Targeting antioxidant pathways with ferrocenylated N-heterocyclic carbene supported gold(<scp>i</scp>) complexes in A549 lung cancer cells

Abstract

Ferrocene containing <i>N</i>-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 (<b>5</b>) and bis(1,3-di(ferrocenylmethyl)imidazol-2-ylidene)-gold(I) chloride (<b>6</b>) revealed a quasi-liner geometry around the gold(I) centers, (i.e., the C<b>-</b>Au<b>-</b>C bond angle were measured to be ~177° and all the Au<b>-</b>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 (IC₅₀ of <b>6 < 5 <</b> bis(1-benzyl-3-mesitylimidazol-2-ylidene)-gold(I) chloride (<b>4</b>)). Complexes <b>4</b>-<b>6</b> 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 <b>6</b> induces endoplasmic reticulum stress response pathways as a result of ROS increase.