RESUMEN
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 (3â»5), p-mercaptobenzoate derivatives (12â»14) and N-acetyl-l-cysteine derivatives (15â»17). All complexes were synthesised in good yields of 57â»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 Auâ»S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6â»311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.
Asunto(s)
Oro , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Metano/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Oro/química , Compuestos Heterocíclicos/química , Humanos , Espectroscopía de Resonancia Magnética , Metano/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Oro/química , Imidazolinas/química , Albúmina Sérica/química , Compuestos de Sulfhidrilo/química , Trastuzumab/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisteína/química , Portadores de Fármacos/química , Semivida , Humanos , Trastuzumab/farmacologíaRESUMEN
Gold monochloride and monobromide can be transformed into monomeric complexes by ligands such as CO, PPh3 or Me2S, 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(C29H24N2)]} and NHC-Au-Br {bromido(1,3-dibenzyl-4,5-diphenylimidazol-2-ylidene)gold, [AuBr(C29H24N2)]}, determined by X-ray crystallography at 100â K, have one and four molecules, respectively, in their asymmetric units. The chloride compound shows an almost linear C-Au-Cl fragment [179.76â (8)°], with an Au-C distance of 1.976â (3)â Å and an Au-Cl distance of 2.3013â (6)â Å, while the bromide compound shows surprisingly large geometry deviations, from 1.969â (12) to 2.016â (10)â Å for the Au-C distance and from 2.4279â (14) to 2.4796â (12)â Å for the Au-Br distance, in the four independent molecules.