Targeted delivery of potent cytotoxic drugs to cancer cells minimizes systemic toxicity and several side effects. NHC*−Au−Cl has already been proven to be a potent anticancer agent. In this study, we explore a strategy based on chemoselective cysteine conjugation of NHC*−Au−Cl to albumin and trastuzumab (Thiomab LC‐V205C) to potentiate drug‐ligand ratio, pharmacokinetics, as well as drug efficacy and safety. This strategy is a step forward towards the use of gold‐based anticancer agents as targeted therapies.
The synthesis of six novel N-heterocyclic carbene silver(I) acetate complexes, three symmetrical and three non-symmetrical, were achieved using 4,5-diphenylimidazole to produce intermediate imidazolium salts and then obtain the corresponding silver(I) complexes through complexation with silver acetate via the Youngs' method. In vitro biological testing, using the Kirby-Bauer disk diffusion method, was conducted against Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli, with a NHC-silver(I) acetate compound, SBC3, and Tetracycline as standards. Silver(I) acetate complex 7 resulted in a 4 mm clearance against MRSA, showing the highest antibiotic activity of the novel derivatives. Crystallographic data revealed similar bond lengths and angles to previously reported NHC-silver(I) acetate complexes, with complex 8 showing interesting g 2-coordination between the silver atom and acetate oxygens. 109 Ag NMR studies were conducted, highlighting the effects of the substituents of the imidazole ring on the silver atom shown by the corresponding shifts in the 109 Ag NMR spectra. The incorporation of isopropyl groups to several of the novel complexes resulted in larger upfield 109 Ag NMR shift values compared to all other substituents.
Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3–5), p-mercaptobenzoate derivatives (12–14) and N-acetyl-l-cysteine derivatives (15–17). All complexes were synthesised in good yields of 57–78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7topo breast cancer, HCT-116wt, and p53 knockout mutant HCT-116−/− colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7topo cell line with 3 displaying an IC50 of 0.28 μM ± 0.03 μM. Complexes incorporating a Au–S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6–311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.
The incorporation of (3RS)‐[2‐14C,(4R)‐4‐3H1]mevalonic acid and (3RS)‐[214‐C,(4S)‐4‐3H1]‐mevalonic acid into plastoquinone, ubiquinone, γ‐tocopherol, α‐tocopherol, α‐tocopherol quinone, β‐carotene, squalene and 3β‐hydroxysterols by maize shoots has been studied.
In agreement with the findings of workers using other tissues the atomic 14C/3H ratios for β‐carotene, squalene and 3β‐hydroxysterols labelled from [2‐14C,4R‐3H1]mevalonic acid are found to be 8:6, 6:6 and 5:3. When [2‐14C,4S‐3H1]mevalonic acid is used 3H is found to be entirely absent.
All the quinones and chromanols examined gave results which are consistent with the prenyl portions of these molecules being biogenetically all‐trans. Thus using [2‐14C,4R‐3H1]mevalonic acid the atomic 14C/3H ratios of ubiquinone, plastoquinone, phylloquinone, γ‐tocopherol, α‐tocopherol and α‐tocopherol quinone are found to be 9:9, 9:9, 4:4, 4:4, 4:4, and 4:4. Confirmation of these results is provided by the finding that when [2‐14C,4S‐3H1]mevalonic acid is used only 14C radioactivity appears in the assembled molecules.
Specific activity data suggest that γ‐tocopherol may be a precursor of α‐tocopherol, and that α‐tocopherol and α‐tocopherol quinone are in equilibrium with each other.
Gold monochloride and monobromide can be transformed into monomeric complexes by ligands such as CO, PPh or MeS, and such ligand-stabilized gold monochloride compounds have been investigated as catalysts, luminescent materials and anticancer drugs, especially when coordinated to a lipophilic benzyl-substituted N-heterocyclic carbene (NHC) ligand. The triclinic structures of NHC-Au-Cl {chlorido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuCl(CHN)]} and NHC-Au-Br {bromido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuBr(CHN)]}, determined by X-ray crystallography at 100 K, have one and four molecules, respectively, in their asymmetric units. The chloride compound shows an almost linear C-Au-Cl fragment [179.76 (8)°], with an Au-C distance of 1.976 (3) Å and an Au-Cl distance of 2.3013 (6) Å, while the bromide compound shows surprisingly large geometry deviations, from 1.969 (12) to 2.016 (10) Å for the Au-C distance and from 2.4279 (14) to 2.4796 (12) Å for the Au-Br distance, in the four independent molecules.
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