Anticancer Profile of a Series of Gold(III) (2‐phenyl)pyridine Complexes

Abstract

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.

Gold(III) Complexes for Antitumor Applications: An Overview

“…Moreover, 23 was shown to increase the amount of intracellular ROS in Hela cells. [56] Imminophosphorane have been used as cyclometalated (C^N) ligands to generate analogueso f24.T he chloro ligands can easily be substituted,f or example by as dithiocarbamates or phosphines. These compounds appeared particularly efficient against acute lymphoblastic leukemia cells (Jurkat).…”

Small molecule inhibitors of mammalian thioredoxin reductase as potential anticancer agents: An update

“…Complexes 136–139 inhibited TrxR in the low micromolar range, whereas complexes 134 and 135 displayed slightly higher values. The inhibition of TrxR was achieved by the formation of a covalent bond between the Sec present at the C terminus of the TrxR active site and the gold atom …”

Preise des Royal Australian Chemical Institute: A. O'Mullane, B. J. Smith, M. G. Banwell, R. J. Payne, D. M. D'Alessandro und C. Wentrup / Preise der Schweizerischen Chemischen Gesellschaft: G. Gasser und N. Banerji

“…Gasser interessiert sich mit seiner Gruppe für den Einsatz von Metallkomplexen für medizinische und biologische Zwecke. In der Angewandten Chemie hat er über die Antitumorwirkung eines Ruthenium(II)‐Komplexes berichtet7a und in ChemMedChem über das Antitumorprofil eines Gold(III)‐Komplexes 7b …”