Book of Abstracts - Ruhr-Universität Bochum

P-69
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Glutathione Reductase/Thioredoxin Reductase Systems as Molecular Target for
Antiproliferative Gold(I) Carbene Complexes
R. Rubbiani a and I. Ott *a
a Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55,
38106 Braunschweig, Germany, r.rubbiani@tu-bs.de
Human Thioredoxin-Reductase (TrxR) and Glutathione-Reductase (GR) are two NADPH-dependent
flavoenzymes belonging to the main responsibles of the antioxidant cellular network. They consist of a
FAD domain, a NADPH domain but they differ for the active site, which is characterized by a
cysteine-cysteine (Cyscys) bridge in the case of GR and by a cysteine-selenocysteine (Secys) bridge in
the case of TrxR. The main substrate of GR is glutathione (Glu), a tripeptide formed by γ-L-Glutamyl-
L-cysteinylglycine that has the role to act directly against reactive oxygen species (ROS). The
substrate of TrxR is thioredoxin (Trx), a protein of 12 kDa with an active disulfide motif. 1 With the
development of Auronafin, it has been demonstrated that certain metal complexes (especially gold
complexes) have a strong affinity for TrxR, based on the formation of a covalent bond. 2 Because of the
overexpression of these enzymes in the tumoral cells, as well as their substrates, they become a
possible target for the developing of new active molecules. Based on a computational study, our
research focuses on gold(I) carbene complexes, a new stable class of compounds that show activity on
these enzymatic systems. We synthesized a series of di-substituted benzimidazole carbenes (see
figure) and evaluated their interactions with the mentioned substrates and enzymes. We also
investigated the proliferation inhibition in two tumoral cell lines. Our results indicate a selective
inhibition of TrxR in the nanomolar range, most probably due to the stronger affinity of gold(I) for
Secys compared to Cys. The proliferation studies showed a cytotoxic activity in the range of 7-16 µM.
References
1. S. Gromer et al., Med. Res. Rev. 2004, 24, 40-89.
2. I. Ott.,Coord. Chem. Rev. 2009, 52, 763-770.
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