Anticancer profile of a series of gold(III) (2-phenyl)pyridine complexes.
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 >49-fold. Because no major differences in bioactivity were observed across the series, [(ppy)Au(FMes)(PPh3 )OTf] (complex 4) was chosen for further in-depth biological characterization. Complex 4 was also found to interact with guanosine monophosphate in (1) H NMR studies under long incubation times. Interestingly, 4 induced a significant increase in intracellular levels of reactive oxygen species, which led to late apoptotic events and cytocidal effects.
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich (Switzerland) http://www.gassergroup.com. riccardo.rubbiani@chem.uzh.ch.
Riccardo
R
Rubbiani
Thomas N
TN
Zehnder
Cristina
C
Mari
Olivier
O
Blacque
Koushik
K
Venkatesan
Gilles
G
Gasser
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D018360:Crystallography, X-Ray; D004355:Drug Stability; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006046:Gold / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D011725:Pyridines; D017382:Reactive Oxygen Species; D006046:Gold; D005980:Glutathione Reductase; D013880:Thioredoxin-Disulfide Reductase; C023666:pyridine
antitumor agents; apoptosis; gold(III) complexes; inorganic chemical biology; medicinal organometallic chemistry; thioredoxin reductase