Cancer continues to be a leading cause of death, and the development of new anticancer drugs is important. So-called “pleiotropic” drugs, which have multiple effects and can address several cancer targets at once, might be able to provide a greater impact on and higher specificity for cancer cells. One could, for example, combine the effects of metals with those of intrinsically bioactive ligands to achieve “metal–drug synergism”. The coordination of an already active compound to a metal fragment often leads to complexes of higher selectivity, a lower risk of unwanted side effects, and a higher retention time due to improved stability.
AC1-004 (pictured) is a known inhibitor of the hypoxia-inducible factor alpha (HIF-1α), which is essential for tumor growth, angiogenesis (the formation of new blood vessels), and metastasis (the spread of cancer cells to other parts of the body). Rainer Schobert, University of Bayreuth, Germany, and colleagues have synthesized gold(I) complexes that are derived from AC1-004 (general structure pictured). They retained the benzimidazole unit of AC1-004 in the form of an N-heterocyclic carbene (NHC) ligand and replaced its 2-aryloxymethyl residue with a thiolato gold(I) fragment. The team first prepared gold chlorido complexes and then exchanged the chlorido ligand for a thiolato ligand.
The researchers hoped to combine the HIF-1α inhibition with effects typical of NHC gold complexes, such as an inhibition of tumoral thioredoxin reductase (TrxR), an increase in reactive oxygen species (ROS), and cytotoxic and antiangiogenic effects. They found that some of the complexes showed greater cytotoxicity and apoptosis induction in cancer cells, including resistant ones, than AC1-004 due to the desired multiple effects on cancer cells. The developed complexes could be useful starting points for further optimization.
- Anti‐Tumoural [NHC(thiolato)] Gold(I) Complexes Derived from HIF‐1α Inhibitor AC1‐004 Target the Mitochondrial Redox System and Show Antiangiogenic Effects in vivo,
Sebastian W. Schleser, Leonhard H. F. Köhler, Florian Riethmüller, Sebastian Reich, Robin Fertig, Luca Schlotte, Jonathan Seib, Alexander Goller, Gerrit Begemann, Rhett Kempe, Rainer Schobert,