Targeting antioxidant pathways with ferrocenylated N-heterocyclic carbene supported gold(i) complexes in A549 lung cancer cells† †Electronic supplementary information (ESI) available. CCDC 1419940 and 1419941. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc03519h

• Published in: Chemical science (Cambridge) Vol. 7; no. 2; pp. 1245 - 1256
• Main Authors: Arambula, J. F., McCall, R., Sidoran, K. J., Magda, D., Mitchell, N. A., Bielawski, C. W., Lynch, V. M., Sessler, J. L., Arumugam, K.
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 29.10.2015
• Subjects: Chemistry
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c5sc03519h

Ferrocenylated-Au( i ) carbenes were designed, synthesized, and studied for their ability to generate reactive oxygen species and target antioxidant pathways via multiple mechanisms. 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–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 the 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 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.