胞（MDA-MB-231、MCF-7）更高的生长抑制作用，并克服了A2780细胞中的顺铂耐药性（在A2780wt中的作用 = A2780cis）。氯代和溴代（NHC）金（I）配合物产生了相当的效果，因为存在快速的Br/Cl交换（6a-d → 5a-d）。碘代（NHC）金（I）配合物7a-d更具活性，这是由于部分降解为8a-d。后者是本研究中细胞毒性最大的化合物。NHC配体的构型不影响配合物的细胞毒性。对映体和非对映体表现出相同的抗代谢作用。以5a-d和8a-d为例，研究了细胞摄取情况。在孵育30分钟内，A2780wt和MDA-MB-231细胞中的金含量达到最大值。在对应于抗增殖作用的半数最大抑制浓度（IC）值的浓度下（5a-d：20 μM，8a-d：5 μM），5b、5c和5d在A2780wt细胞中诱导的金含量几乎相同，比5a低30-50%。[(NHC)Au(I)]配合物的积累趋势为8d < 8a < 8b < 8c。此外，5a-d抑制了A2780wt细胞中的环氧合酶-1（COX-1）和硫氧还蛋白还原酶（TrxR），并上调了谷胱甘肽（GSH）水平。相反，8a-d没有降低COX-1和TrxR活性，但导致GSH适度下调。GSH水平没有因谷胱甘肽二硫化物（GSSG）而降低，表明8a-d影响GSH的形成。© 2017爱思唯尔公司。保留所有权利。
