title: 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-AuI-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.
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106, Braunschweig, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmidt
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research GmbH, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Bianka
authors.initials: B
authors.lastname: Karge
authors.affiliation: Department of Paedriatric Oncology, Children's Hospital Cologne, Amsterdamer Strasse 59, 50735, Cologne, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Misgeld
authors.affiliation: Department of Paedriatric Oncology, Children's Hospital Cologne, Amsterdamer Strasse 59, 50735, Cologne, Germany.
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research GmbH, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Raimo
authors.initials: R
authors.lastname: Franke
authors.affiliation: Department of Chemical Biology, Helmholtz Centre for Infection Research GmbH, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106, Braunschweig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006046:Gold / Q000737:chemistry*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D056831:Coordination Complexes; D006571:Heterocyclic Compounds; C030011:carbene; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase; D008697:Methane
keywords: N-heterocyclic carbenes; antibiotics; atomic absorption spectroscopy; cancer; gold complexes; thioredoxin reductase