Halo and Pseudohalo Gold(I)–NHC Complexes Derived from 4,5-Diarylimidazoles with Excellent <i>In Vitro</i> and <i>In Vivo</i> Anticancer Activities Against HCC

Abstract

A series of halo and pseudohalo gold(I)-NHC complexes (NHC-Au-X) (X = Cl, Br, I, NCO, and OAc) derived from 4,5-diarylimidazoles were synthesized, structurally characterized, and analyzed for their biological activities. The most active complex was iodo(1,3-diethyl-4,5-bis(4-methoxyphenyl)imidazol-2-ylidene)gold(I) (<b>6</b>), which was at least 2-fold more cytotoxic than cisplatin and auranofin against hepatocellular carcinoma (HCC) cells. <i>In vivo</i> studies indicated that complex <b>6</b> exhibited a considerably higher anticancer efficacy (IRT = 75.7%) than cisplatin (IRT = 44.4%) in a HepG2 xenograft mouse model and ameliorated liver injury caused by CCl₄ in chronic HCC. Further studies revealed that complex <b>6</b> can inhibit the expression of the thioredoxin reductase (TrxR) both <i>in vitro</i> and <i>in vivo</i>, block the HepG2 cells in the G2/M phase, induce reactive oxygen species (ROS) production, damage mitochondrial membrane potential (MMP), and promote HepG2 cell apoptosis.