Anticancer Profile of a Series of Gold(III) (2‐phenyl)pyridine Complexes. Issue 12 (5th November 2014)

• Record Type: Journal Article
• Authors: Rubbiani, Riccardo; Zehnder, Thomas N.; Mari, Cristina; Blacque, Olivier; Venkatesan, Koushik; Gasser, Gilles
• Is Part Of: ChemMedChem. Volume 9:Issue 12(2014:Dec.)
• Page Start: 2781
• Page End: 2790
• Publication Date: 2014-11-05
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402446
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Six phosphorescent (2‐phenyl)pyridine (ppy) gold(III) 2, 4, 6‐tris(trifluoromethyl)phenyl (FMes) complexes were synthesized and investigated for their anticancer potential. The compounds demonstrated strong antiproliferative activity, with EC₅₀ values in the low micromolar range, along with significant accumulation in HeLa cancer cells after treatment for only 6 h (up to 119 ng gold per milligram of protein as measured by high‐resolution continuum source atomic spectroscopy). Enzyme inhibition studies showed interaction of the gold(III) complexes with thioredoxin reductase (TrxR), a key homeostasis‐regulation flavoprotein. TrxR was inhibited with IC₅₀ values in the micromolar range. Furthermore, five of the complexes displayed selectivity toward TrxR against glutathione reductase (GR, a disulfide reductase structurally related to TrxR) by up to &gt;49‐fold. Because no major differences in bioactivity were observed across the series, [(ppy)Au(FMes)(PPh₃)OTf] (complex <bold>4</bold>) was chosen for further in‐depth biological characterization. Complex <bold>4</bold> was also found to interact with guanosine monophosphate in ¹H NMR studies under long incubation times. Interestingly, <bold>4</bold> induced a significant increase in intracellular levels of reactive oxygen species, which led to late apoptotic events and cytocidal effects.</p> </abstract>