Targeting Antioxidant Pathways with Ferrocenylated N -Heterocyclic Carbene Supported Gold(I) Complexes in A549 Lung Cancer Cells.

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-liner geometry around the gold(I) centers, (i.e., the C - Au - C bond angle were measured to be ~177° and all the Au - C _carbene 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 amount of ferrocene contained within the [Au(NHC) ₂ ] ⁺ complexes (IC ₅₀ 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 increase chelatable intracellular zinc concentrations. RNA microarray gene expression assays revealed that 6 induces endoplasmic reticulum stress response pathways as a result of ROS increase.