Internal and External Influences on Stability and Ligand Exchange Reactions in Bromido[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) Complexes.

The ligand scrambling reaction of gold(I) complexes is a phenomenon occurring primarily in L-AuI-X (L = phosphine, N-heterocyclic carbene (NHC), and thiol; X = halide and thiol) complexes and has been observed among others for e.g., the bromido[3-ethyl-4-(4-methoxyphenyl)-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(I) complex (7a), which underwent ligand rearrangement in aqueous solutions. In this study, we investigated the influence of substituents on the 4-aryl ring of the related (NHC)AuIBr complexes (1a-9a) in terms of the conversion to the [(NHC)2AuI]+ (1b-9b) and [(NHC)2AuIIIBr2]+ (1c-9c) species. Furthermore, the influence of external factors such as solvent, temperature, concentration, and presence of halides (Cl-, Br-, and I-) or hydroxyl ions was studied to gain a deeper understanding of the ligand rearrangement reaction. The substituent on the 4-aryl ring has a marginal impact on the scrambling reaction. Out of the investigated organic solvents (dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol (EtOH), methanol (MeOH), and acetonitrile (ACN)), only ACN separates single complex molecules. In all other solvents, relatively stable ((NHC)AuIBr)2 dimers are present. The addition of water to ACN solutions forces the formation of such dimeric units, starting the transformation to [(NHC)2AuI]+ and [(NHC)2AuIIIBr2]+. The rate-determining step is the release of Br- from a T-shape intermediate because an excess of KBr terminates this reaction. Furthermore, it is obvious that only single molecules react with halides. The aurophilic interactions between two (NHC)AuIBr molecules are too strong in the presence of water and largely impeded reaction with halides. As a single molecule, the reaction with Cl- (e.g., in a 0.9% NaCl solution) is notable, while I- even leads to a fast and quantitative conversion to (NHC)AuII and finally to [(NHC)2AuI]+.

Investigations of the reactivity, stability and biological activity of halido (NHC)gold(I) complexes.

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-2H-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-2H-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, e.g., 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)2Au(I)]+ complex (5) distorts the results.

Synthesis, characterization and biological activity of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(i) complexes.

A series of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2H-imidazol-2-ylidene]gold(i) complexes (2a-f) containing methyl, fluoro or methoxy substituents at various positions in the 4-aryl ring was synthesized and evaluated for their anti-cancer properties in A2780 (wild-type and Cisplatin-resistant) ovarian carcinoma as well as LAMA 84 (imatinib-sensitive and -resistant) and HL-60 leukemia cell lines. The bis-NHC gold(i) complexes were more active compared to their related mono-NHC gold(i) analogues and reduced proliferation and metabolic activity in a low micromolar range. With the exception of 2d (3-F), the compounds displayed higher potency than the established drugs Auranofin and Cisplatin. The lack of effects against non-cancerous lung fibroblast SV-80 cells indicated a high selectivity towards tumor cells. All tested complexes generated reactive oxygen species in A2780cis cells; however, the induction of apoptosis was very low. Furthermore, thioredoxin reductase is not the main target of these complexes, because its inhibition pattern did not correlate with their biological activity.