Gold(I) NHC Complexes: Antiproliferative Activity, Cellular Uptake, Inhibition of Mammalian and Bacterial Thioredoxin Reductases, and Gram‐Positive Directed Antibacterial Effects

Abstract

Gold complexes with N-heterocyclic carbene (NHC) ligands represent a promising class of metallodrugs for the treatment of cancer or infectious diseases. In this report, the synthesis and the biological evaluation of halogen-containing NHC-Au -Cl complexes are described. The complexes 1 and 5 a-5 f displayed good cytotoxic activity against tumor cells, and cellular uptake studies suggested that an intact Au-NHC fragment is essential for the accumulation of high amounts of both the metal and the NHC ligand. However, the bioavailability was negatively affected by serum components of the cell culture media and was influenced by likely transformations of the complex. One example (5 d) efficiently induced apoptosis in vincristine- and daunorubicin-resistant P-glycoprotein overexpressing Nalm-6 leukemia cells. Cellular uptake studies with this compound showed that both the wild-type and resistant Nalm-6 cells accumulated comparable amounts of gold, indicating that the gold drug was not excreted by P-glycoprotein or other efflux transporters. The effective inhibition of mammalian and bacterial thioredoxin reductases (TrxR) was confirmed for all of the gold complexes. Antibacterial screening of the gold complexes showed a particularly high activity against Gram-positive strains, reflecting their high dependence on an intact Trx/TrxR system. This result is of particular interest as the inhibition of bacterial TrxR represents a relatively little explored mechanism of new anti-infectives.

Pyrimidine Derivatives with Terminal Pyridyl Heterocycles: Facile Synthesis and Their Antiproliferative Activities

“…This implies that 2 and 3 do not show any selectivity for the carcinoma cells in the same doses/concentration range. Nevertheless, the cytotoxicity of these pyridine/pyrimidine‐based molecules against these carcinoma cell lines is superior in comparison with several organic ligands as well as their metal complexes such as N‐heterocyclic carbenes and their organometallic Au(I) , Ru(II), Rh(I), and Cu(I) N‐heterocyclic carbenes complexes.…”

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

“…In biochemical analyses validated across numerous independent studies, auranofin has proven to be a potent inhibitor (IC 50 = 16‐20 nM) of TrxR. Hence, the physiologically attainable levels of 1 to 1.5 μM for humans discussed above should be in the range sufficient to promote cancer cell death.…”

Synthesis and Biological Evaluation of Homogeneous Thiol‐Linked NHC*‐Au‐Albumin and ‐Trastuzumab Bioconjugates

“…Previous cellular uptake studies showed that the presence of the NHC fragment in a gold complex is important for the accumulation of both the metal and the ligand . In addition, a number of strategies explored the attachment of a targeting ligand (i.e., sugars and peptides) through S−Au I bonds.…”

“…A drug:albumin ratio of 1 was found for all the tested conditions. Our data is in good agreement with literature reports by Ott and co‐workers that showed the quantitative binding of NHC*−Au−Cl complexes to serum proteins . The formation of Au‐serum protein adducts decreased both gold uptake and activity.…”