Introduction of 1,3-Diethyl-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-ylidene as New Ligand for the Design of Antitumor-Active (NHC)gold(I) Complexes: An Approach to Reduce Ligand Scrambling and to Increase Tumor Cell Selectivity

Abstract

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)₂Au(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)₂Au(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, A2780cis) 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 IC₅₀ 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)₂Au(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 GSSG, demonstrating that 8a-d influence the formation of GSH.© 2017 Elsevier Inc. All rights reserved.