Cationic and Neutral N‐Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI‐60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation

Abstract

A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF-CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent.

Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

“…All compounds were characterized by 1 H-and 13 C-NMR spectroscopy, high-resolution mass spectrometry and elemental analysis. 13 C-NMR spectroscopy unequivocally evidences the formation of the cationic gold(I) complexes Aubis(n-R) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) with resonance of the carbenic carbons located at 181.8-183.9 ppm. In the case of mono-NHC complexes Au(n-R)Cl (27)(28)(29), the most characteristic features in 13 C NMR spectra are the C2 peaks at 173.3, 174.5 and 173.7 ppm for Au(3-iPr)Cl (27), Au(3-Bn)Cl (28) and Au(3-Quin)Cl (29), respectively.…”

“…In the case of mono-NHC complexes Au(n-R)Cl (27)(28)(29), the most characteristic features in 13 C NMR spectra are the C2 peaks at 173.3, 174.5 and 173.7 ppm for Au(3-iPr)Cl (27), Au(3-Bn)Cl (28) and Au(3-Quin)Cl (29), respectively. The elemental analysis for the gold(I) complexes correspond to the general formula [AuL2][Cl] (except for Aubis(L3-Me) (14) with nitrate anion) for the bis(NHC) complexes Aubis(n-R) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) and AuLCl for the mono(NHC) complexes Au(n-R)Cl (27)(28)(29). The high resolution mass spectra (ESI + ) HRMS spectra of all gold(I) complexes exhibit the classical peak m/z for the cationic fragment [M-X − ] + .…”

“…Our chemical research is mainly focused on the design of bioactive gold(I) NHC complexes for parasitic diseases, P. falciparum [18][19][20] and Leishmania infantum [21,22], and anticancer applications [23][24][25]. Moreover, in the field of anticancer metal-based agents, the ubiquitous selenoenzyme thioredoxin reductase (TrxR), responsible for cell homeostasis regulation, is considered as one of the most relevant targets for gold(I) complexes and inhibition of TrxR could lead to apoptosis though a mitochondrial pathway [24][25][26]. Considering that artemisinins-and dihydroartemisinin, the active metabolite of all artemisinin derivatives-are active against all erythrocytic stages of P. falciparum and are still the best antiplasmodial drugs on the field, we designed hybrid complexes combining an ether derivative of dihydroartemisinin (called here DHA) with a gold(I) cation, covalently integrated in our NHC ligand systems.…”

“…Art ),24.7 (1C, C Art ), 24.6 (1C, C Art ), 20.3 (1C, C Art ), 13.1 (1C, C Art ). HRMS (ESI + ): calcd.…”

Synthesis of heterobimetallic gold(i) ferrocenyl-substituted 1,2,3-triazol-5-ylidene complexes as potential anticancer agents

“…5 Furthermore, the synergistic effect of two metal centers in a heterobimetallic complex would not only lead to enhanced activity but improve their stability and selectivity against cancer cells. 3 Although the anticancer properties of ferrocene ,6-10 gold(I) Nheterocyclic carbene (NHC) complexes [11][12][13][14] and heterobimetallic gold(I) complexes 3,5 are well known, heterobimetallic gold(I) carbene complexes bearing a metallocenyl derivative are less explored for this application. reported on the anticancer properties of cationic gold(I) ferrocenyl biscarbene and the triphenylphosphine complexes ( Fig.…”