Ferrocene containing N-heterocyclic carbene (NHC) ligated gold(I) complexes of the type [Au(NHC)2]+ were prepared and found to be capable of regulating the formation of reactive oxygen species (ROS) via multiple mechanisms. Single crystal X-ray analysis of bis(1-(ferrocenylmethyl)-3-mesitylimidazol-2-ylidene)-gold(I) chloride (5) and bis(1,3-di(ferrocenylmethyl)imidazol-2-ylidene)-gold(I) chloride (6) revealed a quasi-linear geometry around the gold(I) centers (i.e., the C–Au–C bond angle were measured to be ∼177° and all the Au–Ccarbene bonds distances were in the range of 2.00 (7)–2.03 (1) Å). A series of cell studies indicated that cell proliferation inhibition and ROS generation were directly proportional to the amount of ferrocene contained within the [Au(NHC)2]+ complexes (IC50 of 6 < 5 < bis(1-benzyl-3-mesitylimidazol-2-ylidene)-gold(I) chloride (4)). Complexes 4–6 were also confirmed to inhibit thioredoxin reductase as inferred from lipoate reduction assays and increased chelatable intracellular zinc concentrations. RNA microarray gene expression assays revealed that 6 induces endoplasmic reticulum stress response pathways as a result of ROS increase.
Arambula, Jonathan, Rebecca McCall, K, J, Sidoran, Darren Magda, Nicholas Mitchell, Christopher W. Bielawski, Vincent M. Lynch, Jonathan L. Sessler, Kuppuswamy Arumugam.
"Targeting Antioxidant Pathways with Ferrocenylated N-Heterocyclic Carbene Supported Gold(I) Complexes in A549 Lung Cancer Cells."
Chemical Science, 7 (2): 1245-1256.